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Sample records for 3-hydroxy butanoic acid

  1. 40 CFR 721.1930 - Butanoic acid, antimony (3=) salt.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Butanoic acid, antimony (3=) salt. 721... Substances § 721.1930 Butanoic acid, antimony (3=) salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as butanoic acid, antimony (3=) salt (PMN...

  2. 40 CFR 721.1930 - Butanoic acid, antimony (3=) salt.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Butanoic acid, antimony (3=) salt. 721... Substances § 721.1930 Butanoic acid, antimony (3=) salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as butanoic acid, antimony (3=) salt (PMN...

  3. 40 CFR 721.1930 - Butanoic acid, antimony (3=) salt.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Butanoic acid, antimony (3=) salt. 721... Substances § 721.1930 Butanoic acid, antimony (3=) salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as butanoic acid, antimony (3=) salt (PMN...

  4. 40 CFR 721.1930 - Butanoic acid, antimony (3=) salt.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Butanoic acid, antimony (3=) salt. 721... Substances § 721.1930 Butanoic acid, antimony (3=) salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as butanoic acid, antimony (3=) salt (PMN...

  5. 40 CFR 721.1930 - Butanoic acid, antimony (3=) salt.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Butanoic acid, antimony (3=) salt. 721... Substances § 721.1930 Butanoic acid, antimony (3=) salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as butanoic acid, antimony (3=) salt (PMN...

  6. 40 CFR 721.5252 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, zinc salt.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-methylenebis [3-hydroxy-, zinc salt. 721.5252 Section 721.5252 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, zinc salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-,...

  7. 40 CFR 721.5252 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, zinc salt.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-methylenebis [3-hydroxy-, zinc salt. 721.5252 Section 721.5252 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, zinc salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-,...

  8. 40 CFR 721.5252 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, zinc salt.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-methylenebis [3-hydroxy-, zinc salt. 721.5252 Section 721.5252 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, zinc salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-,...

  9. 40 CFR 721.5252 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, zinc salt.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-methylenebis [3-hydroxy-, zinc salt. 721.5252 Section 721.5252 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, zinc salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-,...

  10. 40 CFR 721.5252 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, zinc salt.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...-methylenebis [3-hydroxy-, zinc salt. 721.5252 Section 721.5252 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, zinc salt. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-,...

  11. Occurrence of 3-hydroxy acids in microalgae and cyanobacteria and their geochemical significance

    NASA Astrophysics Data System (ADS)

    Matsumoto, Genki I.; Nagashima, Hideyuki

    1984-08-01

    3-Hydroxy acids were detected in pure cultured microalgae: Chlorophyta— Chlamydomonas reinhardtii and Chlorella pyrenoidosa and Rhodophyta— Cyanidium caldarium (two strains), and cyanobacteria (Cyanophyta)— Anacystis nidulans, Phormidium foveolarum, Anabaena variabilis and Oscillatoria sp. Normal and branched (iso and anteiso) 3-hydroxy acids in the ranges of C 8-C 26 were found in all the samples studied at concentrations ranging from 0.036 to 2.3 and 0.000 to 0.12 mg g -1 of dry sample, respectively. The major constituents were generally even-carbon numbered normal acids with carbon chain lengths below C 20. Microalgae and cyanobacteria may be the important sources of 3-hydroxy acids in natural environments.

  12. Iso-branched 2- and 3-hydroxy fatty acids as characteristic lipid constituents of some gliding bacteria.

    PubMed Central

    Fautz, E; Rosenfelder, G; Grotjahn, L

    1979-01-01

    The fatty acids present in the total hydrolysates of several gliding bacteria (Myxococcus fulvus, Stigmatella aurantiaca, Cytophaga johnsonae, Cytophaga sp. strain samoa and Flexibacter elegans) were analyzed by combined gas-liquid chromatography and mass spectrometry. In addition to 13-methyl-tetradecanoic acid, 15-methyl-hexadecanoic acid, hexadecanoic acid, and hexadecenoic acid, 2- and 3-hydroxy fatty acids comprised up to 50% of the total fatty acids. The majority was odd-numbered and iso-branched. Small amounts of even-numbered and unbranched fatty acids were also present. Whereas 2-hydroxy-15-methyl hexadecanoic acid was characteristic for myxobacteria, 2-hydroxy-13-methyl-tetradecanoic acid, 3-hydroxy-13-methyl-tetradecanoic acid, and 3-hydroxy-15-methyl-hexadecanoic acid were dominant in the Cytophaga-Flexibacter group. PMID:118159

  13. Selective synthesis of 3-hydroxy acids from Meldrum's acids using SmI2-H2O.

    PubMed

    Szostak, Michal; Spain, Malcolm; Procter, David J

    2012-05-01

    The single-step synthesis of 3-hydroxy carboxylic acids from readily available Meldrum's acids involves a selective monoreduction using a SmI(2)-H(2)O complex to give products in high crude purity, and it represents a considerable advancement over other methods for the synthesis of 3-hydroxy acids. The protocol includes a detailed guide to the preparation of a single electron-reducing SmI(2)-H(2)O complex and describes two representative examples of the methodology: monoreduction of a fully saturated Meldrum's acid (5-(4-bromobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione) and tandem conjugate reduction-selective monoreduction of α,β-unsaturated Meldrum's acid (5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione). The protocol for selective monoreduction of Meldrum's acids takes ∼6 h to complete. PMID:22538848

  14. Profiling of 3-hydroxy fatty acids as environmental markers of endotoxin using liquid chromatography coupled to tandem mass spectrometry.

    PubMed

    Uhlig, Silvio; Negård, Mariell; Heldal, Kari K; Straumfors, Anne; Madsø, Lene; Bakke, Berit; Eduard, Wijnand

    2016-02-19

    3-Hydroxy acids are constituents of the lipid A part of lipopolysaccharides and may potentially be used as chemical markers of endotoxin. While commercial enzymatic assays, such as the widely used Limulus amebocyte lysate (LAL) assay, commonly detect merely the water-soluble fraction of the bioactive endotoxin, the chemical approach aims to estimate the total amount of endotoxin present in a sample. Our objective was to develop a simple method for quantitative profiling of 3-hydroxy fatty acids in occupational and environmental samples based on detection with HPLC-MS/MS. We included eleven 3-hydroxy fatty acids (3-hydroxyoctanoic acid to 3-hydroxyoctadecanoic acid) in the HPLC-MS/MS based method, which involved base hydrolysis of filter samples using 1M sodium hydroxide and removal of the base as well as concentration of the fatty acids using solid-phase extraction on a functionalized polystyrene-divinylbenzene polymer. Recovery trials from spiked glass fiber filters, using threo-9,10-dihydroxyhexadecanoic acid as internal standard, gave an overall recovery of 54-86% for 3-hydroxy fatty acids of medium chain length (3-hydroxynonanoic to 3-hydroxypentadecanoic acid). 3-Hydroxyoctanoic acid and the longer chain fatty acids were more problematic yielding overall spike recoveries of 11-39%. While the 3-hydroxy fatty acid profile of pure lipopolysaccharides was dominated by 3-hydroxydecanoic, 3-hydroxydodecanoic and 3-hydroxytetradecanoic acid the aqueous phase from drilling mud contained in addition relatively high amounts of 3-hydroxyoctanoic and 3-hydroxynonanoic acid. Endotoxin activity as measured by the LAL assay was reasonably correlated (R(2)=0.54) to the sum of 3-hydroxydecanoic acid, 3-hydroxydodecanoic acid and 3-hydroxytetradecanoic acid in these samples. PMID:26818235

  15. Effect of 3-hydroxy-3-methylglutaric acid administration on bile lipid composition in humans.

    PubMed

    Di Padova, C; Di Padova, F; Buzzetti, M; Tritapepe, R

    1984-09-01

    The effects of the lipid-lowering agent 3-hydroxy-3-methylglutaric acid (HMGA) on serum lipids and on biliary lipid composition were evaluated in a double-blind, placebo-controlled study in normolipidemic volunteers. After 4 weeks of HMGA administration (1 g three times a day orally) serum total cholesterol showed a significant decrease with regard to both pretreatment values and corresponding values of controls. The bile lipid molar percentage composition and the cholesterol saturation index showed no modification after HMGA and did not differ from the values obtained in the placebo group. These findings indicate that HMGA exerts no adverse effects on bile lipid composition in humans, differing from other hypolipidemic drugs currently in clinical use, which increase the bile cholesterol saturation index. PMID:6083597

  16. Evidence that 3-hydroxy-3-methylglutaric and 3-methylglutaric acids induce DNA damage in rat striatum.

    PubMed

    da Rosa, Mateus Struecker; Scaini, Giselli; Damiani, Adriani Paganini; Longaretti, Luiza Martins; Pereira, Maiara; Seminotti, Bianca; Zapelini, Hugo Galvane; Schuck, Patrícia Fernanda; Streck, Emílio Luiz; de Andrade, Vanessa Moraes; Wajner, Moacir; Leipnitz, Guilhian

    2015-08-01

    3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive disorderaffecting the final step of leucine degradation and ketogenesis and biochemically characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in biological fluids and tissues of affected patients. Considering that previous studies reported that HMG and MGA have pro oxidant properties, the present study evaluated the ex vivo and in vitro effects of HMG and MGA on frequency and index of DNA damage in cerebral cortex and striatum of young rats. The ex vivo effects of both organic acids on 8-hydroxy-2'-deoxyguanosine (OHdG) levels and their in vitro effects on 2',7'-dichlorofluorescin (DCFH) oxidation and glutathione (GSH) concentrations in rat striatum were also determined. We also investigated the ex vivo effects of both organic acids on 8-hydroxy-2'-deoxyguanosine (OHdG) levels in rat striatum. In the ex vivo experiments, DNA damage was determined in striatum homogenates prepared 30 min after a single intrastriatal administration of HMG or MGA. On the other hand, the in vitro evaluation was performed after an incubation of rat cerebral cortex or striatum homogenates or slices in the presence of HMG or MGA during 1 h at 37 °C. We observed that the intrastriatal administration of HMG and MGA increased the frequency and the index of DNA damage, as well as OHdG staining in rat striatum. We also verified that MGA, but not HMG, increased DNA damage frequency and index in vitro in striatum of rats. In contrast, no alterations were verified in vitro in cerebral cortex. Finally, we found that HMG and MGA increased DCFH oxidation and decreased GSH concentrations in rat striatum. Therefore, it may be presumed that DNA damage provoked by HMG and MGA possibly via reactive species generation is involved, at least in part, in the pathophysiology of brain injury, particularly in the striatum of HL-deficient patients. PMID:25939283

  17. 40 CFR 721.10594 - Hexanedioic acid, polymer with 2,2-dimethyl-1,3-propanediol, 1,6-hexanediol, hydrazine, 3-hydroxy...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-dimethyl-1,3-propanediol, 1,6-hexanediol, hydrazine, 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid, 5...-hexanediol, hydrazine, 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid, 5-isocyanato-1-(isocyanatomethyl... hexanedioic acid, polymer with 2,2-dimethyl-1,3-propanediol, 1,6-hexanediol, hydrazine,...

  18. 40 CFR 721.10594 - Hexanedioic acid, polymer with 2,2-dimethyl-1,3-propanediol, 1,6-hexanediol, hydrazine, 3-hydroxy...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-dimethyl-1,3-propanediol, 1,6-hexanediol, hydrazine, 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid, 5...-hexanediol, hydrazine, 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid, 5-isocyanato-1-(isocyanatomethyl... hexanedioic acid, polymer with 2,2-dimethyl-1,3-propanediol, 1,6-hexanediol, hydrazine,...

  19. 3-Hydroxy fatty acids in saliva as diagnostic markers in chronic periodontitis.

    PubMed

    Ferrando, Raúl; Szponar, Bogumila; Sánchez, Arturo; Larsson, Lennart; Valero-Guillén, Pedro L

    2005-09-01

    Saturated straight- and branched-chain 3-hydroxy fatty acids (3-OH FAs) of 10-18 carbon chain lengths were determined in saliva from 27 individuals with chronic periodontitis and 18 healthy individuals by using gas chromatography-tandem mass spectrometry. Of the 14 different 3-OH FAs detected, 3-OH-C(i17:0) was the most abundant in the periodontitis samples while 3-OH-C(14:0) was the most abundant in the healthy individuals. Considering the relative percentages of 3-OH-C(12:0), 3-OH-C(14:0), 3-OH-C(i17:0), and 3-OH-C(17:0), 95.6% of all cases were correctly classified as healthy individuals or periodontitis patients by means of discriminant analysis. The sensitivity, specificity, positive predictive value and negative predictive value of 3-OH FA analysis in diagnosing peridontitis were, respectively, 0.92, 1.00, 1.00, and 0.90. The results indicate that 3-OH FA analysis of saliva samples is a useful diagnostic method in chronic periodontitis. PMID:15941605

  20. Poly-3-hydroxy butyric acid interaction with the transgenic flax fibers: FT-IR and Raman spectra of the composite extracted from a GM flax.

    PubMed

    Wróbel-Kwiatkowska, Magdalena; Zuk, Magdalena; Szopa, Jan; Dymińska, Lucyna; Maczka, Mirosław; Hanuza, Jerzy

    2009-07-15

    The FT-IR and FT-Raman studies have been performed on commercial 3-hydroxy-butyric acid, commercial poly-3-hydroxy butyric acid as well as poly-3-hydroxy butyric acid (PHB) produced by bacteria. The data were compared to those obtained for poly-3-hydroxy butyric acid extracted from natural and genetically modified flax. Genetically modified flax was generated by expression of three bacterial genes coding for synthesis of poly-3-hydroxy butyric acid. Thus transgenic flaxes were enhanced with different amount of the PHB. The discussion of polymer structure and vibrational properties has been done in order to get insight into differences among these materials. The interaction between the cellulose of flax fibers and embedded poly-3-hydroxybutyric acid has been also discussed. The spectroscopic data provide evidences for structural changes in cellulose and in PHB when synthesized in fibers. Based on this data it is suggesting that cellulose and PHB interact by hydrogen and ester bonds. PMID:19328737

  1. Poly-3-hydroxy butyric acid interaction with the transgenic flax fibers: FT-IR and Raman spectra of the composite extracted from a GM flax

    NASA Astrophysics Data System (ADS)

    Wróbel-Kwiatkowska, Magdalena; Żuk, Magdalena; Szopa, Jan; Dymińska, Lucyna; Mączka, Mirosław; Hanuza, Jerzy

    2009-07-01

    The FT-IR and FT-Raman studies have been performed on commercial 3-hydroxy-butyric acid, commercial poly-3-hydroxy butyric acid as well as poly-3-hydroxy butyric acid (PHB) produced by bacteria. The data were compared to those obtained for poly-3-hydroxy butyric acid extracted from natural and genetically modified flax. Genetically modified flax was generated by expression of three bacterial genes coding for synthesis of poly-3-hydroxy butyric acid. Thus transgenic flaxes were enhanced with different amount of the PHB. The discussion of polymer structure and vibrational properties has been done in order to get insight into differences among these materials. The interaction between the cellulose of flax fibers and embedded poly-3-hydroxybutyric acid has been also discussed. The spectroscopic data provide evidences for structural changes in cellulose and in PHB when synthesized in fibers. Based on this data it is suggesting that cellulose and PHB interact by hydrogen and ester bonds.

  2. The methionine precursor DL-2-hydroxy-(4-methylthio)butanoic acid protects intestinal epithelial barrier function.

    PubMed

    Martín-Venegas, Raquel; Brufau, M Teresa; Guerrero-Zamora, Ana Maria; Mercier, Yves; Geraert, Pierre-André; Ferrer, Ruth

    2013-12-01

    DL-2-hydroxy-(4-methylthio)butanoic acid (HMTBA) is a source of dietary methionine (Met) that is widely used in poultry nutrition. We have previously shown that HMTBA is preferentially diverted to the transsulfuration pathway, which gives antioxidant metabolites such as taurine and glutathione. Therefore, here we hypothesize that this Met source can protect epithelial barrier function in an in vitro model of intestinal inflammation of Caco-2 cells. The results show that HMTBA prevents the increase in paracellular permeability induced by H2O2 or tumour necrosis factor-α. This effect can be attributed to the increased production of taurine and reduced glutathione. Similar results were obtained for DL-Met, although the protective role of the amino acid was less pronounced than that of the hydroxy analogue. In conclusion, the diversion to the transsulfuration pathway means that this Met precursor is of greater value than previously thought, due to its capacity to improve intestinal homeostasis and the quality of poultry products destined for human consumption. PMID:23870881

  3. Evaluation of a new protocol for enzymatic dynamic kinetic resolution of 3-hydroxy-3-(aryl)propanoic acids.

    PubMed

    Koszelewski, Dominik; Zysk, Małgorzata; Brodzka, Anna; Żądło, Anna; Paprocki, Daniel; Ostaszewski, Ryszard

    2015-12-01

    The application of tandem metal-enzyme dynamic kinetic resolution (DKR) is a powerful tool for the manufacture of high-value chemical commodities. A new protocol of kinetic resolution based on irreversible enzymatic esterification of carboxylic acids with orthoesters was introduced to obtain optically active β-hydroxy esters. This procedure was combined with metal catalyzed racemization of the target substrate providing both (R) and (S) enantiomers of ethyl 3-hydroxy-3-(4-nitrophenyl)propanoate with a high yield of 89% at 40 °C. A substantial influence of the enzyme type, organic co-solvent, and metal catalyst on the conversion and enantioselectivity of the enzymatic dynamic kinetic resolution was noted. PMID:26383530

  4. Effect of chemical substitutions on photo-switching properties of 3-hydroxy-picolinic acid studied by ab initio methods

    NASA Astrophysics Data System (ADS)

    Rode, Michał F.; Sobolewski, Andrzej L.

    2014-02-01

    Effect of chemical substitutions to the molecular structure of 3-hydroxy-picolinic acid on photo-switching properties of the system operating on excited-state intramolecular double proton transfer (d-ESIPT) process [M. F. Rode and A. L. Sobolewski, Chem. Phys. 409, 41 (2012)] was studied with the aid of electronic structure theory methods. It was shown that simultaneous application of electron-donating and electron-withdrawing substitutions at certain positions of the molecular frame increases the height of the S0-state tautomerization barrier (ensuring thermal stability of isomers) and facilitates a barrierless access to the S1/S0 conical intersection from the Franck-Condon region of the S1 potential-energy surface. Results of study point to the conclusion that the most challenging issue for practical design of a fast molecular photoswitch based on d-ESIPT phenomenon are to ensure a selectivity of optical excitation of a given tautomeric form of the system.

  5. 40 CFR 721.5253 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, strontium salt.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-methylenebis [3-hydroxy-, strontium salt. 721.5253 Section 721.5253 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, strontium salt. (a) Chemical substance and significant new uses subject to reporting...-, strontium salt (PMN P-99-1341; CAS No. 235083-90-6) is subject to reporting under this section for...

  6. 40 CFR 721.5253 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, strontium salt.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-methylenebis [3-hydroxy-, strontium salt. 721.5253 Section 721.5253 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, strontium salt. (a) Chemical substance and significant new uses subject to reporting...-, strontium salt (PMN P-99-1341; CAS No. 235083-90-6) is subject to reporting under this section for...

  7. 40 CFR 721.5253 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, strontium salt.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...-methylenebis [3-hydroxy-, strontium salt. 721.5253 Section 721.5253 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, strontium salt. (a) Chemical substance and significant new uses subject to reporting...-, strontium salt (PMN P-99-1341; CAS No. 235083-90-6) is subject to reporting under this section for...

  8. 40 CFR 721.5253 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, strontium salt.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-methylenebis [3-hydroxy-, strontium salt. 721.5253 Section 721.5253 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, strontium salt. (a) Chemical substance and significant new uses subject to reporting...-, strontium salt (PMN P-99-1341; CAS No. 235083-90-6) is subject to reporting under this section for...

  9. 40 CFR 721.5253 - 2-Naphthalenecarboxylic acid, 4,4′-methylenebis [3-hydroxy-, strontium salt.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-methylenebis [3-hydroxy-, strontium salt. 721.5253 Section 721.5253 Protection of Environment ENVIRONMENTAL...′-methylenebis [3-hydroxy-, strontium salt. (a) Chemical substance and significant new uses subject to reporting...-, strontium salt (PMN P-99-1341; CAS No. 235083-90-6) is subject to reporting under this section for...

  10. Immobilization of nitrilase on bioinspired silica for efficient synthesis of 2-hydroxy-4-(methylthio) butanoic acid from 2-hydroxy-4-(methylthio) butanenitrile.

    PubMed

    Jin, Li-Qun; Guo, Dong-Jing; Li, Zong-Tong; Liu, Zhi-Qiang; Zheng, Yu-Guo

    2016-05-01

    In this paper, a simple and effective method using sodium metasilicate as precursor and amine as additive was first reported to immobilize recombinant nitrilase, for efficient production of 2-hydroxy-4-(methylthio) butanoic acid from 2-hydroxy-4-(methylthio) butanenitrile. High immobilization recovery of enzyme activity (above 90 %) was achieved. The immobilized enzyme displayed better thermal stability, pH stability and shelf life compared to free nitrilase. Moreover, it showed excellent reusability and could be recycled up to 16 batches without significant loss in activity. 200 mM 2-hydroxy-4-(methylthio) butanenitrile was completely converted by the immobilized enzyme within 30 min, and the accumulation amount of 2-hydroxy-4-(methylthio) butanoic acid reached 130 mmol/g of immobilized beads after 16 batches. These encouraging results demonstrated the efficiency of the new technology for nitrilase immobilization, which has great potential in preparation of 2-hydroxy-4-(methylthio) butanoic acid. PMID:26886758

  11. Effect of chemical substitutions on photo-switching properties of 3-hydroxy-picolinic acid studied by ab initio methods

    SciTech Connect

    Rode, Michał F. Sobolewski, Andrzej L.

    2014-02-28

    Effect of chemical substitutions to the molecular structure of 3-hydroxy-picolinic acid on photo-switching properties of the system operating on excited-state intramolecular double proton transfer (d-ESIPT) process [M. F. Rode and A. L. Sobolewski, Chem. Phys. 409, 41 (2012)] was studied with the aid of electronic structure theory methods. It was shown that simultaneous application of electron-donating and electron-withdrawing substitutions at certain positions of the molecular frame increases the height of the S{sub 0}-state tautomerization barrier (ensuring thermal stability of isomers) and facilitates a barrierless access to the S{sub 1}/S{sub 0} conical intersection from the Franck-Condon region of the S{sub 1} potential-energy surface. Results of study point to the conclusion that the most challenging issue for practical design of a fast molecular photoswitch based on d-ESIPT phenomenon are to ensure a selectivity of optical excitation of a given tautomeric form of the system.

  12. Bile acid sulfotransferase I from rat liver sulfates bile acids and 3-hydroxy steroids: purification, N-terminal amino acid sequence, and kinetic properties.

    PubMed

    Barnes, S; Buchina, E S; King, R J; McBurnett, T; Taylor, K B

    1989-04-01

    A bile acid:3'phosphoadenosine-5'phosphosulfate:sulfotransferase (BAST I) from adult female rat liver cytosol has been purified 157-fold by a two-step isolation procedure. The N-terminal amino acid sequence of the 30,000 subunit has been determined for the first 35 residues. The Vmax of purified BAST I is 18.7 nmol/min per mg protein with N-(3-hydroxy-5 beta-cholanoyl)glycine (glycolithocholic acid) as substrate, comparable to that of the corresponding purified human BAST (Chen, L-J., and I. H. Segel, 1985. Arch. Biochem. Biophys. 241: 371-379). BAST I activity has a broad pH optimum from 5.5-7.5. Although maximum activity occurs with 5 mM MgCl2, Mg2+ is not essential for BAST I activity. The greatest sulfotransferase activity and the highest substrate affinity is observed with bile acids or steroids that have a steroid nucleus containing a 3 beta-hydroxy group and a 5-6 double bond or a trans A-B ring junction. These substrates have normal hyperbolic initial velocity curves with substrate inhibition occurring above 5 microM. Of the saturated 5 beta-bile acids, those with a single 3-hydroxy group are the most active. The addition of a second hydroxy group at the 6- or 7-position eliminates more than 99% of the activity. In contrast, 3 alpha,12 alpha-dihydroxy-5 beta-cholan-24-oic acid (deoxycholic acid) is an excellent substrate. The initial velocity curves for glycolithocholic and deoxycholic acid conjugates are sigmoidal rather than hyperbolic, suggestive of an allosteric effect. Maximum activity is observed at 80 microM for glycolithocholic acid. All substrates, bile acids and steroids, are inhibited by the 5 beta-bile acid, 3-keto-5 beta-cholanoic acid. The data suggest that BAST I is the same protein as hydrosteroid sulfotransferase 2 (Marcus, C. J., et al. 1980. Anal. Biochem. 107: 296-304). PMID:2754334

  13. Evaluation of 2-methyl-3-hydroxy-4-pyridinecarboxylic acid as a possible chelating agent for iron and aluminium.

    PubMed

    Dean, Annalisa; Ferlin, Maria Grazia; Brun, Paola; Castagliuolo, Ignazio; Badocco, Denis; Pastore, Paolo; Venzo, Alfonso; Bombi, G Giorgio; Di Marco, Valerio B

    2008-04-01

    In view of a possible application to Fe and Al chelation therapy, 2-methyl-3-hydroxy-4-pyridinecarboxylic acid (DT2) was synthesised, and its complex formation, electrochemical and cytotoxic properties were studied. The complexing properties of DT2 towards Fe(III) and Al(III) were investigated in aqueous 0.6 m (Na)Cl at 25 degrees C by means of potentiometric titrations, UV-vis spectrophotometry, and 1H NMR spectroscopy. DT2 is a triprotic acid (H3L+) having pKa1 = 0.47, pKa2 = 5.64 and pKa3 = 11.18. The metal-ligand complexes observed in solution and their corresponding stability constants (log beta values) are the following: FeLH (19.38), FeL (16.01), FeLH(-1) (12.28), FeL2H2 (37.29), FeL3H3 (53.41), FeL3H2 (47.99), FeL3H (41.21) and FeL3 (34.1); AlLH (17.43), AlL2H2 (33.74), AlL2H (27.6), AlL3H3 (48.72), AlL3H2 (42.67), AlL3H (35.8) and AlL3 (27.92). The complex formation between DT2 and Fe(II) was studied by UV-vis: the weak complex FeLH (log beta = 15.8) was detected. DT2 shows a lower complexation efficiency with Fe(III) and Al(III) than that of other available chelators, but higher than that of its non-methylated analogue 3-hydroxy-4-pyridinecarboxylic acid (DT0). The electrochemical behaviour of DT2 was investigated by means of cyclic voltammetry, indicating that the oxidation of the ligand proceeds through a two electron process with a CECE mechanism. Voltammetric curves suggest that the oxidation or the reduction of DT2 in vivo is unlikely. According to the thermodynamic data, also the Fe(III)-DT2 complexes do not undergo redox cycling at physiological pH. Amperometric titrations of solutions containing Fe(III) and DT2 at pH = 5 indicated the same Fe(III) : ligand stoichiometric ratio as calculated from potentiometric data. The toxicity of DT2 and of other simple hydroxypyridinecarboxylic acids was investigated in vitro and no cytotoxic activity was observed (IC50 > 0.1 mM) on cancer cell lines and also on primary human cells, following a three day

  14. Cellular Plasticity Induced by Anti–α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor Encephalitis Antibodies

    PubMed Central

    Peng, Xiaoyu; Hughes, Ethan G; Moscato, Emilia H; Parsons, Thomas D; Dalmau, Josep; Balice-Gordon, Rita J

    2015-01-01

    Objective Autoimmune-mediated anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis is a severe but treatment-responsive disorder with prominent short-term memory loss and seizures. The mechanisms by which patient antibodies affect synapses and neurons leading to symptoms are poorly understood. Methods The effects of patient antibodies on cultures of live rat hippocampal neurons were determined with immunostaining, Western blot, and electrophysiological analyses. Results We show that patient antibodies cause a selective decrease in the total surface amount and synaptic localization of GluA1- and GluA2-containing AMPARs, regardless of receptor subunit binding specificity, through increased internalization and degradation of surface AMPAR clusters. In contrast, patient antibodies do not alter the density of excitatory synapses, N-methyl-D-aspartate receptor (NMDAR) clusters, or cell viability. Commercially available AMPAR antibodies directed against extracellular epitopes do not result in a loss of surface and synaptic receptor clusters, suggesting specific effects of patient antibodies. Whole-cell patch clamp recordings of spontaneous miniature postsynaptic currents show that patient antibodies decrease AMPAR-mediated currents, but not NMDAR-mediated currents. Interestingly, several functional properties of neurons are also altered: inhibitory synaptic currents and vesicular γ-aminobutyric acid transporter (vGAT) staining intensity decrease, whereas the intrinsic excitability of neurons and short-interval firing increase. Interpretation These results establish that antibodies from patients with anti-AMPAR encephalitis selectively eliminate surface and synaptic AMPARs, resulting in a homeostatic decrease in inhibitory synaptic transmission and increased intrinsic excitability, which may contribute to the memory deficits and epilepsy that are prominent in patients with this disorder. PMID:25369168

  15. Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro.

    PubMed

    Correll, C C; Edwards, P A

    1994-01-01

    The microsomal enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is subject to rapid degradation when cells are incubated with sterols or mevalonic acid (MVA). It has been shown that this rapid degradation is dependent upon both a sterol and another MVA-derived metabolite (Nakanishi, M., Goldstein, J. L., and Brown, M. S. (1988) J. Biol. Chem. 258, 8929-8937). In the current study, inhibitors of the isoprene biosynthetic pathway were used to define further this mevalonic acid derivative involved in the accelerated degradation of HMG-CoA reductase. The accelerated degradation of HMG-CoA reductase in met-18b-2 cells, which is induced by the addition of MVA, was inhibited by the presence of the squalene synthase inhibitor, zaragozic acid/squalestatin, or the squalene epoxidase inhibitor, NB-598. Accelerated degradation of HMG-CoA reductase was observed when NB-598-treated cells were incubated with both MVA and sterols. In contrast, the addition of MVA and sterols to zaragozic acid/squalestatin-treated cells did not result in rapid enzyme degradation. This MVA- and sterol-dependent degradation of HMG-CoA reductase persisted in cells permeabilized with reduced streptolysin O. Finally, the selective degradation of HMG-CoA reductase was also observed in rat hepatic microsomes incubated in vitro in the absence of ATP and cytosol. We conclude that the MVA-derived component that is required for the accelerated degradation of HMG-CoA reductase is derived from farnesyl disphosphate and/or squalene in the isoprenoid biosynthetic pathway. We propose that this component has a permissive effect and does not, by itself, induce the degradation of HMG-CoA reductase. We also conclude that the degradation of HMG-CoA occurs in the endoplasmic reticulum, and, once the degradation of HMG-CoA reductase has been initiated by MVA and sterols, all necessary components for the continued degradation of HMG-CoA reductase reside in the endoplasmic reticulum. PMID:8276863

  16. Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: synthesis and biological evaluation.

    PubMed

    Brun, Paola; Dean, Annalisa; Di Marco, Valerio; Surajit, Pathak; Castagliuolo, Ignazio; Carta, Davide; Ferlin, Maria Grazia

    2013-04-01

    Seven 3-hydroxy-4-pyridinecarboxylic acid derivatives (HPs), aza-analogues of salicylic acid and structurally close to other potent inflammatory pyridine compounds such as aminopyridinylmethanols and aminopyridinamines, were synthesized, and their anti-inflammatory activity was evaluated. The synthesis was performed by adopting a general procedure involving an intramolecular Diels-Alder cycloaddition of oxazoles with acrylic acid to form various substituted pyridinic acids. The newly synthesized HPs did not exhibit cytotoxic activity on human monocytes-derived macrophages at concentrations up to 10(2) μM. Anti-inflammatory activity of the compounds was screened in vitro by evaluating the capability to inhibit cytokines release from lipopolysaccharide (LPS) stimulated human macrophages. 3-Hydroxy-1-methyl-4-pyridinecarboxylic acid (24) was found to be the most active HP. At 10 μM concentration, HP 24 reduced LPS-induced and nuclear factor-κB activation and cyclooxygenase-2 expression, while increased intracellular reactive oxygen species generation and peroxisome proliferator-activated receptor (PPAR-γ) mRNA transcript level. Indeed, pre-treatment of LPS-exposed human macrophages with PPAR-γ specific antagonist completely prevented HP 24-induced TNF-α and IL8 down regulation, demonstrating that the PPARγ pathway is mandatory for the HP 24 anti-inflammatory effect. Finally, daily treatment with HP 24 ameliorated the outcome of DSS-induced colitis in mice, significantly reducing colonic MPO activity and IL-1β tissue levels. PMID:23416190

  17. Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells.

    PubMed

    Yamasaki, Daisuke; Nakamura, Tsutomu; Okamura, Noboru; Kokudai, Makiko; Inui, Naoki; Takeuchi, Kazuhiko; Watanabe, Hiroshi; Hirai, Midori; Okumura, Katsuhiko; Sakaeda, Toshiyuki

    2009-05-12

    In the present study, the ability of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), also known as statins, to regulate the gene expression and function of multidrug resistance protein 1 (MDR1/P-glycoprotein) and differences between their acid and lactone forms were examined in human intestinal epithelial LS180 cells. Some statins had the potential to induce the expression of mRNAs for MDR1 and/or CYP3A in either form. The change in the mRNA expression of MDR1 was accompanied by a change in the CsA-dependent intracellular accumulation of rhodamine 123. Simvastatin lactone, but not the acid form, exhibited a strong inductive effect on the mRNA expression of MDR1 and CYP3A in a dose-dependent manner. Sulforaphane significantly suppressed the expression of MDR1 and CYP3A mRNAs induced by atorvastatin lactone, lovastatin acid, and lovastatin lactone, comparable to the control level, and moderately inhibited that by cerivastatin acid, fluvastatin acid and simvastatin lactone. In the case of pitavastatin acid, sulforaphane had no significant effect on the expression of MDR1 mRNA.These results suggested that some statins could induce MDR1 and CYP3A gene expression and these inductive effects differed between the lactone and active hydroxy acid forms, and that PXR-mediated regulation was rarely associated with the mRNA inducibility by pitavastatin acid, unlike that by other statins. PMID:19429419

  18. The organization of the gene for the functionally dominant alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit GluR-B.

    PubMed

    Köhler, M; Kornau, H C; Seeburg, P H

    1994-07-01

    The murine gene encoding the GluR-B subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors was characterized with respect to exon-intron organization, transcriptional start site, alternatively spliced transcripts, and adenosine to guanosine substitutions between gene and complementary DNA sequence. The GluR-B gene spans > 90 kilobase pairs and harbors 17 exons. Transcription appears to initiate approximately 430 nucleotides upstream of the translational start codon, with no intron in the 5'-untranslated region of the gene. Four alternatively spliced mRNAs are generated from the primary GluR-B transcript, two containing the modules Flip and Flop, and another two with alternate C-terminal coding sequence. The major GluR-B mRNAs in murine brain, 4 and 6 kilobase differ in the length of their 3'-untranslated region. PMID:7545935

  19. Effect of 2-hydroxy-4-methylthio-butanoic acid on ruminal fermentation, bacterial distribution, digestibility, and performance of lactating dairy cows.

    PubMed

    Lee, C; Oh, J; Hristov, A N; Harvatine, K; Vazquez-Anon, M; Zanton, G I

    2015-02-01

    The objective of this experiment was to test the effect of a Met analog, 2-hydroxy-4-methylthio-butanoic acid (HMTBa), on ruminal fermentation and microbial protein synthesis, nutrient digestibility, urinary N losses, and performance of dairy cows. Eight multiparous lactating Holstein dairy cows were assigned to 4 levels of HMTBa [0 (control), 0.05, 0.10, and 0.15% (dry matter basis)] in a replicated 4×4 Latin square trial. Experimental periods were 28 d, including 21 d for adaptation. Ruminal ammonia and microbial N were labeled through a 6-d intraruminal infusion of (15)NH4Cl, and microbial protein synthesis in the rumen was estimated using the reticular sampling technique. Treatment had no effect on dry matter intake (28.4 to 29.8kg/d), milk yield (44.1 to 45.3kg/d), feed efficiency, and milk composition. Total-tract apparent digestibility of nutrients was generally not affected by treatment, except digestibility of crude protein and starch decreased quadratically with HMTBa supplementation. Fecal, but not urinary, and total excreta N losses were increased quadratically by HMTBa. Ruminal pH, ammonia concentration, protozoal counts, and the major volatile fatty acids were not affected by treatment. Microbial N outflow from the rumen was linearly increased by HMTBa. 2-Hydroxy-4-methylthio-butanoic acid linearly increased the proportion of Fecalibacterium and quadratically decreased the proportion of Eubacterium in ruminal contents. Of the individual bacterial species, HMTBa increased or tended to increase Prevotella loescheii and Prevotella oralis. 2-Hydroxy-4-methylthio-butanoic acid linearly increased the concentration (and yield) of 15:0 in milk fat. In the conditions of this crossover experiment, HMTBa had no effect on feed intake and performance of dairy cows, decreased dietary crude protein digestibility, and increased microbial N outflow from the rumen. PMID:25434334

  20. Biodegradation of poly(hydroxy butanoic acid) copolymer mulch films in soil

    NASA Astrophysics Data System (ADS)

    Kukade, Pranav

    Agricultural mulch films that are used to cover soil of crop rows contribute to earlier maturation of crops and higher yield. Incineration and landfill disposals are the most common means of disposal of the incumbent polyethylene (PE) mulch films; however, these are not environment friendly options. Biodegradable mulch films that can be rototilled into the soil after crop harvest are a promising alternative to offset problems such as landfill disposal, film retrieval and disposal costs. In this study, an in-house laboratory scale test method was developed in which the rate of disintegration, as a result of biodegradation of films based on polyhydroxybutanoic acid (PHB) copolymers was investigated in a soil environment using the residual weight loss method. The influence of soil composition, moisture levels in the soil, and industry-standard anti-microbial additive in the film composition on the rate of disintegration of PHB copolymer films was investigated. The soil composition has significant effect on the disintegration kinetics of PHB copolymer films, since the increasing compost levels in the soil lowered the rate of disintegration of the film. Also, with the increase in moisture level up to a threshold limit, the microbial activity and, hence, the rate of disintegration increased. Lastly, the developed lab-scale test protocol was found to be sensitive to even small concentrations of industry-standard antimicrobial additive in the film composition.

  1. Molecular mechanics (MM3) study of the conformations of methyl esters and N, N-dimethylamides of diastereoisomeric 4-cyano-3,4-diphenyl-butanoic acids

    NASA Astrophysics Data System (ADS)

    Ivanov, P. M.

    2000-10-01

    Molecular mechanics (MM3 force field) was used to examine an unexpected observation by NMR for a preference of conformations with synclinal protons around the C(3)-C(4) bond in methyl esters and dimethylamides of diastereoisomeric 4-cyano-3,4-diphenyl-butanoic acids. After the reoptimization of three torsional parameters, related to structural units containing a cyano group, we obtained a good correlation between the MM3 computed populations of the conformations and the estimates from vicinal coupling constants. The electrostatic interactions have the decisive contribution for lowering the energies of the preferred conformations.

  2. Enhancement of Ganoderic Acid Accumulation by Overexpression of an N-Terminally Truncated 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Gene in the Basidiomycete Ganoderma lucidum

    PubMed Central

    Xu, Jun-Wei; Xu, Yi-Ning

    2012-01-01

    Ganoderic acids produced by Ganoderma lucidum, a well-known traditional Chinese medicinal mushroom, exhibit antitumor and antimetastasis activities. Genetic modification of G. lucidum is difficult but critical for the enhancement of cellular accumulation of ganoderic acids. In this study, a homologous genetic transformation system for G. lucidum was developed for the first time using mutated sdhB, encoding the iron-sulfur protein subunit of succinate dehydrogenase, as a selection marker. The truncated G. lucidum gene encoding the catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) was overexpressed by using the Agrobacterium tumefaciens-mediated transformation system. The results showed that the mutated sdhB successfully conferred carboxin resistance upon transformation. Most of the integrated transfer DNA (T-DNA) appeared as a single copy in the genome. Moreover, deregulated constitutive overexpression of the HMGR gene led to a 2-fold increase in ganoderic acid content. It also increased the accumulation of intermediates (squalene and lanosterol) and the upregulation of downstream genes such as those of farnesyl pyrophosphate synthase, squalene synthase, and lanosterol synthase. This study demonstrates that transgenic basidiomycete G. lucidum is a promising system to achieve metabolic engineering of the ganoderic acid pathway. PMID:22941092

  3. Anti-diabetic effect of 3-hydroxy-2-naphthoic acid, an endoplasmic reticulum stress-reducing chemical chaperone.

    PubMed

    Park, Sun-Mi; Choi, Jungsook; Nam, Tae-Gyu; Ku, Jin-Mo; Jeong, Kwiwan

    2016-05-15

    Lots of experimental and clinical evidences indicate that chronic exposure to saturated fatty acids and high level of glucose is implicated in insulin resistance, beta cell failure and ultimately type 2 diabetes. In this study, we set up cell-based experimental conditions to induce endoplasmic reticulum (ER) stress and insulin resistance using high concentration of palmitate (PA). Hydroxynaphthoic acids (HNAs) were formerly identified as novel chemical chaperones to resolve ER stress induced by tunicamycin. In this study, we found the compounds have the same suppressive effect on PA-induced ER stress in HepG2 cells. The representing compound, 3-HNA reduced PA-induced phosphorylation of JNK, IKKβ and IRS1 (S307) and restored insulin signaling cascade which involves insulin receptor β, IRS1 and Akt. The insulin sensitizing effect of 3-HNA was confirmed in 3T3-L1 adipocytes, where the compound augmented insulin signaling and glucose transporter 4 (GLUT4) membrane translocation. 3-HNA also protected the pancreatic beta cells from PA-induced apoptosis by reducing ER stress. Upon 3-HNA treatment to ob/ob mice at 150mg/kg/day dosage, the diabetic parameters including glucose tolerance and systemic insulin sensitivity were significantly improved. Postmortem examination showed that 3-HNA markedly reduced ER stress and insulin resistance in the liver tissues and it sensitized insulin signaling in the liver and the skeletal muscle. Our results demonstrated that 3-HNA can sensitize insulin signaling by coping with lipotoxicity-induced ER stress as a chemical chaperone and suggested it holds therapeutic potential for insulin resistance and type 2 diabetes. PMID:26983645

  4. Surface modification of anatase nanoparticles with fused ring salicylate-type ligands (3-hydroxy-2-naphthoic acids): a combined DFT and experimental study of optical properties

    NASA Astrophysics Data System (ADS)

    Savić, Tatjana D.; Šaponjić, Zoran V.; Čomor, Mirjana I.; Nedeljković, Jovan M.; Dramićanin, Miroslav D.; Nikolić, Marko G.; Veljković, Dušan Ž.; Zarić, Snežana D.; Janković, Ivana A.

    2013-07-01

    The surface modification of nanocrystalline TiO2 particles (45 Å) with salicylate-type ligands consisting of an extended aromatic ring system, specifically 3-hydroxy-2-naphthoic acid, 3,5-dihydroxy-2-naphthoic acid and 3,7-dihydroxy-2-naphthoic acid, was found to alter the optical properties of nanoparticles in a similar way to salicylic acid. The formation of the inner-sphere charge-transfer (CT) complexes results in a red shift of the semiconductor absorption compared to unmodified nanocrystallites and a reduction in the band gap upon the increase in the electron delocalization when including an additional ring. The investigated ligands have the optimal geometry for binding to surface Ti atoms, resulting in ring coordination complexes of a salicylate-type (binuclear bidentate binding-bridging) thus restoring the six-coordinated octahedral geometry of surface Ti atoms. From both absorption measurements in methanol/water = 90/10 solutions and steady-state quenching measurements of modifier fluorescence upon binding to TiO2 in aqueous solutions, stability constants in the order of 103 M-1 have been determined at pH 2 and pH 3. Fluorescence lifetime measurements, in the presence and absence of colloidal TiO2 nanoparticles, indicated that the fluorescence quenching process is primarily static quenching, thus proving the formation of a nonfluorescent CT complex. The binding structures were investigated by using FTIR spectroscopy. Quantum chemical calculations on model systems using density functional theory (DFT) were performed to obtain the vibrational frequencies of charge transfer complexes, and the calculated values were then compared with the experimental data.The surface modification of nanocrystalline TiO2 particles (45 Å) with salicylate-type ligands consisting of an extended aromatic ring system, specifically 3-hydroxy-2-naphthoic acid, 3,5-dihydroxy-2-naphthoic acid and 3,7-dihydroxy-2-naphthoic acid, was found to alter the optical properties of

  5. Protein tyrosine kinase regulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking induced by acute hypoxia in cultured brainstem neurons.

    PubMed

    Wang, H; Yu, L C; Li, Y C

    2016-01-01

    This study was performed to investigate the modulation effect of protein tyrosine kinase on postsynaptic a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking induced by acute hypoxia in cultured brainstem neurons. The cultured neurons were exposed to 1% O2 and the expression of AMPA receptor subunit GluR2 on the cell surface was significantly increased, while total GluR2 was not markedly changed. Furthermore, the hypoxia-induced increase in GluR2 expression on the cell surface was partially blocked by the protein tyrosine kinase membrane-permeable inhibitor genistein. In contrast, both the protein tyrosine kinase agonist nerve growth factor and protein tyrosine phosphatase inhibitor vanadate promoted the hypoxia-induced increase of GluR2 expression on cell surface. Moreover, GluR2 could be phosphorylated by tyrosine under normoxia and hypoxia conditions in vitro on brainstem neurons, and tyrosine phosphorylation of GluR2 was significantly stronger under hypoxia conditions. Our results indicate that acute hypoxia induces the AMPA receptor subunit GluR2 to rapidly migrate to the cell membrane to modify the strength of the synapse. This study indicates that tyrosine phosphorylation of the receptor is an important pathway regulating the rapid migration of GluR2 in the postsynaptic domain induced by hypoxia. PMID:27525851

  6. Modulation of DL-. alpha. -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/quisqualate receptors by phospholipase A sub 2 : A necessary step in long-term potentiation

    SciTech Connect

    Massicotte, G.; Baudry, M. ); Vanderklish, P.; Lynch, G. )

    1991-03-01

    The effects of kainate (KA)-induced epileptic seizures on the binding properites of hippocampal glutamate receptors, on the modulation of DL-{alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/quisqualate receptor by phospholipase A{sub 2} (PLA{sub 2}), and on the formation of long-term potentiation (LTP) were studied in hippocampal membranes and hippocampal slices. Systemic administration of KA produced specific changes in the binding properties of the AMPA/quisqualate receptors and its regulation. Whereas the binding of various ligands to the N-methyl-D-aspartate receptors was not modified by KA treatment, there was a singificant decrease in the maximal number of binding sites for ({sup 3}H)AMPA. The loss of LTP was not due to changes in postsynaptic responses elicited by the bursts that trigger the potentiation effect, thus suggesting that KA treatment disrupts processes that follow N-methyl-D-aspartate receptor activation. Systemic administration of KA was associated with calpain activation as the amount of spectrin breakdown products was increased severalfold in hippocampus but not in cerebellum. Pretreatment of telencephalic membranes with calpain greatly reduced the PLA{sub 2}-induced increase in ({sup 3}H)AMPA binding. The results provide evidence in favor of an essential role of PLA{sub 2} in the development of LTP and suggest that the order of activation of different calcium-dependent processes is critical for producing the final changes underlying LTP.

  7. Regulation of GluA1 α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Function by Protein Kinase C at Serine-818 and Threonine-840

    PubMed Central

    Jenkins, Meagan A.; Wells, Gordon; Bachman, Julia; Snyder, James P.; Jenkins, Andrew; Huganir, Richard L.; Oswald, Robert E.

    2014-01-01

    Three residues within the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluA1 C terminus (Ser818, Ser831, Thr840) can be phosphorylated by Ca2+/phospholipid-dependent protein kinase (PKC). Here, we show that PKC phosphorylation of GluA1 Ser818 or Thr840 enhances the weighted mean channel conductance without altering the response time course or agonist potency. These data support the idea that these residues constitute a hyper-regulatory domain for the AMPA receptor. Introduction of phosphomimetic mutations increases conductance only at these three sites within the proximal C terminus, consistent with a structural model with a flexible linker connecting the distal C-terminal domain to the more proximal domain containing a helix bracketed by Ser831 and Thr840. NMR spectra support this model and raise the possibility that phosphorylation can alter the configuration of this domain. Our findings provide insight into the structure and function of the C-terminal domain of GluA1, which controls AMPA receptor function and trafficking during synaptic plasticity in the central nervous system. PMID:24452473

  8. Arachidonic acid alters tomato HMG expression and fruit growth and induces 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent lycopene accumulation

    SciTech Connect

    Rodriguez-Concepcion, M.; Gruissem, W.

    1999-01-01

    Regulation of isoprenoid end-product synthesis required for normal growth and development in plants is not well understood. To investigate the extent to which specific genes for the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) are involved in end-product regulation, the authors manipulated expression of the HMG1 and HMG2 genes in tomato (Lycopersicon esculentum) fruit using arachidonic acid (AA). In developing young fruit AA blocked fruit growth, inhibited HMG1, and activated HMG2 expression. These results are consistent with other reports indicating that HMG1 expression is closely correlated with growth processes requiring phytosterol production. In mature-green fruit AA strongly induced the expression of HMG2, PSY1 (the gene for phytoene synthase), and lycopene accumulation before the normal onset of carotenoid synthesis and ripening. The induction of lycopene synthesis was not blocked by inhibition of HMGR activity using mevinolin, suggesting that cytoplasmic HMGR is not required for carotenoid synthesis. Their results are consistent with the function of an alternative plastid isoprenoid pathway (the Rohmer pathway) that appears to direct the production of carotenoids during tomato fruit ripening.

  9. Thermochemistry and dissociation dynamics of state-selected C/sub 4/H/sub 8/O/sub 2//sup +/ ions. 2. Butanoic acid

    SciTech Connect

    Butler, J.J.; Fraser-Monteiro, M.L.; Fraser-Monteiro, L.; Baer, T.; Hass, J.R.

    1982-01-01

    Photoionization efficiency curves and appearance energies for C/sub 4/H/sub 8/O/sub 2//sup +/, C/sub 3/H/sub 5/O/sub 2//sup +/, C/sub 2/H/sub 7/O/sup +/, C/sub 2/H/sub 4/O/sub 2//sup +/, C/sub 3/H/sub 7//sup +/, C/sub 3/H/sub 6//sup +/, C/sub 2/H/sub 5//sup +/, and C/sub 2/H/sub 4//sup +/ from butanoic acid have been obtained. Structures and heats of formation for some of the ions are proposed. No evidence for metastable C/sub 4/H/sub 8/O/sub 2//sup +/ ions forming C/sub 3/H/sub 5/O/sub 2//sup +/ (m/e 73) and C/sub 2/H/sub 4/O/sub 2//sup +/ (m/e 60) was found in the photoion-photoelectron coincidence (PIPECO) results. An upper limit to the parent ion lifetimes is 0.1 ..mu..s. In constrast, to the photoionization results, electron impact ionization produces strong C/sub 4/H/sub 8/O/sub 2//sup +/ metastables with lifetimes in the 10-..mu..s range. This paradox can be resolved by postulating that photoionization produces only rapidly dissociating butanoic acid ions, while a long-lived isomerized structure (or structures), such as the enol form are accessible by electron impact.

  10. Hydrodynamic and pharmacological characterization of putative alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-sensitive L-glutamate receptors solubilized from pig brain.

    PubMed Central

    Wu, T Y; Chang, Y C

    1994-01-01

    L-[3H]Glutamate binding sites with characteristics resembling that of membrane-bound alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-subtype L-glutamate receptors have been solubilized from pig brain synaptic junctions by Triton X-114. Binding of [3H]AMPA to these soluble sites in the presence of KSCN results in a curvilinear Scatchard plot that can be resolved into a high-affinity component and a low-affinity component. These Triton-X-114-solubilized sites can be further separated into two species of binding sites by gel-filtration chromatography or sucrose-density-gradient centrifugation. The pharmacological profiles of these two species of binding site are almost identical, and the rank orders of potency for glutamatergic drugs in displacing L-[3H]glutamate binding to these sites are quisqualate > 6,7-dinitroquinoxaline-2,3-dione > 6-cyano-7-nitroquinoxaline-2,3-dione > AMPA > L-glutamate > kainate >> N-methyl-D-aspartate = L-2-amino-4-phosphonobutyrate. Both sites are found to bind [3H]AMPA, and in the presence of KSCN the binding activities are significantly enhanced. Analysis of the hydrodynamic behaviour of these binding sites by sucrose-density-gradient centrifugation in H2O- and 2H2O-based solvents and gel-filtration chromatography has revealed that one of these sites (Stokes radius 8.3 nm, sedimentation coefficient 18.5 S) consists of 562 kDa protein and 281 kDa detergent, and the other site (Stokes radius 9.6 nm, sedimentation coefficient 13.4 S) consists of 352 kDa protein and 569 kDa detergent. Frictional coefficients of these sites indicate that these receptor-detergent complexes are asymmetrical in structure, consistent with large transmembrane proteins. PMID:7516151

  11. Hydrodynamic and pharmacological characterization of putative alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-sensitive L-glutamate receptors solubilized from pig brain.

    PubMed

    Wu, T Y; Chang, Y C

    1994-06-01

    L-[3H]Glutamate binding sites with characteristics resembling that of membrane-bound alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-subtype L-glutamate receptors have been solubilized from pig brain synaptic junctions by Triton X-114. Binding of [3H]AMPA to these soluble sites in the presence of KSCN results in a curvilinear Scatchard plot that can be resolved into a high-affinity component and a low-affinity component. These Triton-X-114-solubilized sites can be further separated into two species of binding sites by gel-filtration chromatography or sucrose-density-gradient centrifugation. The pharmacological profiles of these two species of binding site are almost identical, and the rank orders of potency for glutamatergic drugs in displacing L-[3H]glutamate binding to these sites are quisqualate > 6,7-dinitroquinoxaline-2,3-dione > 6-cyano-7-nitroquinoxaline-2,3-dione > AMPA > L-glutamate > kainate > N-methyl-D-aspartate = L-2-amino-4-phosphonobutyrate. Both sites are found to bind [3H]AMPA, and in the presence of KSCN the binding activities are significantly enhanced. Analysis of the hydrodynamic behaviour of these binding sites by sucrose-density-gradient centrifugation in H2O- and 2H2O-based solvents and gel-filtration chromatography has revealed that one of these sites (Stokes radius 8.3 nm, sedimentation coefficient 18.5 S) consists of 562 kDa protein and 281 kDa detergent, and the other site (Stokes radius 9.6 nm, sedimentation coefficient 13.4 S) consists of 352 kDa protein and 569 kDa detergent. Frictional coefficients of these sites indicate that these receptor-detergent complexes are asymmetrical in structure, consistent with large transmembrane proteins. PMID:7516151

  12. Synthesis, spectroscopic, X-ray crystal structure, biological and DNA interaction studies of organotin(IV) complexes of 2-(4-ethoxybenzylidene) butanoic acid.

    PubMed

    Tariq, Muhammad; Muhammad, Niaz; Ali, Saqib; Shirazi, Jafir Hussain; Tahir, Muhammad Nawaz; Khalid, Nasir

    2014-03-25

    Six organotin(IV) carboxylates of the type R2SnL2 [R=CH3 (1), n-C4H9 (2), n-C8H17 (3)] and R3SnL [R=CH3 (4), n-C4H9 (5), C6H5 (6), where L=2-(4-ethoxybenzylidene) butanoic acid, have been synthesized and characterized by elemental analysis, FT-IR and NMR ((1)H, (13)C). The complex (1) was also analyzed by single crystal X-ray analysis. The complexes were screened for antimicrobial, cytotoxic and anti-tumor activities. The results showed significant activity in each area of the activity with few exceptions. DNA interactions studies of ligand HL and representative complex 2 were investigated by UV-Visible absorption spectroscopy and viscosity measurements. The results showed that both ligand HL and complex 2 interact with SS-DNA via intercalation as well as minor groove binding. PMID:24322756

  13. Use of (2-/sup 14/C)mevalonate and saponin-bound (/sup 14/C)-3-hydroxy-3-methylglutaric acid for the biosynthesis of terpenoids in leaves of Dioscorea deltoidea

    SciTech Connect

    Gurielidze, K.G.; Paseshnichenko, V.A.; Vasil'eva, I.S.

    1986-03-20

    After the introduction of (2-/sup 14/C)acetate into leaves of Dioscorea deltoidea, a radioactive furonanalog of deltafolin - protodeltofolin, containing two-thirds of the label in the 3-hydroxy-3-methylglutaryl portion - was isolated from them. Radioactive ..beta..-careotene and sterols were isolated from cut young leaves of Dioscorea 24 h after the introduction of (/sup 14/C) protodeltofolin into them, using chromatography on a column of silica gel and precipitation of sterols in the form of digitonins for this purpose. The incorporation of radioactivity from (/sup 14/C)-3-hydroxy-3-methyl-glutaric acid, bound in the form of a saponin, and ..beta..-carotene came to 0.18-0.80%, while incorporation into sterols came to 0.07-2.86% of the radioactivity of the alcohol extract. Thereby it was shown that 3-hydroxyl-3-methylglutaric acid, bound in the form of the saponin, can be used to form terpenoids in Dioscorea leaves. It was suggested that the binding of hydroxymethylglutaric acid to saponin represents one of the mechanisms of regulation of the rate of terpenoid biosynthesis in Dioscorea leaves.

  14. Monocarboxylate transporter 1 is up-regulated in Caco-2 cells by the methionine precursor DL-2-hydroxy-(4-methylthio)butanoic acid.

    PubMed

    Martín-Venegas, Raquel; Brufau, M Teresa; Mañas-Cano, Oriol; Mercier, Yves; Nonis, Magalie K; Ferrer, Ruth

    2014-12-01

    The methionine precursor, DL-2-hydroxy-(4-methylthio)butanoic acid (HMTBA), is a synthetic source of dietary methionine, which is widely used as a poultry nutritional supplement. In the intestinal epithelium, HMTBA transport across the apical membrane is mediated by monocarboxylate transporter 1 (MCT1). The first step in biological utilisation of this methionine precursor is the stereospecific conversion of HMTBA to the corresponding keto acid. In the present study, the regulation of trans-epithelial HMTBA transport was investigated in Caco-2 cell monolayers. Differentiated Caco-2 cells were maintained under control conditions (apical compartment: 0.2 mmol/L L-methionine) or in a HMTBA-enriched medium (2 mmol/L HMTBA). The effect of culture on HMTBA transport was evaluated from apical and basolateral kinetic parameters. MCT1 and MCT4 immuno-localisation and gene expression were investigated by confocal microscopy and real-time quantitative RT-PCR, respectively. The results indicated that apical MCT1 was up-regulated by exposure to HMTBA (1.4-fold increase in Vmax without changes in Km). Moreover, total monolayer MCT1 immunoreactivity increased 1.8-fold in HMTBA-supplemented cultures, this effect mainly being localised at the apical membrane. Functional and immuno-localisation data suggest involvement of MCT1 and MCT4 in basolateral HMTBA transport, although, in this case, no effect was observed for HMTBA-enrichment. Molecular analysis confirmed MCT1 mRNA up-regulation (1.8-fold), with no effect on MCT4 mRNA expression. Thus, exposure to HMTBA up-regulates the trans-epithelial transport of this methionine precursor by increasing the expression and the transport capacity of apical MCT1. PMID:25447800

  15. Synthesis of all stereoisomers of 3-hydroxypipecolic acid and 3-hydroxy-4,5-dehydropipecolic acid and their evaluation as glycosidase inhibitors.

    PubMed

    Ohara, Chiaki; Takahashi, Ryouko; Miyagawa, Tatsunori; Yoshimura, Yuichi; Kato, Atsushi; Adachi, Isao; Takahata, Hiroki

    2008-03-15

    A highly practicable synthesis of both enantiomers of 3-hydroxypipecolic acid derivatives 1, 2, 3, 4 is described. Screening of these molecules for glycosidase inhibition has been examined. Compound 3 was shown to be a potent inhibitor of beta-N-acetylglucosaminidase as well as Escherichia coli beta-glucuronidase. PMID:18296050

  16. Assessing the ruminal action of the isopropyl ester of 2-hydroxy-4-(methylthio) butanoic acid in continuous and batch cultures of mixed ruminal microbes.

    PubMed

    Fowler, C M; Plank, J E; Devillard, E; Bequette, B J; Firkins, J L

    2015-02-01

    In dairy rations, Met is often a limiting amino acid that is provided by rumen-undegradable protein and rumen-protected sources of Met. A Met precursor, 2-hydroxy-4-(methylthio) butanoic acid (HMB) has undergone considerable study for ruminal and postruminal metabolism, whereas its isopropyl ester (HMBi) has been evaluated primarily with respect to its supply of metabolizable Met rather than as a preformed source of Met for microbial metabolism. A control and 3 isomolar Met treatments-0.097% dl-Met, 0.048% dl-Met plus 0.055% HMBi (Met + HMBi treatment), and 0.11% HMBi-were pulse-dosed every 8h into continuous cultures simultaneously with feeding. Treatment had no effect on digestibilities of acid-detergent fiber or true organic matter. Digestibilities of neutral detergent fiber and hemicellulose were linearly decreased with increasing HMBi inclusion. Concentration of NH3-N tended to decrease linearly and quadratically, and NH3-N flow tended to decrease linearly, with increasing HMBi inclusion; in contrast, the proportion of bacterial N derived from NH3-N increased linearly. Peptide N increased linearly and tended to be affected quadratically (highest for the HMBi treatment). Acetate and propionate production both decreased with increasing HMBi, but acetate declined more such that acetate:propionate increased linearly. Isobutyrate production decreased, but isovalerate and valerate increased with increasing HMBi inclusion. Relative changes in population abundance were not detected by denaturing gradient gel electrophoresis. In the second study, which was done in batch culture, Met treatments consisted of control, 0.097% l-Met, 0.097% l-Met, 0.125% dl-HMBi, 0.098% dl-HMB, 0.250% dl-HMBi (2× HMBi), 0.049% dl-Met + 0.063% dl-HMBi (Met + HMBi), and 0.098% dl-HMB + 0.039% isopropanol. All of these Met treatments were unlabeled (i.e., at natural abundance of (13)C) but simultaneously dosed with equivalent dosages of [1-(13)C]-l-Met. All 8 treatments were inoculated with

  17. Gender-specific differences between the concentrations of nonvolatile (R)/(S)-3-methyl-3-sulfanylhexan-1-Ol and (R)/(S)-3-hydroxy-3-methyl-hexanoic acid odor precursors in axillary secretions.

    PubMed

    Troccaz, Myriam; Borchard, Gerrit; Vuilleumier, Christine; Raviot-Derrien, Sophie; Niclass, Yvan; Beccucci, Sabine; Starkenmann, Christian

    2009-03-01

    The volatile fatty acid, (R)/(S)-3-hydroxy-3-methylhexanoic acid ((R)/(S)-HMHA), and the human specific volatile thiol, (R)/(S)-3-methyl-3-sulfanylhexan-1-ol ((R)/(S)-MSH), were recently identified as major components of human sweat malodor. Their 2 corresponding precursors were subsequently isolated from sterile and odorless axillary secretions. The purpose of this work was to analyze these 2 odor precursors in 49 male and female volunteers over a period of 3 years to elucidate to which extent they are implicated in the gender-specific character of body odor. Surprisingly, the ratio between the acid precursor 1, a glutamine conjugate, and the "sulfur" precursor 2, a cysteinylglycine-S-conjugate, was 3 times higher in men than in women with no correlation with either the sweat volume or the protein concentration. Indeed, women have the potential to liberate significantly more (R)/(S)-MSH, which has a tropical fruit- and onion-like odor than (R)/(S)-HMHA (possibly transformed into (E)/(Z)-3-methyl-2-hexenoic acid) that has a cheesy, rancid odor. Parallel to this work, sensory analysis on sweat incubated with isolated skin bacteria (Staphylococcus epidermidis Ax3, Corynebacterium jeikeium American Type Culture Collection 43217, or Staphylococcus haemolyticus Ax4) confirmed that intrinsic composition of sweat is important for the development of body odors and may be modulated by gender differences in bacterial compositions. Sweat samples having the highest sulfur intensity were also found to be the most intense and the most unpleasant. PMID:19147808

  18. Tweaking Subtype Selectivity and Agonist Efficacy at (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) Receptors in a Small Series of BnTetAMPA Analogues.

    PubMed

    Wang, Shuang-Yan; Larsen, Younes; Navarrete, Cristina Vara; Jensen, Anders A; Nielsen, Birgitte; Al-Musaed, Ali; Frydenvang, Karla; Kastrup, Jette Sandholm; Pickering, Darryl S; Clausen, Rasmus Prætorius

    2016-03-10

    A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain. PMID:26862980

  19. A study of the oligomeric state of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring glutamate receptors in the synaptic junctions of porcine brain.

    PubMed

    Wu, T Y; Liu, C I; Chang, Y C

    1996-11-01

    The number of the subunits in an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring L-glutamate receptor in the synaptic junctions of porcine brain was investigated in this study. Upon incubation of the synaptic junctions with three cross-linking regents, dimethyl adipimidate (DMA), dimethyl suberimidate (DMS) and N-succinimidyl-(4-azidophenyl)-1,3'-dithiopropionate (SADP), AMPA receptor subunits in higher-molecular-mass aggregates were detected by immunoblotting. These aggregates migrated as proteins of approx. 200, 300 and 400 kDa. The number and identity of the subunits in a solubilized AMPA receptor were also investigated here. Two samples, W1 and W2, enriched in AMPA receptors were prepared from synaptic junctions by a combination of detergent-solubilization, anion-exchange chromatography and wheatgerm agglutinin affinity chromatography. Hydrodynamic behaviour analyses revealed that the majority of the AMPA receptors in either one of these samples were asymmetrical detergent-surrounded particles with a protein mass around 350 kDa. SDS/PAGE analysis revealed that the majority of AMPA receptors in the W1 sample were comprised of dimers of 106 kDa subunits which were covalently linked by disulphide bonds. Cross-linking these receptors with SADP yielded a new band of approx. 400 kDa. The results obtained here, either from the studies of AMPA receptors embedding in synaptic junctions or from those of detergent-solubilized and partially purified receptors, suggest that AMPA receptors contain a basic core structure comprising of four 106 kDa subunits. PMID:8920974

  20. A study of the oligomeric state of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-preferring glutamate receptors in the synaptic junctions of porcine brain.

    PubMed Central

    Wu, T Y; Liu, C I; Chang, Y C

    1996-01-01

    The number of the subunits in an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring L-glutamate receptor in the synaptic junctions of porcine brain was investigated in this study. Upon incubation of the synaptic junctions with three cross-linking regents, dimethyl adipimidate (DMA), dimethyl suberimidate (DMS) and N-succinimidyl-(4-azidophenyl)-1,3'-dithiopropionate (SADP), AMPA receptor subunits in higher-molecular-mass aggregates were detected by immunoblotting. These aggregates migrated as proteins of approx. 200, 300 and 400 kDa. The number and identity of the subunits in a solubilized AMPA receptor were also investigated here. Two samples, W1 and W2, enriched in AMPA receptors were prepared from synaptic junctions by a combination of detergent-solubilization, anion-exchange chromatography and wheatgerm agglutinin affinity chromatography. Hydrodynamic behaviour analyses revealed that the majority of the AMPA receptors in either one of these samples were asymmetrical detergent-surrounded particles with a protein mass around 350 kDa. SDS/PAGE analysis revealed that the majority of AMPA receptors in the W1 sample were comprised of dimers of 106 kDa subunits which were covalently linked by disulphide bonds. Cross-linking these receptors with SADP yielded a new band of approx. 400 kDa. The results obtained here, either from the studies of AMPA receptors embedding in synaptic junctions or from those of detergent-solubilized and partially purified receptors, suggest that AMPA receptors contain a basic core structure comprising of four 106 kDa subunits. PMID:8920974

  1. Positive allosteric modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors differentially modulates the behavioural effects of citalopram in mouse models of antidepressant and anxiolytic action.

    PubMed

    Fitzpatrick, Ciarán M; Larsen, Maria; Madsen, Louise H; Caballero-Puntiverio, Maitane; Pickering, Darryl S; Clausen, Rasmus P; Andreasen, Jesper T

    2016-09-01

    Drugs that increase monoamine neurotransmission are effective in both anxiety and depression. The therapeutic effects of monoamine-based antidepressant drugs may involve indirect effects on neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR). Thus, chronic antidepressant treatment increases AMPAR-mediated neurotransmission and AMPAR-positive allosteric modulators have shown antidepressant-like efficacy in rodents. Here, the effect of enhanced AMPAR neurotransmission on the antidepressant-like and anxiolytic-like actions of the selective serotonin reuptake inhibitor citalopram (0-10 mg/kg) was investigated in mice using the AMPAR-positive allosteric modulator LY451646 (0-3 mg/kg). Antidepressant-like effects were assessed using the forced-swim test (FST), whereas anxiolytic-like effects were tested using the elevated zero maze (EZM) and the marble burying test. LY451646 (3 mg/kg) increased swim distance in the FST and a subactive dose of LY451646 (1 mg/kg) enhanced the effect of citalopram in the FST. In the EZM, LY451646 (3 mg/kg) did not show anxiogenic effects alone, but blocked the anxiolytic-like action of citalopram in the EZM, as reflected by an increase in the latency to enter the open areas and a decrease in the number of entries and time spent in the open areas in citalopram-treated mice. In the marble burying test, LY451646 (3 mg/kg) showed no effect alone, but significantly attenuated the anxiolytic-like effect of citalopram (1.25-2.5 mg/kg) by increasing the number of marbles buried in citalopram-treated mice. These results suggest that AMPAR neurotransmission plays opposite roles in anxiety and depression as AMPAR potentiation facilitated the antidepressant-like effects of citalopram while attenuating its anxiolytic-like effect. These findings have ramifications in the search for AMPAR-based novel anxiolytic and antidepressant treatments. PMID:27341500

  2. Design, synthesis, and biological evaluation of 4-(5-dimethylamino-naphthalene-1-sulfon-amido)-3-(4-iodophenyl)butanoic acid as a novel molecular probe for apoptosis imaging

    SciTech Connect

    Zeng, Wenbin; Miao, Weimin; Le Puil, Michael; Shi, Guangqing; Biggerstaff, John; Kabalka, George W.; Townsend, David

    2010-07-30

    Research highlights: {yields} Annexin V is the gold standard probe for imaging apoptosis. {yields} Unfavorable profiles of Annexin V make it difficult to apply in the clinic. {yields} A novel small-molecular probe DNSBA was designed as an alternative to Annexin V. {yields} DNSBA specifically and selectively detect apoptotic cancer cells at all stages. {yields} DNSBA is a potential SPECT and PET agent when labeled with radioiodine. -- Abstract: Apoptosis (programmed cell death) plays a crucial role in the pathogenesis of many disorders, thus the detection of apoptotic cells can provide the physician with important information to further therapeutic strategies and would substantially advance patient care. A small molecule, 4-(5-dimethylamino-naphthalene-1-sulfonamido)-3-(4-iodo-phenyl)butanoic acid (DNSBA), was designed as a novel probe for imaging apoptosis and synthesized with good yield. The biological characterization demonstrated that DNSBA can be used to specifically and selectively detect apoptotic cancer cells at all stages. DNSBA is also designed as a potential SPECT and PET probe when labeled with radioiodine (I-123, -124, and -131).

  3. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, K.N.; Xu, J.

    1997-04-29

    Disclosed is a series of improved metal chelating agents, which are highly effective upon both injection and oral administration; several of the most effective are of low toxicity. These chelating agents incorporate within their structure 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy or oxo groups of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with its adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provides a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. Also disclosed is a method of making the chelating agents and a method of producing a known compound, 3-hydroxy-1-alkyl-2(1H)pyridinone, used as a precursor to the chelating agent, safely and in large quantities. 2 figs.

  4. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, Kenneth N.; Xu, Jide

    1997-01-01

    Disclosed is a series of improved metal chelating agents, which are highly effective upon both injection and oral administration; several of the most effective are of low toxicity. These chelating agents incorporate within their structure 1-hydroxy-2-pyridinone (1,2-HOPO) and 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy or oxo groups of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity of the hydroxypyridinones. In the metal complexes of said chelating agents, the amide protons form very strong hydrogen bonds with its adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provides a certain degree of lipophilicity to said 3,2-HOPO, increasing oral activity. Also disclosed is a method of making the chelating agents and a method of producing a known compound, 3-hydroxy-1-alkyl-2(1H)pyridinone, used as a precursor to the chelating agent, safely and in large quantities.

  5. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, Kenneth; Xu, Jide

    1999-01-01

    Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity.

  6. 3-hydroxy-2(1H)-pyridinone chelating agents

    DOEpatents

    Raymond, K.; Xu, J.

    1999-04-06

    Disclosed is a series of improved chelating agents and the chelates formed from these agents, which are highly effective upon both injection and oral administration. Several of the most effective are of low toxicity. These chelating agents incorporate within their structure 3-hydroxy-2-pyridinone (3,2-HOPO) moieties with a substituted carbamoyl group ortho to the hydroxy group of the hydroxypyridinone ring. The electron-withdrawing carbamoyl group increases the acidity, as well as the chemical stability towards oxidation and reduction, of the hydroxypyridinones. In the metal complexes of the chelating agents, the amide protons form very strong hydrogen bonds with the adjacent HOPO oxygen donor, making these complexes very stable at physiological conditions. The terminal N-substituents provide a certain degree of lipophilicity to the 3,2-HOPO, increasing oral activity. 2 figs.

  7. Liquid chromatography-electrospray ionization-tandem mass spectrometry quantitation of urinary [pyridine-D4]4-hydroxy-4-(3-pyridyl)butanoic acid, a biomarker of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation in smokers.

    PubMed

    Jing, Meng; Wang, Yaohua; Upadhyaya, Pramod; Jain, Vipin; Yuan, Jian-Min; Hatsukami, Dorothy K; Hecht, Stephen S; Stepanov, Irina

    2014-09-15

    4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 1) is a potent tobacco-specific lung carcinogen believed to play a key role in the development of lung cancer in smokers. Metabolic activation of NNK to DNA damaging reactive intermediates proceeds via α-hydroxylation pathways. The end products of these pathways are excreted in the urine of smokers as 4-oxo-4-(3-pyridyl)butanoic acid (keto acid, 3) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid, 4). The sum of these biomarkers (after NaBH4 treatment), referred to as total hydroxy acid, could potentially be used to measure the extent of NNK metabolic activation in smokers. However, the same metabolites are formed from nicotine; therefore, there is a need to distinguish the NNK- and nicotine-derived keto and hydroxy acid in smokers' urine. We previously developed a unique methodology based on the use of [pyridine-D4]NNK ([D4]1), which metabolizes to the correspondingly labeled biomarkers. In this study, we developed a sensitive and reproducible assay for the detection and quantitation of total [pyridine-D4]hydroxy acid ([D4]4) in human urine. A two-step derivatization approach was used to convert [D4]4 to [pyridine-D4]methyl 4-hexanoyl-4-(3-pyridyl)butanoate ([D4]6), and an LC-ESI-MS/MS method was developed for the analysis of this derivative with excellent sensitivity, accuracy, and precision. The robustness and reproducibility of the assay was further confirmed by its application for the analysis of urine samples from 87 smokers who smoked [D4]1-containing cigarettes for 1 week. The measured level averaged 130 fmol/mL urine. The developed assay can be used in future studies that may require evaluation of the relative efficiency of NNK metabolic activation in humans. PMID:25098652

  8. Liquid Chromatography–Electrospray Ionization–Tandem Mass Spectrometry Quantitation of Urinary [Pyridine-D4]4-hydroxy-4-(3-pyridyl)butanoic Acid, a Biomarker of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Metabolic Activation in Smokers

    PubMed Central

    2015-01-01

    4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 1) is a potent tobacco-specific lung carcinogen believed to play a key role in the development of lung cancer in smokers. Metabolic activation of NNK to DNA damaging reactive intermediates proceeds via α-hydroxylation pathways. The end products of these pathways are excreted in the urine of smokers as 4-oxo-4-(3-pyridyl)butanoic acid (keto acid, 3) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid, 4). The sum of these biomarkers (after NaBH4 treatment), referred to as total hydroxy acid, could potentially be used to measure the extent of NNK metabolic activation in smokers. However, the same metabolites are formed from nicotine; therefore, there is a need to distinguish the NNK- and nicotine-derived keto and hydroxy acid in smokers’ urine. We previously developed a unique methodology based on the use of [pyridine-D4]NNK ([D4]1), which metabolizes to the correspondingly labeled biomarkers. In this study, we developed a sensitive and reproducible assay for the detection and quantitation of total [pyridine-D4]hydroxy acid ([D4]4) in human urine. A two-step derivatization approach was used to convert [D4]4 to [pyridine-D4]methyl 4-hexanoyl-4-(3-pyridyl)butanoate ([D4]6), and an LC-ESI-MS/MS method was developed for the analysis of this derivative with excellent sensitivity, accuracy, and precision. The robustness and reproducibility of the assay was further confirmed by its application for the analysis of urine samples from 87 smokers who smoked [D4]1-containing cigarettes for 1 week. The measured level averaged 130 fmol/mL urine. The developed assay can be used in future studies that may require evaluation of the relative efficiency of NNK metabolic activation in humans. PMID:25098652

  9. [3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency as a cause of severe neurological damage].

    PubMed

    Dodelson de Kremer, R; Kelley, R I; Depetris de Boldini, C; Paschini de Capra, A; Corbella, L; Givogri, I; Giner de Ayala, A; Albarenque, M

    1992-01-01

    This paper describes the first Argentine case of 3-hydroxy-3-methylglutaric aciduria, a genetic defect of ketogenesis and leucine catabolism step. At the age of 4 months, the patient presented a life-threatening episode of hypoglucemia, metabolic acidosis and hyperammonemia resembling Reye syndrome. The lack of urinary ketone bodies, normal levels of plasma aminoacids and normal urinary excretion of p-hydroxyphenolic acids, led us to look for a ketogenic defect. An abnormal profile of urinary organic acids detected by thin layer chromatography and later characterized and quantified by gas chromatography-mass spectrometry (Figs. 1, 2; Table 1), showed a marked increase in the acidic metabolites typical of the 3-hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. The activity of 3-hydroxy-3-methylglutaryl coenzyme A lyase was absent in white cell pellets and between 2-5% of the control values in skin fibroblasts (Table 2). Treatment of the disorder, mainly restricted leucine or low-protein diet and addition of L-carnitine had no significant effect on the severe neurological injuries present since the first illness. MRI of the brain, at the age of 1 year and 8 months, showed images in T1 suggestive of marked cerebral atrophy and in T2 hyperintensive images predominating in the right frontal and posterior parietal areas and of the punctiform lesions in the basal ganglia, particularly in the heads of both caudate nuclei.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1302289

  10. Effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid supplementation on growth performance, indices of ascites syndrome, and antioxidant capacity of broilers reared at low ambient temperature

    NASA Astrophysics Data System (ADS)

    Yang, G. L.; Zhang, K. Y.; Ding, X. M.; Zheng, P.; Luo, Y. H.; Bai, S. P.; Wang, J. P.; Xuan, Y.; Su, Z. W.; Zeng, Q. F.

    2016-01-01

    This study examined the effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid (DL-HMTBA) supplementation on growth performance, antioxidant capacity, and ascites syndrome (AS) in broilers reared at low ambient temperature (LAT) from 7 to 28 days of age. Eight hundred 7-day-old broilers were randomly assigned to two ambient temperatures (LAT and normal ambient temperature [NAT]), four supplemental DL-HMTBA levels (0.17, 0.34, 0.51, and 0.68 %) of the basal diet in a 2 × 4 factorial arrangement (ten replicate pens; ten birds/pen). LAT and NAT indicate temperatures of 12-14 and 24-26 °C in two chambers, respectively, and broilers were reared at these temperatures from 7 to 28 days of age. LAT significantly decreased body weight gain (P < 0.001), serum glutathione (GSH) content (day 14, P = 0.02; day 28, P = 0.045), glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC) at 21 days (P = 0.001, 0.015) and 28 days (P = 0.017, 0.010) and increased feed conversion ratio (FCR) (P < 0.001), serum malondialdehyde (day 21, P = 0.000) and protein carbonyl Level (day 14, P = 0.003; day 21, P = 0.035). As for incidence of AS, there were significant effects of LAT on red blood cell (RBC) count (P < 0.05), hematocrit (HCT) (P < 0.05), and the right to total ventricular weight ratio (RV/TV) at 21 days (P = 0.012) and 28 days (P = 0.046). Supplementation of DL-HMTBA markedly decreased RV/TV at day 28 (P = 0.021), RBC (day 21, P = 0.008), HCT (day 21, P < 0.001), mean cell hemoglobin (day 14, P = 0.035; day 21, P = 0.003), and serum protein carbonyl level (day 21, P = 0.009), while significantly increased serum GSH content (day 14, P = 0.022; day 28, P = 0.001), SOD and GSH-Px activities at 21 days of age (P < 0.001 and P = 0.037). The optimal supplemental DL-HMTBA levels in basal diet of broilers aged from 7 to 28 days under low or normal temperatures were similar, so the authors recommended supplemental of DL-HMTBA level was 0.46 %.

  11. Effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid supplementation on growth performance, indices of ascites syndrome, and antioxidant capacity of broilers reared at low ambient temperature

    NASA Astrophysics Data System (ADS)

    Yang, G. L.; Zhang, K. Y.; Ding, X. M.; Zheng, P.; Luo, Y. H.; Bai, S. P.; Wang, J. P.; Xuan, Y.; Su, Z. W.; Zeng, Q. F.

    2016-08-01

    This study examined the effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid (DL-HMTBA) supplementation on growth performance, antioxidant capacity, and ascites syndrome (AS) in broilers reared at low ambient temperature (LAT) from 7 to 28 days of age. Eight hundred 7-day-old broilers were randomly assigned to two ambient temperatures (LAT and normal ambient temperature [NAT]), four supplemental DL-HMTBA levels (0.17, 0.34, 0.51, and 0.68 %) of the basal diet in a 2 × 4 factorial arrangement (ten replicate pens; ten birds/pen). LAT and NAT indicate temperatures of 12-14 and 24-26 °C in two chambers, respectively, and broilers were reared at these temperatures from 7 to 28 days of age. LAT significantly decreased body weight gain ( P < 0.001), serum glutathione (GSH) content (day 14, P = 0.02; day 28, P = 0.045), glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC) at 21 days ( P = 0.001, 0.015) and 28 days ( P = 0.017, 0.010) and increased feed conversion ratio (FCR) ( P < 0.001), serum malondialdehyde (day 21, P = 0.000) and protein carbonyl Level (day 14, P = 0.003; day 21, P = 0.035). As for incidence of AS, there were significant effects of LAT on red blood cell (RBC) count ( P < 0.05), hematocrit (HCT) ( P < 0.05), and the right to total ventricular weight ratio (RV/TV) at 21 days ( P = 0.012) and 28 days ( P = 0.046). Supplementation of DL-HMTBA markedly decreased RV/TV at day 28 ( P = 0.021), RBC (day 21, P = 0.008), HCT (day 21, P < 0.001), mean cell hemoglobin (day 14, P = 0.035; day 21, P = 0.003), and serum protein carbonyl level (day 21, P = 0.009), while significantly increased serum GSH content (day 14, P = 0.022; day 28, P = 0.001), SOD and GSH-Px activities at 21 days of age ( P < 0.001 and P = 0.037). The optimal supplemental DL-HMTBA levels in basal diet of broilers aged from 7 to 28 days under low or normal temperatures were similar, so the authors recommended supplemental of DL-HMTBA level was 0.46 %.

  12. Effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid supplementation on growth performance, indices of ascites syndrome, and antioxidant capacity of broilers reared at low ambient temperature.

    PubMed

    Yang, G L; Zhang, K Y; Ding, X M; Zheng, P; Luo, Y H; Bai, S P; Wang, J P; Xuan, Y; Su, Z W; Zeng, Q F

    2016-08-01

    This study examined the effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid (DL-HMTBA) supplementation on growth performance, antioxidant capacity, and ascites syndrome (AS) in broilers reared at low ambient temperature (LAT) from 7 to 28 days of age. Eight hundred 7-day-old broilers were randomly assigned to two ambient temperatures (LAT and normal ambient temperature [NAT]), four supplemental DL-HMTBA levels (0.17, 0.34, 0.51, and 0.68 %) of the basal diet in a 2 × 4 factorial arrangement (ten replicate pens; ten birds/pen). LAT and NAT indicate temperatures of 12-14 and 24-26 °C in two chambers, respectively, and broilers were reared at these temperatures from 7 to 28 days of age. LAT significantly decreased body weight gain (P < 0.001), serum glutathione (GSH) content (day 14, P = 0.02; day 28, P = 0.045), glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC) at 21 days (P = 0.001, 0.015) and 28 days (P = 0.017, 0.010) and increased feed conversion ratio (FCR) (P < 0.001), serum malondialdehyde (day 21, P = 0.000) and protein carbonyl Level (day 14, P = 0.003; day 21, P = 0.035). As for incidence of AS, there were significant effects of LAT on red blood cell (RBC) count (P < 0.05), hematocrit (HCT) (P < 0.05), and the right to total ventricular weight ratio (RV/TV) at 21 days (P = 0.012) and 28 days (P = 0.046). Supplementation of DL-HMTBA markedly decreased RV/TV at day 28 (P = 0.021), RBC (day 21, P = 0.008), HCT (day 21, P < 0.001), mean cell hemoglobin (day 14, P = 0.035; day 21, P = 0.003), and serum protein carbonyl level (day 21, P = 0.009), while significantly increased serum GSH content (day 14, P = 0.022; day 28, P = 0.001), SOD and GSH-Px activities at 21 days of age (P < 0.001 and P = 0.037). The optimal supplemental DL-HMTBA levels in basal diet of broilers aged from 7 to 28 days under low or normal temperatures were similar, so the authors recommended

  13. Synthesis and biological evaluation of novel 9-heteroaryl substituted 7-chloro-4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQX) as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists.

    PubMed

    Catarzi, Daniela; Colotta, Vittoria; Varano, Flavia; Filacchioni, Guido; Gratteri, Paola; Sgrignani, Jacopo; Galli, Alessandro; Costagli, Chiara

    2008-08-01

    In this paper, we report a study on some new 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylate derivatives (TQXs), bearing a nitrogen-containing heterocycle at position-9, and designed as (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. These compounds ensue from the structural modification of previously reported 8-heteroaryl-TQXs which were endowed with high affinity and selectivity for the AMPA receptor. All the newly synthesized compounds were biologically evaluated for their binding at the AMPA receptor. Gly/N-methyl-D-aspartic acid (NMDA) and kainic acid (KA) high-affinity binding assays were performed to assess the selectivity of the reported derivatives toward the AMPA receptor. This study produced some new TQXs which are less potent than the reference compounds, and endowed with a mixed AMPA and Gly/NMDA receptor binding affinity. To rationalize the experimental findings, a molecular modeling study was performed by docking some TQX derivatives to the AMPA receptor model. PMID:18670107

  14. Distribution of 3-hydroxy iC17:0 in subgingival plaque and gingival tissue samples: relationship to adult periodontitis.

    PubMed

    Nichols, F C

    1994-09-01

    Gram-negative organisms incorporate hydroxy fatty acids into the lipid A moiety of lipopolysaccharide (LPS), and in the case of some members of the family Enterobacteriaceae, hydroxy fatty acids are incorporated exclusively into lipid A. However, a limited number of Bacteroides species have been shown to incorporate several classes of 3-hydroxy fatty acids, particularly 3-hydroxy iC17:0, into constitutive lipids as well as LPS. The present study examined the distribution of hydroxy fatty acids in two periodontal pathogens, Prevotella intermedia and Porphyromonas gingivalis, by employing a phospholipid extraction procedure (E. G. Bligh and W. J. Dyer, Can. J. Biochem. Physiol. 37:911-917, 1959) which partitioned constitutive lipids into the organic solvent phase and LPS into the aqueous phase. The distribution of hydroxy fatty acids within organic solvent and aqueous extracts of these bacterial species was then compared with the distribution in subgingival plaque samples isolated from either gingivitis or severe periodontitis sites as well as the distribution in gingival tissue samples. The organic solvent and aqueous extracts were hydrolyzed under strong alkaline conditions, and the free fatty acids were treated to form pentafluorobenzyl-ester, trimethylsilyl-ether derivatives. Hydroxy fatty acid levels were quantified by using gas chromatography-negative-ion chemical ionization-mass spectrometry. By using this approach, the mean values of the 3-hydroxy iC17:0 recovered within organic solvent extracts of P. gingivalis strains ranged from 56 to 63% of total 3-hydroxy iC17:0. Substantially less 3-hydroxy iC17:0 (< 5%) was recovered in organic solvent extracts of P. intermedia. By comparison, 75% of the 3-hydroxy iC17:0 in periodontitis subgingival plaque samples was recovered in organic solvent extracts, while only 43% of the 3-hydroxy iC17:0 in gingivitis plaque samples from the same patients was recovered in organic solvent extracts. However, 3-hydroxy iC17:0 was

  15. 7-Chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-Dioxide as Positive Allosteric Modulator of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor. The End of the Unsaturated-Inactive Paradigm?

    PubMed

    Citti, Cinzia; Battisti, Umberto M; Cannazza, Giuseppe; Jozwiak, Krzysztof; Stasiak, Natalia; Puja, Giulia; Ravazzini, Federica; Ciccarella, Giuseppe; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino; Zoli, Michele

    2016-02-17

    5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-PAMs) have received particular attention in the past decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemize in physiological conditions, and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable to that of the parent compound. Molecular modeling studies were performed to rationalize these results. Furthermore, mice cerebral microdialysis studies suggest that 2 is able to cross the blood-brain barrier and increases acetylcholine and serotonin levels in the hippocampus. The experimental data disclose that the achiral hepatic metabolite 2 possesses the same pharmacological activity of its parent compound 1 but with an enhanced chemical and stereochemical stability, as well as an improved pharmacokinetic profile compared with 1. PMID:26580317

  16. Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria.

    PubMed

    Dos Santos Mello, Mariana; Ribas, Graziela Schmitt; Wayhs, Carlos Alberto Yasin; Hammerschmidt, Tatiane; Guerreiro, Gilian Batista Balbueno; Favenzani, Jéssica Lamberty; Sitta, Ângela; de Moura Coelho, Daniella; Wajner, Moacir; Vargas, Carmen Regla

    2015-04-01

    3-hydroxy-3-methylglutaric aciduria (HMGA; OMIM 246450) is a rare autosomal recessive disorder, caused by the deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (4.1.3.4), which results in the accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Recent in vivo and in vitro animal studies have demonstrated that the accumulation of these metabolites can disturb the cellular redox homeostasis, which can contribute to the neurological manifestations presented by the patients. So, in the present work, we investigated oxidative stress parameters in plasma and urine samples from HMGA patients, obtained at the moment of diagnosis of this disorder and during therapy with low-protein diet and L-carnitine supplementation. It was verified that untreated HMGA patients presented higher levels of urinary di-tyrosine and plasma thiobarbituric acid-reactive substances (TBA-RS), which are markers of protein and lipid oxidative damage, respectively, as well as a reduction of the urinary antioxidant capacity. Treated HMGA patients also presented an increased protein oxidative damage, as demonstrated by their higher concentrations of plasma protein carbonyl groups and urinary di-tyrosine, as well as by the reduction of total sulfhydryl groups in plasma, in relation to controls. On the other hand, HMGA patients under therapy presented normal levels of TBA-RS and urinary antioxidant capacity, which can be related, at least in part, to the antioxidant and antiperoxidative effects exerted by L-carnitine. The results of this work are the first report showing that a redox imbalance occurs in patients with HMGA what reinforces the importance of the antioxidant therapy in this disorder. PMID:25557019

  17. Novel 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes to investigate structure/activity relationships.

    PubMed

    Rangel, Maria; Amorim, M João; Nunes, Ana; Leite, Andreia; Pereira, Eulália; de Castro, Baltazar; Sousa, Carla; Yoshikawa, Yutaka; Sakurai, Hiromu

    2009-04-01

    A previous evaluation of the insulin-like activity of three 3-hydroxy-4-pyridinonato oxidovanadium(IV) complexes raised questions about structure/activity relationships, namely the influence of the hydrophilic/lipophilic balance of the complex and the capacity of the ligand to stabilize the +4 oxidation state of vanadium ion, on achieving an positive effect. To address these questions, we synthesized six new oxidovanadium(IV) complexes with variable hydrophilic/lipophilic balance, obtained by introducing different substituents on the nitrogen atom, and used two 3-hydroxy-4-pyrones as starting reagents to provide methyl and ethyl groups in the ortho position of the ring. For the new and previously reported complexes, we studied the oxidation-reduction properties and insulin-like activity in terms of inhibitory effect on Free fatty acid (FFA) release in isolated rat adipocytes. The results obtained show that only one of the complexes, Bis(3-hydroxy-1(H)-2-methyl-4-pyridonato)oxidovanadium(IV), VO(mpp)(2), exhibits a significantly greater capacity to inhibit FFA release than VOSO(4) and consequently is worthy to be considered for further studies. The establishment of structure activity relationships was not attainable but this study brings new information about the influence of some properties of the compounds on the achievement of an insulin-like effect. The results reveal that: (i) the oxidation-reduction cycles of the complexes are identical; (ii) the presence of more lipophilic substituents on the nitrogen atom does not enhance insulin-like properties; (iii) a high solubility in water proved to be not sufficient for a positive activity in inhibiting FFA release; (iv) a small molecular size may be an important property for reaching the right targets. PMID:19195710

  18. Residues of carbosulfan and its metabolites carbofuran and 3-hydroxy carbofuran in rice field ecosystem in China.

    PubMed

    Zhang, Chang P; He, Hong M; Yu, Jian Z; Hu, Xiu Q; Zhu, Ya H; Wang, Qiang

    2016-06-01

    The fate of carbosulfan (seed treatment dry powder) was studied in rice field ecosystem, and a simple and reliable analytical method was developed for determination of carbosulfan, carbofuran, and 3-hydroxyl carbofuran in brown rice, rice straw, paddy water, and soil. The target compounds were extracted using acetonitrile or dichloromethane, cleaned up on acidic alumina or florisil solid phase extraction (SPE) cartridge, and analyzed by gas chromatography. The average recoveries of carbosulfan, carbofuran and 3-hydroxy carbofuran in brown rice, rice straw, paddy water, and soil ranged from 72.71% to 105.07%, with relative standard deviations of 2.00-8.80%. The limits of quantitation (LOQs) of carbosulfan, carbofuran and 3-hydroxy carbofuran in the samples (brown rice, rice straw, paddy water and soil) were 0.011, 0.0091, 0.014, 0.010 mg kg(-1), 0.016, 0.019, 0.025, 0.013 mg kg(-1), and 0.031, 0.039, 0.035, 0.036 mg kg(-1), respectively. The trials results showed that the half-lives of carbosulfan, carbofuran and 3-hydroxy carbofuran in rice straw were 4.0, 2.6 days, 3.9, 6.0 days, and 5.8, 7.0 days in Zhejiang and Hunan, respectively. Carbosulfan, carbofuran and 3-hydroxy carbofuran were detected in soils. Carbosulfan and 3-hydroxy carbofuran were almost undetectable in paddy water. Carbofuran was detected in paddy water. The final residues of carbosulfan, carbofuran and 3-hydroxy carbofuran in brown rice were lower than 0.05 mg kg(-1), which were lower than 0.5 mg kg(-1) (MRL of carbosulfan) or 0.1 mg kg(-1) (MRL of carbofuran). Therefore, a dosage of 420 g active ingredient per 100 kg seed was recommended, which could be considered as safe to human beings and animals. These would contribute to provide the scientific basis of using this insecticide. PMID:26963425

  19. New polyhydroxylated flavon-3-ols and 3-hydroxy-2-styrylchromones: synthesis and ROS/RNS scavenging activities.

    PubMed

    Sousa, Joana L C; Proença, Carina; Freitas, Marisa; Fernandes, Eduarda; Silva, Artur M S

    2016-08-25

    New polyhydroxylated flavon-3-ols and 3-hydroxy-2-styrylchromones were prepared and assessed as reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavengers. The synthetic strategy involved the preparation of 2'-hydroxychalcones and 2'-hydroxycinnamylidenoacetophenones from base-catalyzed aldol reaction of appropriate 2'-hydroxyacetophenones and benzaldehydes/cinnamaldehydes, followed by an Algar-Flynn-Oyamada (AFO) reaction to give the polyalkoxy(flavon-3-ols and 3-hydroxy-2-styrylchromones). The last step of this synthetic route consisted in the cleavage of the protecting groups affording the expected polyhydroxylated derivatives. The present work consisted in the study of the in vitro scavenging activities of the synthetized compounds against the most physiologically relevant ROS [superoxide radical (O2(-)), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen ((1)O2) and peroxyl radical (ROO)] and RNS [nitric oxide (NO) and peroxynitrite anion (ONOO(-))]. Generally, all the tested new polyhydroxylated flavon-3-ols and 3-hydroxy-2-styrylchromones exhibited scavenging effects dependent on the concentration, and with IC50 values found within the micromolar range. This work allowed the establishment of new structure-activity relationships and brought the knowledge about the selective choice of a structure depending on the targeted reactive species. PMID:27213247

  20. Structures of deepoxytrichothecene metabolites from 3'-hydroxy HT-2 toxin and T-2 tetraol in rats.

    PubMed Central

    Yoshizawa, T; Sakamoto, T; Kuwamura, K

    1985-01-01

    3'-Hydroxy HT-2 toxin and T-2 tetraol, in vivo metabolites of T-2 toxin, were orally administered to Wistar rats, and four metabolites having a trichothec-9,12-diene nucleus, which were termed deepoxytrichothecenes, were newly found in the excreta. Their structures were confirmed as 3'-hydroxy-deepoxy HT-2, 3'-hydroxy-deepoxy T-2 triol, 15-acetyl-deepoxy T-2 tetraol, and deepoxy T-2 tetraol on the basis of mass and nuclear magnetic resonance spectroscopy. Resolution of T-2 metabolites and corresponding deepoxytrichothecenes by gas-liquid and thin-layer chromatography was also described. PMID:4073895

  1. 40 CFR 180.296 - Dimethyl phosphate of 3-hydroxy-N-methyl-cis-crotonamide; tolerances for residues.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 23 2010-07-01 2010-07-01 false Dimethyl phosphate of 3-hydroxy-N... RESIDUES IN FOOD Specific Tolerances § 180.296 Dimethyl phosphate of 3-hydroxy-N-methyl-cis-crotonamide... phosphate of 3-hydroxy-N-methyl-cis-crotonamide in or on the following raw agricultural...

  2. Synthesis, Characterization, and Cu(2+) Coordination Studies of a 3-Hydroxy-4-pyridinone Aza Scorpiand Derivative.

    PubMed

    López-Martínez, Luis M; Pitarch-Jarque, Javier; Martínez-Camarena, Àlvar; García-España, Enrique; Tejero, Roberto; Santacruz-Ortega, Hisila; Navarro, Rosa-Elena; Sotelo-Mundo, Rogerio R; Leyva-Peralta, Mario Alberto; Doménech-Carbó, Antonio; Verdejo, Begoña

    2016-08-01

    The synthesis, acid-base behavior, and Cu(2+) coordination chemistry of a new ligand (L1) consisting of an azamacrocyclic core appended with a lateral chain containing a 3-hydroxy-2-methyl-4(1H)-pyridinone group have been studied by potentiometry, cyclic voltammetry, and NMR and UV-vis spectroscopy. UV-vis and NMR studies showed that phenolate group was protonated at the highest pH values [log K = 9.72(1)]. Potentiometric studies point out the formation of Cu(2+) complexes of 1:2, 2:2, 4:3, 1:1, and 2:1 Cu(2+)/L1 stoichiometries. UV-vis analysis and electrochemical studies evidence the implication of the pyridinone moieties in the metal coordination of the 1:2 Cu(2+)/L1 complexes. L1 shows a stronger chelating ability than the reference chelating ligand deferiprone. While L1 shows no cytotoxicity in HeLa and ARPE-19 human cell lines (3.1-25.0 μg/mL), it has significant antioxidant activity, as denoted by TEAC assays at physiological pH. The addition of Cu(2+) diminishes the antioxidant activity because of its coordination to the pyridinone moiety phenolic group. PMID:27433814

  3. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis.

    PubMed Central

    Hegardt, F G

    1999-01-01

    Cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthases were first recognized as different chemical entities in 1975, when they were purified and characterized by Lane's group. Since then, the two enzymes have been studied extensively, one as a control site of the cholesterol biosynthetic pathway and the other as an important control site of ketogenesis. This review describes some key developments over the last 25 years that have led to our current understanding of the physiology of mitochondrial HMG-CoA synthase in the HMG-CoA pathway and in ketogenesis in the liver and small intestine of suckling animals. The enzyme is regulated by two systems: succinylation and desuccinylation in the short term, and transcriptional regulation in the long term. Both control mechanisms are influenced by nutritional and hormonal factors, which explains the incidence of ketogenesis in diabetes and starvation, during intense lipolysis, and in the foetal-neonatal and suckling-weaning transitions. The DNA-binding properties of the peroxisome-proliferator-activated receptor and other transcription factors on the nuclear-receptor-responsive element of the mitochondrial HMG-CoA synthase promoter have revealed how ketogenesis can be regulated by fatty acids. Finally, the expression of mitochondrial HMG-CoA synthase in the gonads and the correction of auxotrophy for mevalonate in cells deficient in cytosolic HMG-CoA synthase suggest that the mitochondrial enzyme may play a role in cholesterogenesis in gonadal and other tissues. PMID:10051425

  4. Novel 1-Phenyl-3-hydroxy-4-pyridinone Derivatives as Multifunctional Agents for the Therapy of Alzheimer's Disease.

    PubMed

    Sheng, Rong; Tang, Li; Jiang, Liu; Hong, Lingjuan; Shi, Ying; Zhou, Naiming; Hu, Yongzhou

    2016-01-20

    A series of novel 1-phenyl-3-hydroxy-4-pyridinone derivatives were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy through incorporation of 3-hydroxy-4-pyridinone moiety from deferiprone into the scaffold of H3 receptor antagonists. Most of these new compounds displayed designed quadruple functions, H3 receptor antagonism, Aβ aggregation inhibition, metal ion chelation, and radical scavenging. Especially, the most promising compound 5c displayed nanomolar IC50 values in H3 receptor antagonism with high selectivity, efficient capability to interrupt the formation of Aβ(1-42) fibrils, good copper and iron chelating properties, and more potent 2,2'-azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS(•+)) scavenging activity than Trolox. Further biological evaluation revealed that it did not show obvious cytotoxicity and hERG potassium channel inhibition at micromolar concentration. In addition, compound 5c demonstrated suitable pharmacokinetic properties and acceptable blood-brain barrier (BBB) permeability in vivo. All these results indicate that compound 5c is a potential multifunctional candidate for AD therapy. PMID:26479744

  5. Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity in Human Fibroblasts by Lipoproteins

    PubMed Central

    Brown, Michael S.; Dana, Suzanna E.; Goldstein, Joseph L.

    1973-01-01

    The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34), the rate-limiting enzyme of hepatic cholesterol biosynthesis, is suppressed in human fibroblasts cultured in the presence of serum. This enzyme activity increases by more than 10-fold after the removal of serum from the medium. The rise in enzyme activity requires de novo protein synthesis and is not accompanied by changes in the activities of several other cellular enzymes. The factor responsible for the suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured fibroblasts is present in the sera of at least four mammalian species, and in human serum it is found in the low-density lipoproteins. Human high-density lipoproteins, very low-density lipoproteins from chicken egg yolk, and the fraction of human serum containing no lipoproteins do not suppress the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. PMID:4352976

  6. Quantitative determination of LSD and a major metabolite, 2-oxo-3-hydroxy-LSD, in human urine by solid-phase extraction and gas chromatography-tandem mass spectrometry.

    PubMed

    Reuschel, S A; Percey, S E; Liu, S; Eades, D M; Foltz, R L

    1999-09-01

    An assay has been developed for quantitative determination of lysergic acid diethylamide (LSD) and a major metabolite of LSD in human urine at concentrations as low as 10 pg/mL. In most LSD-positive urine samples the metabolite, 2-oxo-3-hydroxy-LSD, is present at higher concentrations than LSD and can be detected for a longer time than LSD after ingestion of the drug. Urine samples are extracted using Varian Bond Elut Certify extraction cartridges. Confirmatory identification is accomplished by trimethylsilylation of LSD and 2-oxo-3-hydroxy-LSD, followed by gas chromatography-tandem mass spectrometry analysis using positive ion chemical ionization and selected reaction monitoring. Commercially available lysergic acid methylpropylamide and 2-oxo-3-hydroxy-LAMPA are used as internal standards. With selected reaction monitoring, both compounds gave linear calibration curves from 10 pg/mL to 5000 pg/mL. Forty-nine human urine samples that had previously been shown to contain LSD were reanalyzed by the new method. These samples showed an average LSD concentration of 357 pg/mL and an average 2-oxo-3-hydroxy-LSD concentration of 3470 pg/mL. Additional experiments using clinical samples in which two subjects were dosed with LSD support the conclusion that analysis for 2-oxo-3-hydroxy-LSD can permit identification of LSD users for a longer period following ingestion than analysis for the parent drug. PMID:10488916

  7. Uncovering novel 3-hydroxy-4-pyridinone metal ion complexes with potential anti-inflammatory properties.

    PubMed

    Chisté, Renan Campos; Ribeiro, Daniela; Freitas, Marisa; Leite, Andreia; Moniz, Tânia; Rangel, Maria; Fernandes, Eduarda

    2016-02-01

    Ligands of the 3-hydroxy-4-pyridinone (3,4-HPO) type, with one (Hmpp) or two methyl groups (Hdmpp), have been reported to possess biomedical, chemical and analytical applications. In this first screening study aiming to uncover new promising agents to mitigate the oxidative damage highly present in several metabolic disorders, such as diabetes mellitus, we assessed the potential of twelve 3,4-HPO metal ion complexes to modulate oxidative burst in human neutrophils. Metal ion 3,4-HPO complexes of Ni, Fe, V, Co, Cu and Zn were synthesized and tested up to 15μM. Among all the compounds, [Cu(mpp)2] and [Cu(dmpp)2] exhibited the highest scavenging capacity against superoxide radical (O2(-)) (IC50=0.36±0.07 and 0.30±0.06μM, respectively) and against hypochlorous acid (HOCl) (IC50=0.6±0.3 and 0.4±0.1μM, respectively). In the particular case of O2(-), [Fe(mpp)3] and [Fe(dmpp)3] (both at 15μM) presented 35% and 22% of inhibition, respectively, while all the other compounds were neither able to scavenge O2(-) nor stimulate its production. Regarding the scavenging capacity against hydrogen peroxide (H2O2), all the compounds showed low efficiency (from 6-39%). Finally, with exception of [VO(mpp)2] and [VO(dmpp)2], all compounds exhibited scavenging activity against HOCl (39-81%) and the most efficient compounds were Cu(II) and Zn(II) complexes. Thus, these preliminary results uncover promising new metal ion complexes, inhibitors of neutrophil's oxidative burst, with potential anti-inflammatory properties, which may be seen as an useful strategy for further studies in the treatment of a number of diseases where oxidative damage is a serious issue. PMID:26606288

  8. Formation of Isobutene from 3-Hydroxy-3-Methylbutyrate by Diphosphomevalonate Decarboxylase▿

    PubMed Central

    Gogerty, David S.; Bobik, Thomas A.

    2010-01-01

    Isobutene is an important commercial chemical used for the synthesis of butyl rubber, terephthalic acid, specialty chemicals, and a gasoline performance additive known as alkylate. Currently, isobutene is produced from petroleum and hence is nonrenewable. Here, we report that the Saccharomyces cerevisiae mevalonate diphosphate decarboxylase (ScMDD) can convert 3-hydroxy-3-methylbutyrate (3-HMB) to isobutene. Whole cells of Escherichia coli producing ScMDD with an N-terminal 6×His tag (His6-ScMDD) formed isobutene from 3-HMB at a rate of 154 pmol h−1 g cells−1. In contrast, no isobutene was detected from control cells lacking ScMDD. His6-ScMDD was purified by nickel affinity chromatography and shown to produce isobutene from 3-HMB at a rate of 1.33 pmol min−1 mg−1 protein. Controls showed that both His6-ScMDD and 3-HMB were required for detectable isobutene formation. Isobutene was identified by gas chromatography (GC) with flame ionization detection as well as by GC-mass spectrometry (MS). ScMDD was subjected to error-prone PCR, and two improved variants were characterized, ScMDD1 (I145F) and ScMDD2 (R74H). Whole cells of E. coli producing ScMDD1 and ScMDD2 produced isobutene from 3-HMB at rates of 3,000 and 5,888 pmol h−1 g cells−1, which are 19- and 38-fold increases compared to rates for cells producing His6-ScMDD. This showed that genetic modifications can be used to increase the rate at which ScMDD converts 3-HMB to isobutene. Because 3-HMB can be produced from l-leucine, ScMDD has a potential application for the production of renewable isobutene. Moreover, isobutene is a gas, which might simplify its purification from a fermentation medium, substantially reducing production costs. PMID:20971863

  9. Central and peripheral antinociceptive activity of 3-(2-oxopropyl)-3-hydroxy-2-oxindoles.

    PubMed

    Giorno, Thais Biondino Sardella; Ballard, Yáskara L L; Cordeiro, Millena Santos; Silva, Bárbara V; Pinto, Angelo C; Fernandes, Patricia Dias

    2015-08-01

    Convolutamydine A has been shown to develop a significant antinociceptive effect. Here we demonstrated that new analogues (5-iodo-3-(2-oxopropyl)-3-hydroxy-2-oxindole (5-Iisa), 5-fluoro-3-(2-oxopropyl)-3-hydroxy-2-oxindole (5-Fisa), 5-chloro-3-(2-oxopropyl)-3-hydroxy-2-oxindole (5-Clisa) and 5-methyl-3-(2-oxopropyl)-3-hydroxy-2-oxindole (5-Meisa)), at 0.1-10mg/kg doses, have significant peripheral and central antinociceptive effects in thermal and chemical models of nociception. Oral administered analogues demonstrated more pronounced antinociceptive effects than that obtained with the classical opioid drug morphine (5mg/kg) in the first and second phases of formalin-induced licking. In the tail flick model, 5-Clisa and 5-Meisa antinociceptive effect was almost twice as that observed with the same dose of morphine. The concomitant administration of diverse antagonists and the analogues indicates that 5-Iisa effects involve the activation of opioid pathway. On the other hand, 5-Fisa and 5-Clisa have the participation of opioid, nitrergic, cholinergic adrenergic and serotoninergic pathways and 5-Meisa has the involvement of opioid, serotoninergic and cholinergic pathways. In conclusion, our results suggest that the new four analogues from Convolutamydine A have significant antinociceptive effects in thermal and chemical induced nociception and could be used in development of new drugs to be used in pain treatment with reduced side effects. PMID:25989045

  10. Discovery of 3-Hydroxy-3-phenacyloxindole Analogues of Isatin as Potential Monoamine Oxidase Inhibitors.

    PubMed

    Tripathi, Rati K P; Krishnamurthy, Sairam; Ayyannan, Senthil R

    2016-01-01

    A series of 3-hydroxy-3-phenacyloxindole analogues of isatin were designed, synthesized, and evaluated in vitro for their inhibitory activity toward monoamine oxidase (MAO) A and B. Most of the synthesized compounds proved to be potent and selective inhibitors of MAO-A rather than MAO-B. 1-Benzyl-3-hydroxy-3-(4'-hydroxyphenacyl)oxindole (compound 18) showed the highest MAO-A inhibitory activity (IC50 : 0.009 ± 0.001 μM, Ki : 3.69 ± 0.003 nM) and good selectivity (selectivity index: 60.44). Kinetic studies revealed that compounds 18 and 16 (1-benzyl-3-hydroxy-3-(4'-bromophenacyl)oxindole) exhibit competitive inhibition against MAO-A and MAO-B, respectively. Structure-activity relationship studies suggested that the 3-hydroxy group is an essential feature for these analogues to exhibit potent MAO-A inhibitory activity. Computational studies revealed the possible molecular interactions between the inhibitors and MAO isozymes. The computational data obtained are congruent with experimental results. Further studies on the lead inhibitors, including co-crystallization of inhibitor-MAO complexes and in vivo evaluations, are essential for their development as potential therapeutic agents for the treatment of MAO-associated neurological disorders. PMID:26592797

  11. Reaction pathways for the thermal decomposition of methyl butanoate.

    PubMed

    Akbar Ali, Mohamad; Violi, Angela

    2013-06-21

    In recent years, biodiesel fuels, consisting of long-chain alkyl (methyl, ethyl, propyl) esters, have emerged as viable alternatives to petroleum-based fuels. From a combustion chemistry standpoint, there is great interest in developing accurate reaction models for these new molecules that can be used to predict their behaviors in various regimes. In this paper, we report a detailed study of the unimolecular decomposition pathways of methyl butanoate (MB), a short-chain ester that contains the basic chemical structure of biodiesel fuels. Using ab initio/DFT methods, we identified five homolytic fissions of C-C and C-O bonds and five hydrogen transfer reactions. Rate constants were determined using the G3B3 theory coupled with both variational transition state theory and Rice-Ramsperger-Kassel-Marcus/master equation simulations with hindered rotation corrections. Branching ratios in the temperature range 1500-2200 K indicate that the main pathway for thermal decomposition of MB is the reaction CH3CH2CH2C(═O)OCH3 → C2H5 + CH2C(═O)OCH3. The results, in terms of reaction pathways and rate constants, can be used for future development of mechanisms for long alkyl-chain esters. PMID:23679139

  12. Metabolism of sinapic acid and related compounds in the rat

    PubMed Central

    Griffiths, L. A.

    1969-01-01

    1. Administration of sinapic acid to the rat results in the excretion of 3-hydroxy-5-methoxyphenylpropionic acid, dihydrosinapic acid, 3-hydroxy-5-methoxycinnamic acid and unchanged sinapic acid in the urine. The sinapic acid conjugate sinalbin is also catabolized to free sinapic acid and 3-hydroxy-5-methoxyphenylpropionic acid in the rat. 2. 3,4,5-Trimethoxycinnamic acid is metabolized in part to sinapic acid and 3-hydroxy-5-methoxyphenylpropionic acid. 3. 3,5-Dimethoxycinnamic acid is metabolized to 3-hydroxy-5-methoxycinnamic acid and 3-hydroxy-5-methoxyphenylpropionic acid. 4. The metabolic interrelationships of these compounds were studied by the administration of intermediates and a metabolic pathway is proposed. 5. The metabolism of the corresponding benzoic acids was studied, but these compounds and their metabolites were shown not to be intermediates or products of the metabolism of the related cinnamic acids. PMID:5386182

  13. Metabolism of sinapic acid and related compounds in the rat.

    PubMed

    Griffiths, L A

    1969-07-01

    1. Administration of sinapic acid to the rat results in the excretion of 3-hydroxy-5-methoxyphenylpropionic acid, dihydrosinapic acid, 3-hydroxy-5-methoxycinnamic acid and unchanged sinapic acid in the urine. The sinapic acid conjugate sinalbin is also catabolized to free sinapic acid and 3-hydroxy-5-methoxyphenylpropionic acid in the rat. 2. 3,4,5-Trimethoxycinnamic acid is metabolized in part to sinapic acid and 3-hydroxy-5-methoxyphenylpropionic acid. 3. 3,5-Dimethoxycinnamic acid is metabolized to 3-hydroxy-5-methoxycinnamic acid and 3-hydroxy-5-methoxyphenylpropionic acid. 4. The metabolic interrelationships of these compounds were studied by the administration of intermediates and a metabolic pathway is proposed. 5. The metabolism of the corresponding benzoic acids was studied, but these compounds and their metabolites were shown not to be intermediates or products of the metabolism of the related cinnamic acids. PMID:5386182

  14. Crystallization and diffraction data of 1H-3-hydroxy-4-oxoquinoline 2,4-dioxygenase: a cofactor-free oxygenase of the α/β-hydrolase family

    SciTech Connect

    Qi, Ruhu; Fetzner, Susanne; Oakley, Aaron J.

    2007-05-01

    Preliminary crystallographic data for 1H-3-hydroxy-4-oxoquinoline 2,4-dioxygenase from P. putida 33/1 are reported. 1H-3-Hydroxy-4-oxoquinoline 2,4-dioxygenase (QDO) from Pseudomonas putida 33/1 catalyses the oxygenolysis of 1H-3-hydroxy-4-oxoquinoline to form N-formylanthranilic acid and carbon monoxide without the aid of cofactors. Both N-terminally His{sub 6}-tagged and native QDO were overexpressed in Escherichia coli and purified by conventional chromatographic procedures. Untagged QDO, but not His{sub 6}-tagged QDO, was crystallized by the vapour-diffusion method, giving hexagonal bipyramid crystals belonging to space group P6{sub 1}22. Selenomethionine-containing native QDO was prepared and crystallized under identical conditions. The unit-cell parameters were a = b = 90.1, c = 168.6 Å, α = β = 90, γ = 120°. Using synchrotron radiation, these crystals diffract to 2.5 Å. The expression, purification and crystallization of QDO are reported here.

  15. 3-Hydroxy-3-methylglutaric aciduria with bilateral basal ganglia lesion: A case report

    PubMed Central

    HAO, XIAOSHENG; WANG, JIANGTAO; LIU, SONGYAN; CHEN, YINBO; ZHANG, YAN; HAO, YUNPENG

    2016-01-01

    3-Hydroxy-3-methylglutaric aciduria (3-HMG, OMIN 246450) is a rare autosomal recessive metabolic disorder caused by a deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase, a key enzyme in leucine metabolism and ketone body synthesis. Acute episodes of 3-HMG may be triggered by fasting or infection, and symptoms include vomiting, diarrhea, lethargy and hypotonia. If left untreated, prolonged hypoglycemia and metabolic acidosis may cause breathing problems, seizures, and coma. In addition, 3-HMG is associated with damage to the central nervous system, and there are several reports of white matter abnormality or cerebral atrophy. The presence of bilateral basal ganglia damage in 3-HMG has been rarely reported. Here, we present a case report of a 20-month old male with severe 3-HMG and prominent bilateral lesions in the basal ganglia. PMID:27284350

  16. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: effects on cholesterol balance.

    PubMed Central

    Grundy, S M; Bilheimer, D W

    1984-01-01

    Patients with heterozygous familial hypercholesterolemia (FH) have a deficiency of receptors for plasma low-density lipoprotein (LDL) that impairs removal of LDL from plasma. In these patients, mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase [mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88], increases receptors for LDL and decreases LDL concentrations. To determine whether mevinolin also causes severe decreases in total body synthesis of cholesterol, fecal excretions of neutral steroids and acidic steroids were determined in five FH heterozygotes before and during treatment with mevinolin. The drug produced an average decrease in plasma total cholesterol of 23% and in LDL cholesterol of 24%. Mevinolin caused a significant decrease in the output of neutral and acidic steroids in three patients, but it caused no alterations in two others. Changes in fecal output of steroids did not correlate with the degree of lowering of the patients' LDL-cholesterol level. In none of the patients did the output of fecal steroids fall below the values seen in normal subjects studied under similar conditions. One patient had a previous ileal exclusion operation and had a massive output of acidic steroids in the control period; mevinolin therapy caused a slight decrease in excretion of acidic steroids, but the output was still markedly above normal. We conclude that the LDL lowering action of mevinolin does not appear to require a severe decrease in cholesterol synthesis that might lead to depletion of vital body stores of cholesterol. PMID:6371816

  17. A unique cis-3-hydroxy-l-proline dehydratase in the enolase superfamily.

    PubMed

    Zhang, Xinshuai; Kumar, Ritesh; Vetting, Matthew W; Zhao, Suwen; Jacobson, Matthew P; Almo, Steven C; Gerlt, John A

    2015-02-01

    The genome of Labrenzia aggregata IAM 12614 encodes an uncharacterized member of the muconate lactonizing enzyme (MLE) subgroup of the enolase superfamily (UniProt ID A0NXQ8 ). The gene encoding A0NXQ8 is located between genes that encode members of the proline racemase superfamily, 4R-hydroxyproline 2-epimerase (UniProt ID A0NXQ7 ; 4HypE) and trans-3-hydroxy-l-proline dehydratase (UniProt ID A0NXQ9 ; t3LHypD). A0NXQ8 was screened with a library of proline analogues; two reactions were observed with cis-3-hydroxy-l-proline (c3LHyp), competing 2-epimerization to trans-3-hydroxy-d-proline (1,1-proton transfer) and dehydration to Δ(1)-pyrroline-2-carboxylate (β-elimination; c3LHyp dehydratase), with eventual total dehydration. The genome context encoding A0NXQ8 both (1) confirms its novel c3LHyp dehydratase function and (2) provides evidence for metabolic pathways that allow L. aggregata to utilize several isomeric 3- and 4-hydroxyprolines as sole carbon sources. PMID:25608448

  18. Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells.

    PubMed

    Sacher, Julia; Weigl, Lukas; Werner, Martin; Szegedi, Csaba; Hohenegger, Martin

    2005-09-01

    The 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are widely used and well tolerated cholesterol-lowering drugs. In rare cases, side effects occur in skeletal muscle, including myositis or even rhabdomyolysis. However, the molecular mechanisms are not well understood that lead to these muscle-specific side effects. Here, we show that statins cause apoptosis in differentiated human skeletal muscle cells. The prototypical representative of statins, simvastatin, triggered sustained intracellular Ca(2+) transients, leading to calpain activation. Intracellular chelation of Ca(2+) completely abrogated cell death. Moreover, ryanodine also completely prevented the simvastatin-induced calpain activation. Nevertheless, an activation of the ryanodine receptor by simvastatin could not be observed. Downstream of the calpain activation simvastatin led to a translocation of Bax to mitochondria in a caspase 8-independent manner. Consecutive activation of caspase 9 and 3 execute apoptotic cell death that was in part reversed by the coadministration of mevalonic acid. Conversely, the simvastatin-induced activation of calpain was not prevented by mevalonic acid. These data delineate the signaling cascade that leads to muscle injury caused by statins. Our observations also have implications for improving the safety of this important medication and explain to some extent why physical exercise aggravates skeletal muscle side effects. PMID:15914674

  19. Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)*

    PubMed Central

    Sharpe, Laura J.; Brown, Andrew J.

    2013-01-01

    3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the target of the statins, important drugs that lower blood cholesterol levels and treat cardiovascular disease. Consequently, the regulation of HMGCR has been investigated in detail. However, this enzyme acts very early in the cholesterol synthesis pathway, with ∼20 subsequent enzymes needed to produce cholesterol. How they are regulated is largely unexplored territory, but there is growing evidence that enzymes beyond HMGCR serve as flux-controlling points. Here, we introduce some of the known regulatory mechanisms affecting enzymes beyond HMGCR and highlight the need to further investigate their control. PMID:23696639

  20. 3-hydroxy 3-methylglutaryl coenzyme A reductase: a new biomarker of fish exposure to water pollution.

    PubMed

    Pallottini, Valentina; Scalici, Massimiliano; Gibertini, Giancarlo; Marino, Maria; Trentalance, Anna

    2010-10-01

    The aim of this study was to identify a new putative biomarker in Salmo trutta exposed to water pollution. Variations in the levels of hepatic 3-hydroxy 3-methylglutaryl Coenzyme A reductase (HMG-CoAR), the rate-limiting enzyme of cholesterol biosynthesis, were compared to heat shock protein 70 and hypoxia inducible factor α, biomarkers of pollution exposure and lowered O₂, respectively. The results confirm that HMG-CoAR levels increase in polluted water irrespective of water temperature or O₂ content, indicating that HMG-CoAR could be used as a specific biomarker for water pollution. PMID:20835703

  1. Synthesis of New Bis(3-hydroxy-4-pyridinone) Ligands as Chelating Agents for Uranyl Complexation.

    PubMed

    Jin, Bo; Zheng, Rongzong; Peng, Rufang; Chu, Shijin

    2016-01-01

    Five new bis(3-hydroxy-4-pyridinone) tetradentate chelators were synthesized in this study. The structures of these tetradentate chelators were characterized by ¹H-NMR, (13)C-NMR, FT-IR, UV-vis, and mass spectral analyses. The binding abilities of these tetradentate chelators for uranyl ion at pH 7.4 were also determined by UV spectrophotometry in aqueous media. Results showed that the efficiencies of these chelating agents are dependent on the linker length. Ligand 4b is the best chelator and suitable for further studies. PMID:27005598

  2. Genome-Based Analysis and Gene Dosage Studies Provide New Insight into 3-Hydroxy-4-Methylvalerate Biosynthesis in Ralstonia eutropha

    PubMed Central

    Ushimaru, Kazunori; Mizuno, Shoji

    2015-01-01

    Recombinant Ralstonia eutropha strain PHB−4 expressing the broad-substrate-specificity polyhydroxyalkanoate (PHA) synthase 1 from Pseudomonas sp. strain 61-3 (PhaC1Ps) synthesizes a PHA copolymer containing the branched side-chain unit 3-hydroxy-4-methylvalerate (3H4MV), which has a carbon backbone identical to that of leucine. Mutant strain 1F2 was derived from R. eutropha strain PHB−4 by chemical mutagenesis and shows higher levels of 3H4MV production than does the parent strain. In this study, to understand the mechanisms underlying the enhanced production of 3H4MV, whole-genome sequencing of strain 1F2 was performed, and the draft genome sequence was compared to that of parent strain PHB−4. This analysis uncovered four point mutations in the 1F2 genome. One point mutation was found in the ilvH gene at amino acid position 36 (A36T) of IlvH. ilvH encodes a subunit protein that regulates acetohydroxy acid synthase III (AHAS III). AHAS catalyzes the conversion of pyruvate to 2-acetolactate, which is the first reaction in the biosynthesis of branched amino acids such as leucine and valine. Thus, the A36T IlvH mutation may show AHAS tolerance to feedback inhibition by branched amino acids, thereby increasing carbon flux toward branched amino acid and 3H4MV biosynthesis. Furthermore, a gene dosage study and an isotope tracer study were conducted to investigate the 3H4MV biosynthesis pathway. Based on the observations in these studies, we propose a 3H4MV biosynthesis pathway in R. eutropha that involves a condensation reaction between isobutyryl coenzyme A (isobutyryl-CoA) and acetyl-CoA to form the 3H4MV carbon backbone. PMID:25645560

  3. Genome-based analysis and gene dosage studies provide new insight into 3-hydroxy-4-methylvalerate biosynthesis in Ralstonia eutropha.

    PubMed

    Saika, Azusa; Ushimaru, Kazunori; Mizuno, Shoji; Tsuge, Takeharu

    2015-04-01

    Recombinant Ralstonia eutropha strain PHB(-)4 expressing the broad-substrate-specificity polyhydroxyalkanoate (PHA) synthase 1 from Pseudomonas sp. strain 61-3 (PhaC1Ps) synthesizes a PHA copolymer containing the branched side-chain unit 3-hydroxy-4-methylvalerate (3H4MV), which has a carbon backbone identical to that of leucine. Mutant strain 1F2 was derived from R. eutropha strain PHB(-)4 by chemical mutagenesis and shows higher levels of 3H4MV production than does the parent strain. In this study, to understand the mechanisms underlying the enhanced production of 3H4MV, whole-genome sequencing of strain 1F2 was performed, and the draft genome sequence was compared to that of parent strain PHB(-)4. This analysis uncovered four point mutations in the 1F2 genome. One point mutation was found in the ilvH gene at amino acid position 36 (A36T) of IlvH. ilvH encodes a subunit protein that regulates acetohydroxy acid synthase III (AHAS III). AHAS catalyzes the conversion of pyruvate to 2-acetolactate, which is the first reaction in the biosynthesis of branched amino acids such as leucine and valine. Thus, the A36T IlvH mutation may show AHAS tolerance to feedback inhibition by branched amino acids, thereby increasing carbon flux toward branched amino acid and 3H4MV biosynthesis. Furthermore, a gene dosage study and an isotope tracer study were conducted to investigate the 3H4MV biosynthesis pathway. Based on the observations in these studies, we propose a 3H4MV biosynthesis pathway in R. eutropha that involves a condensation reaction between isobutyryl coenzyme A (isobutyryl-CoA) and acetyl-CoA to form the 3H4MV carbon backbone. PMID:25645560

  4. The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

    PubMed

    Ravid, T; Doolman, R; Avner, R; Harats, D; Roitelman, J

    2000-11-17

    3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), the key regulatory enzyme in the mevalonate (MVA) pathway, is rapidly degraded in mammalian cells supplemented with sterols or MVA. This accelerated turnover was blocked by N-acetyl-leucyl-leucyl-norleucinal (ALLN), MG-132, and lactacystin, and to a lesser extent by N-acetyl-leucyl-leucyl-methional (ALLM), indicating the involvement of the 26 S proteasome. Proteasome inhibition led to enhanced accumulation of high molecular weight polyubiquitin conjugates of HMGR and of HMGal, a chimera between the membrane domain of HMGR and beta-galactosidase. Importantly, increased amounts of polyubiquitinated HMGR and HMGal were observed upon treating cells with sterols or MVA. Cycloheximide inhibited the sterol-stimulated degradation of HMGR concomitantly with a marked reduction in polyubiquitination of the enzyme. Inhibition of squalene synthase with zaragozic acid blocked the MVA- but not sterol-stimulated ubiquitination and degradation of HMGR. Thus, similar to yeast, the ubiquitin-proteasome pathway is involved in the metabolically regulated turnover of mammalian HMGR. Yet, the data indicate divergence between yeast and mammals and suggest distinct roles for sterol and nonsterol metabolic signals in the regulated ubiquitination and degradation of mammalian HMGR. PMID:10964918

  5. Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer.

    PubMed

    Wei, Tzu-Tang; Lin, Yi-Ting; Chen, Wen-Shu; Luo, Ping; Lin, Yu-Chin; Shun, Chia-Tung; Lin, Yi-Hsin; Chen, Jhih-Bin; Chen, Nai-Wei; Fang, Jim-Min; Wu, Ming-Shiang; Yang, Kai-Chien; Chang, Li-Chun; Tai, Kang-Yu; Liang, Jin-Tung; Chen, Ching-Chow

    2016-08-01

    Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and Apc(Min/+) CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC. PMID:27448759

  6. Differential activation of potato 3-hydroxy-3-methylglutaryl coenzyme A reductase genes by wounding and pathogen challenge.

    PubMed Central

    Yang, Z; Park, H; Lacy, G H; Cramer, C L

    1991-01-01

    Potato genes encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) were expressed in response to pathogen, elicitor, and wounding. HMGR catalyzes the rate-limiting step in isoprenoid biosynthesis leading to accumulation of phytoalexins and steroid glycoalkaloids. Wounding caused increases in HMGR mRNA levels. A rapid and transient peak occurred 30 minutes after wounding, followed by a slower peak at 14 hours; both were correlated with increased enzyme activity. Induction of HMGR mRNA by the soft rot pathogen Erwinia carotovora subsp carotovora or arachidonic acid began 8 hours after challenge and continued through 22 hours. Potato HMGR is encoded by a gene family. An HMGR gene-specific probe was used to demonstrate that one isogene of the HMGR family is pathogen activated and is distinct from isogene(s) that are wound activated. This provides evidence that defense-related increases in HMGR activity are due to mRNA level increases and that HMGR isogenes are activated differentially by wounding or pathogen challenge. PMID:1840919

  7. Surface-active novel glycolipid and linked 3-hydroxy fatty acids produced by Serratia rubidaea.

    PubMed Central

    Matsuyama, T; Kaneda, K; Ishizuka, I; Toida, T; Yano, I

    1990-01-01

    A Serratia rubidaea isolate with wetting activity when grown at 30 but not 37 degrees C was examined for the production of specific lipids. Two novel lipids (rubiwettins R1 and RG1) were isolated and shown to be able to lower the surface tension of saline to 26 mN/m. These lipids were located in extracellular vesicles found in a 30 degrees C culture of S. rubidaea. Chemical structures of these biosurfactants were determined by degradation product analyses, infrared spectroscopy, mass spectrometry, and proton nuclear magnetic resonance spectroscopy. Rubiwettin R1 was proposed to be a mixture of 3-(3'-hydroxytetradecanoyloxy)decanoate, 3-(3'-hydroxyhexadecenoyloxy)decanoate, and minor molecular isomers. The structure of rubiwettin RG1 was proposed to be beta-D-glucopyranosyl 3-(3'-hydroxytetradecanoyloxy)decanoate. The importance of such surface-active exolipids in bacterial occupancy on surfaces was suggested. Images PMID:2345132

  8. Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.

    PubMed

    Dragovich, Peter S; Fauber, Benjamin P; Boggs, Jason; Chen, Jinhua; Corson, Laura B; Ding, Charles Z; Eigenbrot, Charles; Ge, HongXiu; Giannetti, Anthony M; Hunsaker, Thomas; Labadie, Sharada; Li, Chiho; Liu, Yichin; Liu, Yingchun; Ma, Shuguang; Malek, Shiva; Peterson, David; Pitts, Keith E; Purkey, Hans E; Robarge, Kirk; Salphati, Laurent; Sideris, Steve; Ultsch, Mark; VanderPorten, Erica; Wang, Jing; Wei, BinQing; Xu, Qing; Yen, Ivana; Yue, Qin; Zhang, Huihui; Zhang, Xuying; Zhou, Aihe

    2014-08-15

    A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 μM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 μM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%). PMID:25037916

  9. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase modulator: toward age- and sex-personalized medicine.

    PubMed

    Pallottini, Valentina

    2015-01-01

    Cholesterol homeostasis maintenance is regulated by a cellular feedback system that senses cholesterol amount in cellular membranes. 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGR) plays a pivotal role in cholesterol metabolism as it is the key rate-limiting enzyme of its biosynthetic pathway; its inhibition provokes a feedback response capable of reducing plasma cholesterol content. HMGR inhibition is a keystone in the treatment and prevention of cardiovascular disease and, therefore, statins (HMGR inhibitors) are widely prescribed even though they may sometimes induce side effects. These drugs are prescribed indifferently to both man and women even if there are several well-known differences in cholesterol metabolism depending on the gender and the age. Thus, gender-related differences in cholesterol metabolism should be taken into account to identify new targets for customized pharmacological treatments for hypercholesterolemia. PMID:26135220

  10. Experimental and chemical kinetic modeling study of small methyl esters oxidation: Methyl (E)-2-butenoate and methyl butanoate

    SciTech Connect

    Gail, S.; Sarathy, S.M.; Thomson, M.J.; Dievart, P.; Dagaut, P.

    2008-12-15

    This study examines the effect of unsaturation on the combustion of fatty acid methyl esters (FAME). New experimental results were obtained for the oxidation of methyl (E)-2-butenoate (MC, unsaturated C{sub 4} FAME) and methyl butanoate (MB, saturated C{sub 4} FAME) in a jet-stirred reactor (JSR) at atmospheric pressure under dilute conditions over the temperature range 850-1400 K, and two equivalence ratios ({phi}=0.375,0.75) with a residence time of 0.07 s. The results consist of concentration profiles of the reactants, stable intermediates, and final products, measured by probe sampling followed by on-line and off-line gas chromatography analyses. The oxidation of MC and MB in the JSR and under counterflow diffusion flame conditions was modeled using a new detailed chemical kinetic reaction mechanism (301 species and 1516 reactions) derived from previous schemes proposed in the literature. The laminar counterflow flame and JSR (for {phi}=1.13) experimental results used were from a previous study on the comparison of the combustion of both compounds. Sensitivity analyses and reaction path analyses, based on rates of reaction, were used to interpret the results. The data and the model show that MC has reaction pathways analogous to that of MB under the present conditions. The model of MC oxidation provides a better understanding of the effect of the ester function on combustion, and the effect of unsaturation on the combustion of fatty acid methyl ester compounds typically found in biodiesel. (author)

  11. Use of polyurethane foam and 3-hydroxy-7,8-benzo-1,2,3,4-tetrahydroquinoline for determination of nitrite by diffuse reflectance spectroscopy and colorimetry.

    PubMed

    Apyari, V V; Dmitrienko, S G; Ostrovskaya, V M; Anaev, E K; Zolotov, Y A

    2008-07-01

    Polyurethane foam (PUF) has been suggested as a solid polymeric reagent for determination of nitrite. The determination is based on the diazotization of end toluidine groups of PUF with nitrite in acidic medium followed by coupling of polymeric diazonium cation with 3-hydroxy-7,8-benzo-1,2,3,4-tetrahydroquinoline. The intensely colored polymeric azodye formed in this reaction can be used as a convenient analytic form for the determination of nitrite by diffuse reflectance spectroscopy (c (min) = 0.7 ng mL(-1)). The possibility of using a desktop scanner, digital camera, and computer data processing for the numerical evaluation of the color intensity of the polymeric azodye has been investigated. A scanner and digital camera can be used for determination of nitrite with the same sensitivity and reproducibility as with diffuse reflectance spectroscopy. The approach developed was applied for determination of nitrite in river water and human exhaled breath condensate. PMID:18431561

  12. Metabolically Regulated Endoplasmic Reticulum-associated Degradation of 3-Hydroxy-3-methylglutaryl-CoA Reductase

    PubMed Central

    Leichner, Gil S.; Avner, Rachel; Harats, Dror; Roitelman, Joseph

    2011-01-01

    In mammalian cells, the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), which catalyzes the rate-limiting step in the mevalonate pathway, is ubiquitylated and degraded by the 26 S proteasome when mevalonate-derived metabolites accumulate, representing a case of metabolically regulated endoplasmic reticulum-associated degradation (ERAD). Here, we studied which mevalonate-derived metabolites signal for HMGR degradation and the ERAD step(s) in which these metabolites are required. In HMGR-deficient UT-2 cells that stably express HMGal, a chimeric protein between β-galactosidase and the membrane region of HMGR, which is necessary and sufficient for the regulated ERAD, we tested inhibitors specific to different steps in the mevalonate pathway. We found that metabolites downstream of farnesyl pyrophosphate but upstream to lanosterol were highly effective in initiating ubiquitylation, dislocation, and degradation of HMGal. Similar results were observed for endogenous HMGR in cells that express this protein. Ubiquitylation, dislocation, and proteasomal degradation of HMGal were severely hampered when production of geranylgeranyl pyrophosphate was inhibited. Importantly, inhibition of protein geranylgeranylation markedly attenuated ubiquitylation and dislocation, implicating for the first time a geranylgeranylated protein(s) in the metabolically regulated ERAD of HMGR. PMID:21778231

  13. Anti-hepatitis C virus activity of 3-hydroxy caruilignan C from Swietenia macrophylla stems.

    PubMed

    Wu, S-F; Lin, C-K; Chuang, Y-S; Chang, F-R; Tseng, C-K; Wu, Y-C; Lee, J-C

    2012-05-01

    Chronic hepatitis C virus (HCV) infection ultimately leads to chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma (HCC). As the standard treatment is not completely efficacious, a safer and more effective agent against HCV infection needs to be developed. In this report, we demonstrated that 3-hydroxy caruilignan C (3-HCL-C) isolated from Swietenia macrophylla stems exhibited high anti-HCV activity at both protein and RNA levels at nontoxic concentrations, with an EC(50) value of 10.5 ± 1.2 μm. Combinations of 3-HCL-C and interferon-α (IFN-α), an HCV NS5B polymerase inhibitor (2'-C-methylcytidine; NM-107) or an HCV NS3/4A protease inhibitor (Telaprevir; VX-950) increased the suppression of HCV RNA replication. The results suggested that 3-HCL-C may be a potential anti-viral agent. We then demonstrated that 3-HCL-C interfered with HCV replication by inducing IFN-stimulated response element transcription and IFN-dependent anti-viral gene expression. PMID:22497816

  14. Organotin Compound Derived from 3-Hydroxy-2-formylpyridine Semicarbazone: Synthesis, Crystal Structure, and Antiproliferative Activity

    PubMed Central

    Wiecek, Joanna; Kovala-Demertzi, Dimitra; Ciunik, Zbigniew; Wietrzyk, Joanna; Zervou, Maria; Demertzis, Mavroudis A.

    2010-01-01

    The novel diphenyltin(IV) compound [Ph2(HyFoSc)Sn] (2), where H2HyFoSc (1) is 3-hydroxy-2-formylpyridine semicarbazone, was prepared and characterized by vibrational and NMR (1H, 13C) spectroscopy. The structure of [Ph2(HyFoSc)Sn] was confirmed by single-crystal X-ray crystallography. The doubly deprotonated ligand is coordinated to the tin atom through the enolic-oxygen, the azomethine-nitrogen, and phenolic-oxygen, and so acts as an anionic tridentate ligand with the ONO donors. Two carbon atoms complete the fivefold coordination at the tin(IV) center. Intermolecular hydrogen bonding, C–H → π, and π → π interactions combine to stabilize the crystal structure. Compounds 1 and 2 have been evaluated for antiproliferative activity in vitro against the cells of three human tumor cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A549 (nonsmall cell lung carcinoma), and a mouse fibroblast L-929 cancer cell line. PMID:20490260

  15. The management of pregnancy and delivery in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

    PubMed

    Pipitone, Angela; Raval, Donna B; Duis, Jessica; Vernon, Hilary; Martin, Regina; Hamosh, Ada; Valle, David; Gunay-Aygun, Meral

    2016-06-01

    3-hydroxy-3-methylglutaric (HMG)-CoA lyase is required for ketogenesis and leucine degradation. Patients with HMG-CoA lyase deficiency typically present with hypoketotic hypoglycemia and metabolic acidosis, which can be fatal if untreated. The patient is a 28-year-old female with HMG-CoA lyase deficiency who presented at 4 weeks gestation for prenatal care. Protein intake as well as carnitine supplementation were gradually increased to support maternal and fetal demands up to 65 g per day for protein and 80 mg/kg/day for carnitine. Fetal growth was appropriate. At 36 5/7 weeks, she presented with spontaneous rupture of membranes. Twice maintenance 10% glucose-containing intravenous fluids were initiated. During labor, vomiting and metabolic acidosis developed. Delivery was by cesarean. Preeclampsia developed postpartum. The patient recovered well and was discharged home on postpartum day 5. Stress of pregnancy and labor and delivery can lead to metabolic decompensation in HMG-CoA lyase deficiency. Patients should be monitored closely by a biochemical geneticist, dietitian, and high-risk obstetrician at a tertiary care center during their pregnancy. Fasting should be avoided. Intravenous 10% glucose-containing fluids should be provided to prevent catabolism and metabolic decompensation during labor and delivery. © 2016 Wiley Periodicals, Inc. PMID:26997609

  16. The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis

    PubMed Central

    Profant, Deborah A.; Roberts, Christopher J.; Koning, Ann J.; Wright, Robin L.

    1999-01-01

    In all cells examined, specific endoplasmic reticulum (ER) membrane arrays are induced in response to increased levels of the ER membrane protein 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase. In yeast, expression of Hmg1p, one of two yeast HMG-CoA reductase isozymes, induces assembly of nuclear-associated ER stacks called karmellae. Understanding the features of HMG-CoA reductase that signal karmellae biogenesis would provide useful insights into the regulation of membrane biogenesis. The HMG-CoA reductase protein consists of two domains, a multitopic membrane domain and a cytosolic catalytic domain. Previous studies had indicated that the HMG-CoA reductase membrane domain was exclusively responsible for generation of ER membrane proliferations. Surprisingly, we discovered that this conclusion was incorrect: sequences at the carboxyl terminus of HMG-CoA reductase can profoundly affect karmellae biogenesis. Specifically, truncations of Hmg1p that removed or shortened the carboxyl terminus were unable to induce karmellae assembly. This result indicated that the membrane domain of Hmg1p was not sufficient to signal for karmellae assembly. Using β-galactosidase fusions, we demonstrated that the carboxyl terminus was unlikely to simply serve as an oligomerization domain. Our working hypothesis is that a truncated or misfolded cytosolic domain prevents proper signaling for karmellae by interfering with the required tertiary structure of the membrane domain. PMID:10512876

  17. Anticonvulsant and Toxicological Evaluation of Parafluorinated/Chlorinated Derivatives of 3-Hydroxy-3-ethyl-3-phenylpropionamide

    PubMed Central

    Garrido-Acosta, Osvaldo; Meza-Toledo, Sergio E.; Anguiano-Robledo, Liliana; Soriano-Ursúa, Marvin A.; Correa-Basurto, José; Davood, Asghar; Chamorro-Cevallos, Germán

    2016-01-01

    Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets—GABAA receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor. PMID:27006945

  18. Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in mouse peritoneal macrophages.

    PubMed Central

    Angelin, B

    1988-01-01

    The lipoprotein-mediated regulation of 3-hydroxy-3-methylglutaryl-(HMG-) CoA reductase in cultured mouse peritoneal macrophages has been investigated. In contrast to what has been reported for other cells, HMG-CoA reductase activity is not suppressed by normal serum or by normal low density lipoproteins (LDL) from humans or dogs. Suppression of reductase activity occurred when cells were cultured in the presence of beta-migrating very low density lipoproteins (beta-VLDL) or LDL from hypercholesterolaemic dogs, or LDL modified by acetoacetylation. Human beta-VLDL from an atypical type III hyperlipoproteinaemic patient was also effective, as was apolipoprotein (apo) E-containing high density lipoproteins (HDL) from cholesterol-fed dogs (apo-E HDLc). The results indicate that cholesterol biosynthesis in mouse peritoneal macrophages is regulated by lipoprotein cholesterol entering via receptor-mediated endocytosis. Normal LDL were not effective because of the poor binding and uptake of these lipoproteins by the apo-B, E (LDL) receptor. Only beta-VLDL, apo-E HDLc, and hypercholesterolaemic LDL were avidly taken up by this receptor and were able to suppress HMG-CoA reductase. Acetoacetylated LDL were internalized via the acetyl-LDL (scavenger) receptor. Thus, mouse macrophages differ from human fibroblasts and smooth muscle cells in their physiological regulation of cholesterogenesis. PMID:3202831

  19. Theoretical study on the molecular tautomerism of the 3-hydroxy-pyridin-4-one system

    NASA Astrophysics Data System (ADS)

    Zborowski, Krzysztof K.; Mohammadpour, Mehrdad; Sadeghi, Amir; Proniewicz, Leonard M.

    2013-04-01

    3-hydroxy-pyridin-4-one is a parent molecule for the family of hydroxypyridinones that are known in coordination chemistry as efficient metal ions chelators. In this work, relative stabilities of some possible tautomers were investigated using several quantum chemical methods: CBS (complete basis set methods), Gn, DFT (density functional theory), Hartree-Fock and MP2. Performed calculations show that the system under consideration exists as a mixture of two tautomers with comparable energies. Among them, the hydroxypyridinone structure of the studied molecular system seems to be a bit more stable than the o-dihydroxypyridine one, by a few kJ/mol only. Aromaticity and intra-molecular hydrogen bonding are the main effects influencing the stability of the studied tautomeric structures. Consequently, aromatic effects were calculated using several indices of aromaticity: HOMA (harmonic oscillator model of aromaticity), NICS (nucleus independent chemical shift), H, PDI (para delocalisation index), MCI (multi-centre index) and ASE (aromatic stabilisation energy). The strength of possible intra-molecular hydrogen bonds (H-bonds) was determined by means of the AIM (atoms-in-molecules) method and by calculating enthalpies for theoretical reactions that do or do not involve H-bonds. The AIM method was employed to understand how variations in atomic energies influence the stability of different tautomeric structures.

  20. 40 CFR 180.318 - 4-(2-Methyl-4-chlorophenoxy) butyric acid; tolerance for residues.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... established for the combined residues, free and conjugated, of the herbicide MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid, and its metabolite MCPA, (4-chloro-2-methylphenoxy)acetic acid, in or on the following...

  1. Subcellular Localization of Arabidopsis 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase1

    PubMed Central

    Leivar, Pablo; González, Víctor M.; Castel, Susanna; Trelease, Richard N.; López-Iglesias, Carmen; Arró, Montserrat; Boronat, Albert; Campos, Narciso; Ferrer, Albert; Fernàndez-Busquets, Xavier

    2005-01-01

    Plants produce diverse isoprenoids, which are synthesized in plastids, mitochondria, endoplasmic reticulum (ER), and the nonorganellar cytoplasm. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) catalyzes the synthesis of mevalonate, a rate-limiting step in the cytoplasmic pathway. Several branches of the pathway lead to the synthesis of structurally and functionally varied, yet essential, isoprenoids. Several HMGR isoforms have been identified in all plants examined. Studies based on gene expression and on fractionation of enzyme activity suggested that subcellular compartmentalization of HMGR is an important intracellular channeling mechanism for the production of the specific classes of isoprenoids. Plant HMGR has been shown previously to insert in vitro into the membrane of microsomal vesicles, but the final in vivo subcellular localization(s) remains controversial. To address the latter in Arabidopsis (Arabidopsis thaliana) cells, we conducted a multipronged microscopy and cell fractionation approach that included imaging of chimeric HMGR green fluorescent protein localizations in transiently transformed cell leaves, immunofluorescence confocal microscopy in wild-type and stably transformed seedlings, immunogold electron microscopy examinations of endogenous HMGR in seedling cotyledons, and sucrose density gradient analyses of HMGR-containing organelles. Taken together, the results reveal that endogenous Arabidopsis HMGR is localized at steady state within ER as expected, but surprisingly also predominantly within spherical, vesicular structures that range from 0.2- to 0.6-μm diameter, located in the cytoplasm and within the central vacuole in differentiated cotyledon cells. The N-terminal region, including the transmembrane domain of HMGR, was found to be necessary and sufficient for directing HMGR to ER and the spherical structures. It is believed, although not directly demonstrated, that these vesicle-like structures are derived from segments of HMGR

  2. 3-Hydroxy-2-butanone and the first encounter fight in the male lobster cockroach, Nauphoeta cinerea

    NASA Astrophysics Data System (ADS)

    Kou, Rong; Chen, Shu-Chun; Chen, Ying-Ru; Ho, Hsiao-Yung

    2006-06-01

    Although agonistic behavior in the male lobster cockroach, Nauphoeta cinerea, has been known for more than 40 years, this is the first study to directly collect and quantify the emitted pheromones. In the present study, emitted volatile pheromones were collected from each male pair for 60 min during the first encounter fight and identified and quantified by gas chromatography mass spectrometry. The major compound collected was 3-hydroxy-2-butanone (3H-2B). The strength of the attack by the dominant male was classified into three categories from weakest (C) to strongest (A). Of the 92 pairs, eight (8.7%) showed no agonistic interactions, and the amount of 3H-2B collected was 121.8±37.7 ng/male pair. In the five pairs (5.4%) displaying attack strength C, the amount of 3H-2B collected was 689.6±273.7 ng/male pair, and the attack duration was 9.6±2.4 min. In the 53 pairs (57.6%) showing attack strength B, the corresponding values were 5396.2±449.0 ng/male pair and 22.7±1.6 min, while those for the 26 pairs (28.3%) showing attack strength A were 7910.4±1120.6 ng/male pair and 24.9±2.9 min. For both attack strengths A and B, a linear relationship was found between the amount of 3H-2B collected and attack duration, suggesting that the longer the duration of the attack, the more 3H-2B was emitted. In addition, the rate of 3H-2B emission for attack strength A was significantly higher than that for attack strength B. Using Vaseline-coating, we demonstrated that, in the first encounter fight, the 3H-2B was emitted by the dominant male.

  3. Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an enzyme of isopentenyl diphosphate biosynthesis.

    PubMed

    Sutherlin, Autumn; Hedl, Matija; Sanchez-Neri, Barbara; Burgner, John W; Stauffacher, Cynthia V; Rodwell, Victor W

    2002-08-01

    Biosynthesis of the isoprenoid precursor isopentenyl diphosphate (IPP) proceeds via two distinct pathways. Sequence comparisons and microbiological data suggest that multidrug-resistant strains of gram-positive cocci employ exclusively the mevalonate pathway for IPP biosynthesis. Bacterial mevalonate pathway enzymes therefore offer potential targets for development of active site-directed inhibitors for use as antibiotics. We used the PCR and Enterococcus faecalis genomic DNA to isolate the mvaS gene that encodes 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, the second enzyme of the mevalonate pathway. mvaS was expressed in Escherichia coli from a pET28 vector with an attached N-terminal histidine tag. The expressed enzyme was purified by affinity chromatography on Ni(2+)-agarose to apparent homogeneity and a specific activity of 10 micromol/min/mg. Analytical ultracentrifugation showed that the enzyme is a dimer (mass, 83.9 kDa; s(20,w), 5.3). Optimal activity occurred in 2.0 mM MgCl(2) at 37(o)C. The DeltaH(a) was 6,000 cal. The pH activity profile, optimum activity at pH 9.8, yielded a pK(a) of 8.8 for a dissociating group, presumably Glu78. The stoichiometry per monomer of acetyl-CoA binding was 1.2 +/- 0.2 and that of covalent acetylation was 0.60 +/- 0.02. The K(m) for the hydrolysis of acetyl-CoA was 10 microM. Coupled conversion of acetyl-CoA to mevalonate was demonstrated by using HMG-CoA synthase and acetoacetyl-CoA thiolase/HMG-CoA reductase from E. faecalis. PMID:12107122

  4. The Ralstonia solanacearum pathogenicity regulator HrpB induces 3-hydroxy-oxindole synthesis.

    PubMed

    Delaspre, Fabien; Nieto Peñalver, Carlos G; Saurel, Olivier; Kiefer, Patrick; Gras, Emmanuel; Milon, Alain; Boucher, Christian; Genin, Stéphane; Vorholt, Julia A

    2007-10-01

    The transcriptional activator HrpB of the bacterial wilt causing betaproteobacterium Ralstonia solanacearum represents a key regulator for pathogenicity. In particular, it drives expression of hrp genes encoding a type III secretion system (T3SS) as well as effector molecules for delivery into the host cytosol to promote disease. However, the HrpB regulon extends beyond this T3SS. We describe here an HrpB-activated operon of six genes that is responsible for the synthesis of a fluorescent isatin derivative of 149 Amu that we named HDF for HrpB-dependent factor and that we purified from culture supernatants. The structure of the labile molecule was solved by using NMR and CD spectroscopy to be (3S)-3-hydroxy-indolin-2-one and confirmed by its chemical synthesis and MS spectrometry. HDF was found to be present at 20 nM in wild-type cultures grown on minimal medium, and its synthesis increased 15-fold upon overproduction of HrpB, confirming that HrpB activates HDF synthesis. The addition of tryptophan significantly stimulated HDF biosynthesis and was shown to represent the precursor molecule for HDF synthesis. A search for the biological function of the molecule revealed that HDF induces acyl-homoserine lactone receptor-mediated reporter activity of the well studied LuxR transcriptional regulator of Vibrio fischeri. Thus, our results provide evidence that the specificity of acyl-homoserine lactone (acyl-HSL) receptors is clearly broader than previously considered. The failure to detect induction by HDF of the described endogenous quorum-sensing circuits of the pathogen points to a role in interfering with cell-cell signaling of rivalling bacteria. PMID:17890323

  5. 3-Hydroxy-4-pyridinone derivatives designed for fluorescence studies to determine interaction with amyloid protein as well as cell permeability.

    PubMed

    Telpoukhovskaia, Maria A; Cawthray, Jacqueline F; Rodríguez-Rodríguez, Cristina; Scott, Lauren E; Page, Brent D G; Patrick, Brian O; Orvig, Chris

    2015-09-01

    Finding a cure for Alzheimer's disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL21) and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL22). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood-brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting. PMID:26141772

  6. Atypical expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in subcutaneous adipose tissue of male rats.

    PubMed

    Thumelin, S; Kohl, C; Girard, J; Pégorier, J P

    1999-06-01

    The mRNAs encoding mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mtHMG-CoA synthase), the rate limiting enzyme in ketone body production, are highly expressed in subcutaneous (SC) and, to a lesser extent, in peri-epididymal (PE) rat adipose tissues. This atypical mtHMG-CoA synthase gene expression is dependent on the age (from 9 weeks of age) and sex (higher in male than in female) of the rats. In contrast, the expression of mtHMG-CoA synthase in SC adipose deposit is independent of the nutritional state (fed versus starved) or of the thermic environment (24 degrees C versus 4 degrees C). The expression of mtHMG-CoA synthase is suppressed in SC fat pads of castrated male rats whereas treatment of castrated rats with testosterone restores a normal level of expression. Moreover, testosterone injection induces the expression mtHMG-CoA synthase in SC adipose tissue of age-matched females. The presence of the mtHMG-CoA synthase immunoreactive protein confers to mitochondria isolated from SC adipose deposits, the capacity to produce ketone bodies at a rate similar to that found in liver mitochondria (SC = 13.7 +/- 0.7, liver = 16.4 +/- 1.4 nmol/min/mg prot). mtHMG-CoA synthase is expressed in the stromal vascular fraction (SVF) whatever the adipose deposit considered. While acetyl-CoA carboxylase (ACC) is only expressed in mature adipocytes, the other lipogenic enzymes, fatty acid synthase (FAS) and citrate cleavage enzyme (CCE), are expressed both in SVF cells and mature adipocytes. The expression of lipogenic enzyme genes is markedly reduced in adipocytes but not in SVF cells isolated from 48-h starved male rats. When SVF is subfractionated, mtHMG-CoA synthase mRNAs are mainly recovered in two fractions containing poorly digested structures such as microcapillaries whereas the lowest expression is found in the pre-adipocyte fraction. Interestingly, FAS and CCE mRNAs co-segregate with mtHMG-CoA synthase mRNA. The possible physiological relevance of such

  7. Profiling and characterisation by liquid chromatography/multi-stage mass spectrometry of the chlorogenic acids in Gardeniae Fructus.

    PubMed

    Clifford, Michael N; Wu, Weiguo; Kirkpatrick, Jo; Jaiswal, Rakesh; Kuhnert, Nikolai

    2010-11-15

    The chlorogenic acids of Gardeniae Fructus used traditionally as a Chinese herbal medicine (zhizi) have been investigated qualitatively by liquid chromatography/multi-stage mass spectrometry (LC/MS(4)). Twenty-nine chlorogenic acids were detected and twenty-five characterised to regioisomer level on the basis of their fragmentation, twenty-four for the first time from this source. Assignment to the level of individual regioisomers was possible for three caffeoylquinic acids, three dicaffeoylquinic acids, three sinapoylquinic acids, four caffeoyl-sinapoylquinic acids, two feruloyl-sinapoylquinic acids, one p-coumaroyl-sinapoylquinic acid, three (3-hydroxy, 3-methyl)glutaroylquinic acids, two (3-hydroxy, 3-methyl)glutaroyl-feruloylquinic acids, one (3-hydroxy, 3-methyl)glutaroyl-dicaffeoylquinic acid, and one (3-hydroxy, 3-methyl)glutaroyl-caffeoyl-feruloylquinic acid. Six (3-hydroxy, 3-methyl)glutaroyl-caffeoylquinic acids were detected and two were tentatively assigned as 3-caffeoyl-4-(3-hydroxy, 3-methyl)glutaroylquinic acid and 3-caffeoyl-5-(3-hydroxy, 3-methyl)glutaroylquinic acid. The (3-hydroxy, 3-methyl)glutaroyl residue modifies the mass spectral fragmentation behavior and elution sequence compared with the chlorogenic acids that contain only a cinnamic acid residue(s). Fourteen of these twenty-nine chlorogenic acids have not previously been reported from any source. PMID:20941757

  8. Genetics Home Reference: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

    MedlinePlus

    ... body cannot process a particular protein building block ( amino acid ) called leucine. Additionally, the disorder prevents the body ... Specifically, it is responsible for processing leucine, an amino acid that is part of many proteins. HMG-CoA ...

  9. A Metal-free Approach to 3-Aryl-3-hydroxy-2-oxindoles by Treatment of 3-Acyloxy-2-oxindoles with Diaryliodonium Salts.

    PubMed

    Li, Xiaokang; Ni, Wei; Mao, Fei; Wang, Wei; Li, Jian

    2016-01-01

    A mild, metal-free approach has been realized for the facile construction of highly valuable 3-(hetero)aryl-3-hydroxy-2-oxindoles. Direct arylations of 3-acyloxy-2-oxindoles with diaryliodonium salts as arylation reagents are implemented in the presence of K2 CO3 at room temperature without using an organometallic promoter to deliver an array of 3-(hetero)aryl-3-hydroxy-2-oxindoles in good yields. PMID:26481872

  10. Characterization of a transient intermediate formed in the liver alcohol dehydrogenase catalyzed reduction of 3-hydroxy-4-nitrobenzaldehyde

    SciTech Connect

    MacGibbon, A.K.H.; Koerber, S.C.; Pease, K.; Dunn, M.F.

    1987-06-02

    The compounds 3-hydroxy-4-nitrobenzaldehyde and 3-hydroxy-4-nitrobenzyl alcohol are introduced as new chromophoric substrates for probing the catalytic mechanism of horse liver alcohol dehydrogenase (LADH). Ionization of the phenolic hydroxyl group shifts the spectrum of the aldehyde from 360 to 433 nm (pK/sub a/ = 6.0), whereas the spectrum of the alcohol shifts from 350 to 417 nm (pK/sub a/ = 6.9). Rapid-scanning, stopped-flow (RSSF) studies at alkaline pH show that the LADH-catalyzed interconversion of these compounds occurs via the formation of an enzyme-bound intermediate with a blue-shifted spectrum. When reaction is limited to a single turnover of enzyme sites, the formation and decay of the intermediate when aldehyde reacts with enzyme-bound reduced nicotinamide adenine dinucleotide E(NADH) are characterized by two relaxations. Detailed stopped-flow kinetic studies were carried out to investigate the disappearance of aldehyde and NADH, the formation and decay of the intermediate, the displacement of Auramine O by substrate, and /sup 2/H kinetic isotope effects. It was found that (1) NADH oxidation takes place at the rate of the slower relaxation (2) when NADD is substituted for NADH, lambda/sub s/ is subject to a small primary isotope effect; and (3) the events that occur in lambda/sub s/ precede lambda/sub f/. These findings identify the intermediate as a ternary complex containing bound oxidized nicotinamide adenine dinucleotide (NAD/sup +/) and some form of 3-hydroxy-4-nitrobenzyl alcohol. The authors conclude that the LADH substrate site can be divided into two subsites: a highly polar, electropositive subsite in the vicinity of the active-site zinc and, just a few angstroms away, a rather nonpolar region.

  11. Complexation of iron with the orally active decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone).

    PubMed

    Kline, M A; Orvig, C

    1992-04-01

    The stability constants for the Fe(III) complexes of the orally active iron decorporation drug L1 (3-hydroxy-1,2-dimethyl-4-pyridinone) have been determined by potentiometric titration [glass electrode, 25.0 degrees C, mu = 0.15 mol/L (isotonic) NaCl]. A simple computer model of blood plasma (citrate 100 mumol/L, transferrin 37 mumol/L) has been used to compare the Fe(III) binding efficacies in blood of L1 and the clinically used intravenously administered chelating agent deferoxamine. PMID:1568323

  12. Development and validation a LC-MS/MS method for the simultaneous determination of agomelatine and its metabolites, 7-desmethyl-agomelatine and 3-hydroxy-agomelatine in human plasma: Application to a bioequivalence study.

    PubMed

    Li, Meizhen; Tang, Fang; Xie, Feifan; Lv, Yisha; Yu, Peng; Liu, Zhi; Cheng, Zeneng

    2015-10-15

    A novel sensitive and selective LC-MS/MS method for the determination of agomelatine, 7-desmethyl-agomelatine and 3-hydroxy-agomelatine in human plasma was developed and validated. After simple protein precipitation, the analytes were separated on a Phenomenex ODS3 column (4.6×150 mm, 5μm, Phenomenex, USA) with mobile phase consisted of methanol and 5mM ammonium formate solution (containing 0.2% formic acid) at a ratio of 70:30 (v/v) with a flow rate of 0.8mL/min. The MS acquisition was performed in multiple reactions monitoring (MRM) mode with a positive electrospray ionization source. The mass transitions monitored were m/z 244.1→185.1, m/z 230.1→171.1, m/z 260.1→201.1 and m/z 180.1→110.1 for agomelatine, 7-desmethyl-agomelatine, 3-hydroxy-agomelatine and internal standard (phenacetin), respectively. The method was validated for specificity, linearity and lower limit of quantification, precision and accuracy, extraction recovery, matrix effect and stability. The calibration curves for agomelatine, 7-desmethyl-agomelatine and 3-hydroxy-agomelatine in human plasma were linear over concentration ranges of 0.0457-100ng/mL, 0.1372-300ng/mL and 0.4572-1000ng/mL, respectively. Intra- and inter-day precisions and accuracies data met the acceptance criteria of FDA guideline for bioanalytical method validation. The developed method has been successfully applied to a bioequivalence study in healthy Chinese volunteers. PMID:26409931

  13. Double layer structure-based virtual screening reveals 3'-Hydroxy-A-Naphthoflavone as novel inhibitor candidate of human acetylcholinesterase

    NASA Astrophysics Data System (ADS)

    Ichsan, Mochammad; Pangastuti, Ardini; Habibi, Mohammad Wildan; Juliana, Kartika

    2016-03-01

    One of the most effective target for Alzheimer's disease's (AD) treatment is the inhibition of human acetylcholinesterase (hAChE) eventhough it has many side effects. So that, this study was aimed to discover a new candidate of hAChE's inhibitor that has more negative binding affinity than existing drugs. hAChE's 3D model used in this study has a good quality according to its number of residues in most favoured regions (92%), three bad contacts, >50 ERRAT's score (85,870) and successfully passed the VERIFY 3D threshold (>80%). Based on the first layer of SBVS againts more than 12.180.630 ligands, we discovered 11.806 hits and then we found 359 hits from the second layer of SBVS. Based on our previous steps, we found that 3'-Hydroxy-a-Naphthoflavone was the only one candidate, that directly interacted with Trp286 via hydrogen bond and hydrophobic interactions and also has the most negative binding affinity (-10,6 kcal/mol) and also has more negative than existing hAChE's inhibitors, such as tacrine, donepezil, etc. 3'-Hydroxy-a-Naphthoflavone is the best candidate of hAChE's inhibitor based on its binding affinity (-10,6 kcal/mol) that is more negative than existing hAChE's inhibitors, such as tacrine, donepezil, etc.

  14. Up-regulation of an N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase enhances production of essential oils and sterols in transgenic Lavandula latifolia.

    PubMed

    Muñoz-Bertomeu, Jesús; Sales, Ester; Ros, Roc; Arrillaga, Isabel; Segura, Juan

    2007-11-01

    Spike lavender (Lavandula latifolia) essential oil is widely used in the perfume, cosmetic, flavouring and pharmaceutical industries. Thus, modifications of yield and composition of this essential oil by genetic engineering should have important scientific and commercial applications. We generated transgenic spike lavender plants expressing the Arabidopsis thaliana HMG1 cDNA, encoding the catalytic domain of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR1S), a key enzyme of the mevalonic acid (MVA) pathway. Transgenic T0 plants accumulated significantly more essential oil constituents as compared to controls (up to 2.1- and 1.8-fold in leaves and flowers, respectively). Enhanced expression of HMGR1S also increased the amount of the end-product sterols, beta-sitosterol and stigmasterol (average differences of 1.8- and 1.9-fold, respectively), but did not affect the accumulation of carotenoids or chlorophylls. We also analysed T1 plants derived from self-pollinated seeds of T0 lines that flowered after growing for 2 years in the greenhouse. The increased levels of essential oil and sterols observed in the transgenic T0 plants were maintained in the progeny that inherited the HMG1 transgene. Our results demonstrate that genetic manipulation of the MVA pathway increases essential oil yield in spike lavender, suggesting a contribution for this cytosolic pathway to monoterpene and sesquiterpene biosynthesis in leaves and flowers of the species. PMID:17714440

  15. Metabolic Control of Avocado Fruit Growth (Isoprenoid Growth Regulators and the Reaction Catalyzed by 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase).

    PubMed Central

    Cowan, A. K.; Moore-Gordon, C. S.; Bertling, I.; Wolstenholme, B. N.

    1997-01-01

    The effect of isoprenoid growth regulators on avocado (Persea americana Mill. cv Hass) fruit growth and mesocarp 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity was investigated during the course of fruit ontogeny. Both normal and small-fruit phenotypes were used to probe the interaction between the end products of isoprenoid biosynthesis and the activity of HMGR in the metabolic control of avocado fruit growth. Kinetic analysis of the changes in both cell number and size revealed that growth was limited by cell number in phenotypically small fruit. In small fruit a 70% reduction in microsomal HMGR activity was associated with an increased mesocarp abscisic acid (ABA) concentration. Application of mevastatin, a competitive inhibitor of HMGR, reduced the growth of normal fruit and increased mesocarp ABA concentration. These effects were reversed by co-treatment of fruit with mevalonic acid lactone, isopentenyladenine, or N-(2-chloro-4-pyridyl)-N-phenylurea, but were not significantly affected by either gibberellic acid or stigmasterol. However, stigmasterol appeared to partially restore fruit growth when co-injected with mevastatin in either phase II or III of fruit growth. In vivo application of ABA reduced fruit growth and mesocarp HMGR activity and accelerated fruit abscission, effects that were reversed by co-treatment with isopentenyladenine. Together, these observations indicate that ABA accumulation down-regulates mesocarp HMGR activity and fruit growth, and that in situ cytokinin biosynthesis modulates these effects during phase I of fruit ontogeny, whereas both cytokinins and sterols seem to perform this function during the later phases. PMID:12223724

  16. Purification and cloning of a proline 3-hydroxylase, a novel enzyme which hydroxylates free L-proline to cis-3-hydroxy-L-proline.

    PubMed Central

    Mori, H; Shibasaki, T; Yano, K; Ozaki, A

    1997-01-01

    Proline 3-hydroxylase was purified from Streptomyces sp. strain TH1, and its structural gene was cloned. The purified enzyme hydroxylated free L-proline to cis-3-hydroxy-L-proline and showed properties of a 2-oxoglutarate-dependent dioxygenase (H. Mori, T. Shibasaki, Y. Uosaki, K. Ochiai, and A. Ozaki, Appl. Environ. Microbiol, 62:1903-1907, 1996). The molecular mass of the purified enzyme was 35 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The isoelectric point of the enzyme was 4.3. The optimal pH and temperature were 7.0 and 35 degrees C, respectively. The K(m) values were 0.56 and 0.11 mM for L-proline and 2-oxoglutarate, respectively. The Kcat value of hydroxylation was 3.2 s-1. Determined N-terminal and internal amino acid sequences of the purified protein were not found in the SwissProt protein database. A DNA fragment of 74 bp was amplified by PCR with degenerate primers based on the determined N-terminal amino acid sequence. With this fragment as a template, a digoxigenin-labeled N-terminal probe was synthesized by PCR. A 6.5-kbp chromosome fragment was cloned by colony hybridization with the labeled probe. The determined DNA sequence of the cloned fragment revealed a 870-bp open reading frame (ORF 3), encoding a protein of 290 amino acids with a calculated molecular weight of 33,158. No sequence homolog was found in EMBL, GenBank, and DDBJ databases. ORF 3 was expressed in Escherichia coli DH1. Recombinants showed hydroxylating activity five times higher than that of the original bacterium, Streptomyces sp. strain TH1. It was concluded that the ORF 3 encodes functional proline 3-hydroxylase. PMID:9294421

  17. 3-Hydroxy-3-methylglutaryl CoA lyase (HL): Mouse and human HL gene (HMGCL) cloning and detection of large gene deletions in two unrelated HL-deficient patients

    SciTech Connect

    Wang, S.P.; Robert, M.F.; Mitchell, G.A.

    1996-04-01

    3-hydroxy-3-methylglutaryl CoA lyase (HL, EC 4.1.3.4) catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetic acid and acetyl CoA, the final reaction of both ketogenesis and leucine catabolism. Autosomal-recessive HL deficiency in humans results in episodes of hypoketotic hypoglycemia and coma. Using a mouse HL cDNA as a probe, we isolated a clone containing the full-length mouse HL gene that spans about 15 kb of mouse chromosome 4 and contains nine exons. The promoter region of the mouse HL gene contains elements characteristic of a housekeeping gene: a CpG island containing multiple Sp1 binding sites surrounds exon 1, and neither a TATA nor a CAAT box are present. We identified multiple transcription start sites in the mouse HL gene, 35 to 9 bases upstream of the translation start codon. We also isolated two human HL genomic clones that include HL exons 2 to 9 within 18 kb. The mouse and human HL genes (HGMW-approved symbol HMGCL) are highly homologous, with identical locations of intron-exon junctions. By genomic Southern blot analysis and exonic PCR, was found 2 of 33 HL-deficient probands to be homozygous for large deletions in the HL gene. 26 refs., 4 figs., 2 tabs.

  18. NMR and computational studies on tautomerism of 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one

    NASA Astrophysics Data System (ADS)

    Chans, Guillermo M.; Laura Moyano, E.; Baumgartner, María Teresa

    2014-02-01

    The tautomeric system of 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one 1 has been investigated by NMR spectroscopy between 224 and 298 K. At all temperatures an endocyclic enol tautomer was the major isomer; however, at low temperatures two other enol isomers were found. Conformational search of the potential energy surfaces of all tautomers of cyclohexenone 1 was also carried out. Extensive calculations were performed for two triketones and four cis-endocyclic double bond enol tautomers with the lowest energies. Syntheses of 3-methoxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one 2 and 2-benzoyl-3-hydroxycyclohex-2-en-1-one 3 were carried out to analyze the features of thienyl group rotation and structural differences with a symmetrical substituent, respectively.

  19. Studies on the growth and characterization of a non linear optical crystal: 3 Hydroxy Pyridinium Tartrate Mono Hydrate (3HPTMH).

    PubMed

    Balaji, J; Prabu, S; Srinivasan, P; Srinivasan, T; Velmurugan, D

    2015-06-01

    Single crystals of 3 Hydroxy Pyridinium Tartrate Mono Hydrate (3HPTMH) was synthesised and successfully grown in mixed solvent of ethanol and water by slow evaporation technique at room temperature. 3HPTMH belongs to the orthorhombic crystal system with space group P212121. The lattice parameters of 3HPTMH are a=7.4597(2)Å, b=8.7012(3)Å, c=17.8786(5)Å, V=1160.47(6)Å(3), obtained by single crystal X ray diffraction studies. Hyperpolarizability and HOMO-LUMO analysis were performed for grown crystal using DFT calculations using Gaussian 03 software. Functional groups were identified by FT-IR studies. The lower cut-off wavelength of the 3HPTMH has been identified by UV-Vis study. The thermal behavior has been studied by thermal gravimetric analysis and differential thermal analysis. The powder second harmonic generation efficiency of 3HPTMH was compared with KDP. PMID:25754389

  20. Cloning, Expression Profiling and Functional Analysis of CnHMGS, a Gene Encoding 3-hydroxy-3-Methylglutaryl Coenzyme A Synthase from Chamaemelum nobile.

    PubMed

    Cheng, Shuiyuan; Wang, Xiaohui; Xu, Feng; Chen, Qiangwen; Tao, Tingting; Lei, Jing; Zhang, Weiwei; Liao, Yongling; Chang, Jie; Li, Xingxiang

    2016-01-01

    Roman chamomile (Chamaemelum nobile L.) is renowned for its production of essential oils, which major components are sesquiterpenoids. As the important enzyme in the sesquiterpenoid biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMGS) catalyze the crucial step in the mevalonate pathway in plants. To isolate and identify the functional genes involved in the sesquiterpene biosynthesis of C. nobile L., a HMGS gene designated as CnHMGS (GenBank Accession No. KU529969) was cloned from C. nobile. The cDNA sequence of CnHMGS contained a 1377 bp open reading frame encoding a 458-amino-acid protein. The sequence of the CnHMGS protein was highly homologous to those of HMGS proteins from other plant species. Phylogenetic tree analysis revealed that CnHMGS clustered with the HMGS of Asteraceae in the dicotyledon clade. Further functional complementation of CnHMGS in the mutant yeast strain YSC6274 lacking HMGS activity demonstrated that the cloned CnHMGS cDNA encodes a functional HMGS. Transcript profile analysis indicated that CnHMGS was preferentially expressed in flowers and roots of C. nobile. The expression of CnHMGS could be upregulated by exogenous elicitors, including methyl jasmonate and salicylic acid, suggesting that CnHMGS was elicitor-responsive. The characterization and expression analysis of CnHMGS is helpful to understand the biosynthesis of sesquiterpenoid in C. nobile at the molecular level and also provides molecular wealth for the biotechnological improvement of this important medicinal plant. PMID:27005600

  1. Design of a Water Soluble Fluorescent 3-Hydroxy-4-Pyridinone Ligand Active at Physiological pH Values.

    PubMed

    Leite, Andreia; Silva, Ana M G; Coutinho, Catarina; Cunha-Silva, Luís; de Castro, Baltazar; Rangel, Maria

    2016-09-01

    In the present work we report the structure and the spectroscopic characterization of a new fluorescent 3-hydroxy-4-pyridinone ligand D-3,4-HPO. The synthesis of the compound was performed in two steps, which involve the reaction of the commercially available fluorophore dansyl chloride with a 3-hydroxy-4-pyridinone chelating unit and further deprotection. The new fluorescent chelator was characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR, MS, absorption and fluorescence spectroscopies. The analysis of the variation of the absorption spectrum with pH allowed the determination of four pK a values (pK a1  = 3.50, pK a2  = 4.50, pK a3  = 9.60, pK a4  = 10.20) and establishment of the corresponding distribution diagram. The study of the fluorescence properties of the ligand show that in the pH range between 4 and 9 the fluorescence intensity is constant and has its maximum value thus allowing its further use at physiological pH values. The interaction of the ligand with copper(II) was accessed by fluorescence spectroscopy in MOPS buffer and the results show that the presence of copper(II) quenches the fluorescence of the ligand in ca 94 % at a ligand: metal ratio of 2:1. The latter result is consistent with the formation of a copper(II) complex with the bidentate ligand, as confirmed by the EPR spectroscopy. Graphical Abstract New water soluble fluorescent ligand active at physiological pH values. PMID:27357392

  2. Synthesis and iron sequestration equilibria of novel exocyclic 3-hydroxy-2-pyridinone donor group siderophore mimics.

    PubMed

    Harrington, James M; Chittamuru, Sumathi; Dhungana, Suraj; Jacobs, Hollie K; Gopalan, Aravamudan S; Crumbliss, Alvin L

    2010-09-20

    The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pK(a)'s of N(2)(etLH)(2), N(2)(prLH)(2), and N(3)(etLH)(3), were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N(2)(etLH)(2) and N(2)(prLH)(2), and hexadentate N(3)(etLH)(3), were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N(3)(etLH)(3) forms a 1:1 complex with Fe(III) with log β(110) = 27.34 ± 0.04. N(2)(prLH)(2) forms a 3:2 L:Fe complex with Fe(III) where log β(230) = 60.46 ± 0.04 and log β(110) = 20.39 ± 0.02. While N(2)(etLH)(2) also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log β(230); log β(110) was found to be 20.45 ± 0.04. The pFe values of 26.5 for N(3)(etLH)(3) and 24.78 for N(2)(prLH)(2) are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents. PMID:20715813

  3. Simultaneous determination of LSD and 2-oxo-3-hydroxy LSD in hair and urine by LC-MS/MS and its application to forensic cases.

    PubMed

    Jang, Moonhee; Kim, Jihyun; Han, Inhoi; Yang, Wonkyung

    2015-11-10

    Lysergic acid diethylamide (LSD) is administered in low dosages, which makes its detection in biological matrices a major challenge in forensic toxicology. In this study, two sensitive and reliable methods based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) were established and validated for the simultaneous determination of LSD and its metabolite, 2-oxo-3-hydroxy-LSD (O-H-LSD), in hair and urine. Target analytes in hair were extracted using methanol at 38°C for 15h and analyzed by LC-MS/MS. For urine sample preparation, liquid-liquid extraction was performed. Limits of detection (LODs) in hair were 0.25pg/mg for LSD and 0.5pg/mg for O-H-LSD. In urine, LODs were 0.01 and 0.025ng/ml for LSD and O-H-LSD, respectively. Method validation results showed good linearity and acceptable precision and accuracy. The developed methods were applied to authentic specimens from two legal cases of LSD ingestion, and allowed identification and quantification of LSD and O-H-LSD in the specimens. In the two cases, LSD concentrations in hair were 1.27 and 0.95pg/mg; O-H-LSD was detected in one case, but its concentration was below the limit of quantification. In urine samples collected from the two suspects 8 and 3h after ingestion, LSD concentrations were 0.48 and 2.70ng/ml, respectively, while O-H-LSD concentrations were 4.19 and 25.2ng/ml, respectively. These methods can be used for documenting LSD intake in clinical and forensic settings. PMID:26188861

  4. Identification of a 3-hydroxy-3-methylglutaryl-CoA reductase gene highly expressed in the root tissue of Taraxacum kok-saghyz

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Kazak dandelion (Taraxacum kok-saghyz, Tk) is a rubber-producing plant currently being investigated as a source of natural rubber for industrial applications. Like many other isoprenoids, rubber is a downstream product of the mevalonate pathway. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) en...

  5. In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: a potential pathophysiological mechanism of striatal damage in this disorder.

    PubMed

    Fernandes, Carolina Gonçalves; da Rosa, Mateus Struecker; Seminotti, Bianca; Pierozan, Paula; Martell, Rafael Wolter; Lagranha, Valeska Lizzi; Busanello, Estela Natacha Brandt; Leipnitz, Guilhian; Wajner, Moacir

    2013-06-01

    3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a genetic disorder biochemically characterized by predominant accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Clinically, the patients present neurological symptoms and basal ganglia injury, whose pathomechanisms are partially understood. In the present study, we investigated the ex vivo effects of intrastriatal administration of HMG and MGA on important parameters of oxidative stress in striatum of developing rats. Our results demonstrate that HMG and MGA induce lipid and protein oxidative damage. HMG and MGA also increased 2',7'-dichlorofluorescein oxidation, whereas only HMG elicited nitric oxide production, indicating a role for reactive oxygen (HMG and MGA) and nitrogen (HMG) species in these effects. Regarding the enzymatic antioxidant defenses, both organic acids decreased reduced glutathione concentrations and the activities of superoxide dismutase and glutathione reductase and increased glutathione peroxidase activity. HMG also provoked an increase of catalase activity and a diminution of glucose-6-phosphate dehydrogenase activity. We finally observed that antioxidants fully prevented or attenuated HMG-induced alterations of the oxidative stress parameters, further indicating the participation of reactive species in these effects. We also observed that MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, prevented some of these effects, indicating the involvement of the NMDA receptor in HMG effects. The present data provide solid evidence that oxidative stress is induced in vivo by HMG and MGA in rat striatum and it is presumed that this pathomechanism may explain, at least in part, the cerebral alterations observed in HL deficiency. PMID:23611578

  6. Growth and characterization of novel organic 3-Hydroxy Benzaldehyde-N-methyl 4 Stilbazolium Tosylate crystals for NLO applications

    NASA Astrophysics Data System (ADS)

    Jagannathan, K.; Umarani, P.; Ratchagar, V.; Ramesh, V.; Kalainathan, S.

    2016-01-01

    The 3-Hydroxy Benzaldehyde-N-methyl 4-Stilbazolium Tosylate (3- HBST) is a new organic NLO crystal and it is a new derivative in stilbazolium tosylate family. In this work we have synthesized 3-HBST and the single crystal was grown by conventional slow cooling method. The structure and lattice parameters of the grown crystal were determined by the single crystal X-ray diffraction (XRD) technique and it is exhibiting good crystalline nature which is observed from the powder XRD. In order to check the crystalline quality the rocking curve was recorded using multi crystal X-ray diffractometer. The functional groups were identified from both FTIR and NMR spectral analyses. The π-π* and n-π* optical transition energy levels were estimated from the absorption peaks. The NLO property was confirmed by measuring relative SHG efficiency by Kurtz powder test; it shows 24 times higher SHG efficiency than that of urea. In order to test the mechanical stability the Vickers and Knoop micro hardness measurement were carried out and found that the micro hardness number decreases with increasing load. The melting point was determined from Differential Scanning Colorimetry (DSC).

  7. Involvement of tristetraprolin in transcriptional activation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase by insulin

    SciTech Connect

    Ness, Gene C.; Edelman, Jeffrey L.; Brooks, Patricia A.

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer siRNAs to tristetraprolin blocks transcription of HMGR in vivo in rat liver. Black-Right-Pointing-Pointer siRNAs to tristetraprolin inhibits insulin activation of HMGR transcription. Black-Right-Pointing-Pointer Insulin acts to rapidly increase tristetraprolin in liver nuclear extracts. -- Abstract: Several AU-rich RNA binding element (ARE) proteins were investigated for their possible effects on transcription of hepatic 3-hydroxy-3-methyglutaryl coenzyme A reductase (HMGR) in normal rats. Using in vivo electroporation, four different siRNAs to each ARE protein were introduced together with HMGR promoter (-325 to +20) luciferase construct and compared to saline controls. All four siRNAs to tristetraprolin (TTP) completely eliminated transcription from the HMGR promoter construct. Since insulin acts to rapidly increase hepatic HMGR transcription, the effect of TTP siRNA on induction by insulin was tested. The 3-fold stimulation by insulin was eliminated by this treatment. In comparison, siRNA to AU RNA binding protein/enoyl coenzyme A hydratase (AUH) had no effect. These findings indicate a role for TTP in the insulin-mediated activation of hepatic HMGR transcription.

  8. Growth and characterization of novel organic 3-Hydroxy Benzaldehyde-N-methyl 4 Stilbazolium Tosylate crystals for NLO applications.

    PubMed

    Jagannathan, K; Umarani, P; Ratchagar, V; Ramesh, V; Kalainathan, S

    2016-01-15

    The 3-Hydroxy Benzaldehyde-N-methyl 4-Stilbazolium Tosylate (3- HBST) is a new organic NLO crystal and it is a new derivative in stilbazolium tosylate family. In this work we have synthesized 3-HBST and the single crystal was grown by conventional slow cooling method. The structure and lattice parameters of the grown crystal were determined by the single crystal X-ray diffraction (XRD) technique and it is exhibiting good crystalline nature which is observed from the powder XRD. In order to check the crystalline quality the rocking curve was recorded using multi crystal X-ray diffractometer. The functional groups were identified from both FTIR and NMR spectral analyses. The π-π* and n-π* optical transition energy levels were estimated from the absorption peaks. The NLO property was confirmed by measuring relative SHG efficiency by Kurtz powder test; it shows 24 times higher SHG efficiency than that of urea. In order to test the mechanical stability the Vickers and Knoop micro hardness measurement were carried out and found that the micro hardness number decreases with increasing load. The melting point was determined from Differential Scanning Colorimetry (DSC). PMID:26476071

  9. Biodegradation improvement of poly(3-hydroxy-butyrate) films by entomopathogenic fungi and UV-assisted surface functionalization.

    PubMed

    Kessler, Felipe; Marconatto, Leticia; Rodrigues, Roberta da Silva Bussamara; Lando, Gabriela Albara; Schrank, Augusto; Vainstein, Marilene Henning; Weibel, Daniel Eduardo

    2014-01-01

    Ultraviolet (UV)-assisted surface modification in the presence of oxygen was used as initial step to achieve controlled degradation of poly(3-hydroxy-butyrate), PHB, films by entomopathogenic fungi. Treated surfaces were investigated by surface analysis techniques (water contact angle, Fourier Transformed Infrared Spectroscopy in Attenuated Total Reflectance mode, X-ray Photoelectron Spectroscopy, Near-edge X-ray Absorption Fine Structure, Gel Permeation Chromatography, Optical Microscopy, Scanning Electron Microscopy, and weight loss). After the UV-assisted treatments, new carbonyl groups in new chemical environments were detected by XPS and NEXAFS spectroscopy. The oxidizing atmosphere did not allow the formation of CC bonds, indicating that Norrish Type II mechanism is suppressed during or by the treatments. The higher hydrophilicity and concentration of oxygenated functional groups at the surface of the treated films possibly improved the biodegradation of the films. It was observed a clear increase in the growth of this fungus when oxygenated groups were grafted on the polymers surfaces. This simple methodology can be used to improve and control the degradation rate of PHB films in applications that require a controllable degradation rate. PMID:24300992

  10. Ten novel HMGCL mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria.

    PubMed

    Menao, Sebastián; López-Viñas, Eduardo; Mir, Cecilia; Puisac, Beatriz; Gratacós, Esther; Arnedo, María; Carrasco, Patricia; Moreno, Susana; Ramos, Mónica; Gil, María Concepción; Pié, Angeles; Ribes, Antonia; Pérez-Cerda, Celia; Ugarte, Magdalena; Clayton, Peter T; Korman, Stanley H; Serra, Dolors; Asins, Guillermina; Ramos, Feliciano J; Gómez-Puertas, Paulino; Hegardt, Fausto G; Casals, Nuria; Pié, Juan

    2009-03-01

    3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and L-leucine catabolism. The clinical acute symptoms include vomiting, convulsions, metabolic acidosis, hypoketotic hypoglycaemia and lethargy. To date, 33 mutations in 100 patients have been reported in the HMGCL gene. In this study 10 new mutations in 24 patients are described. They include: 5 missense mutations: c.109G>A, c.425C>T, c.521G>A, c.575T>C and c.598A>T, 2 nonsense mutations: c.242G>A and c.559G>T, one small deletion: c.853delC, and 2 mutations in intron regions: c.497+4A>G and c.750+1G>A. Two prevalent mutations were detected, 109G>T (E37X) in 38% of disease alleles analyzed and c.504_505delCT in 10% of them. Although patients are mainly of European origin (71%) and mostly Spanish (54%), the group is ethnically diverse and includes, for the first time, patients from Pakistan, Palestine and Ecuador. We also present a simple, efficient method to express the enzyme and we analyze the possible functional effects of missense mutations. The finding that all identified missense mutations cause a >95% decrease in the enzyme activity, indicates that the disease appears only in very severe genotypes." PMID:19177531

  11. Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

    SciTech Connect

    Sarver, Ronald W.; Bills, Elizabeth; Bolton, Gary; Bratton, Larry D.; Caspers, Nicole L.; Dunbar, James B.; Harris, Melissa S.; Hutchings, Richard H.; Kennedy, Robert M.; Larsen, Scott D.; Pavlovsky, Alexander; Pfefferkorn, Jeffrey A.; Bainbridge, Graeme

    2008-10-02

    Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2--7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC{sub 50} = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a {Delta}H of -17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.

  12. (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication.

    PubMed Central

    Snoeck, R; Sakuma, T; De Clercq, E; Rosenberg, I; Holy, A

    1988-01-01

    From a series of phosphonylmethoxyalkylpurine and -pyrimidine derivatives, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] emerged as a particularly potent and selective inhibitor of the replication of human cytomegalovirus (CMV). Its potency against CMV was similar to that of the structurally related adenine derivative (S)-HPMPA but higher than that of the reference compounds phosphonoformate and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). The minimum concentrations of phosphonoformate, DHPG, (S)-HPMPA, and (S)-HPMPC required to inhibit CMV plaque formation by 50% were 15, 0.7, 0.1, and 0.07 microgram/ml, respectively. The selectivity indices of phosphonoformate, DHPG, (S)-HPMPA, and (S)-HPMPC, as determined by the ratio of the 50% inhibitory concentration for cell growth to the 50% inhibitory concentration for plaque formation for CMV (AD-169 strain), were 14, 150, 200 and 1,500, respectively. Corresponding values for the CMV Davis strain were 20, 200, 100, and 1,000, respectively. (S)-HPMPC was inhibitory to CMV plaque formation even when added to the cells at 24 or 48 h postinfection. When (S)-HPMPC was added immediately postinfection, a 24- or 48-h incubation time sufficed to obtain a marked inhibitory effect on CMV replication. Such limited incubation time was insufficient for DHPG to achieve any protection against CMV. PMID:2854454

  13. Inhibition kinetics of cabbage butterfly (Pieris rapae L.) larvae phenoloxidase activity by 3-hydroxy-4-methoxybenzaldehyde thiosemicarbazone.

    PubMed

    Xue, Chao-Bin; Luo, Wan-Chun; Jiang, Lin; Xie, Xian-Ye; Xiao, Ting; Yan, Lei

    2007-11-01

    Phenoloxidase (PO) is a key enzyme in insect development, responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the kinetic assay in air-saturated solutions and the kinetic behavior of PO from Pieris rapae (Lepidoptera) larvae in the oxidation of L-tyrosine (a monophenol) and L-DOPA (l-3, 4-dihydroxyphenylalanine) (a diphenol) was studied. The inhibitory effects of 3-hydroxy-4-methoxybenzaldehyde thiosemicarbazone (3-H-4-MBT) on the monophenolase and diphenolase activities of PO were also studied. The results show that 3-H-4-MBT can inhibit both the monophenolase and diphenolase activities of PO. The lag period of L-tyrosine oxidation catalyzed by the enzyme was obviously lengthened and the steady-state activities of the enzyme sharply decreased. The inhibitor was found to be noncompetitively reversible with a K I (K I = K IS) of 0.30 micromol/L and an estimated IC50 of 0.14 +/- 0.02 micromol/L for monophenolase and 0.26 +/- 0.04 micromol/L for diphenolase. In the time course of the oxidation of L-DOPA catalyzed by the enzyme in the presence of different concentrations of 3-H-4-MBT, the rate decreased with increasing time until a straight line was approached. The microscopic rate constants for the reaction of 3-H-4-MBT with the enzyme were determined. PMID:18025600

  14. Modulation of Dendritic Cell Immunobiology via Inhibition of 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) Reductase

    PubMed Central

    Luessi, Felix; Bendix, Ivo; Paterka, Magdalena; Prozorovski, Timour; Treue, Denise; Luenstedt, Sarah; Herz, Josephine; Siffrin, Volker; Infante-Duarte, Carmen; Zipp, Frauke; Waiczies, Sonia

    2014-01-01

    The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC in vitro and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells in vitro. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities. PMID:25013913

  15. Preparation of 4-amino-2,4-dioxobutanoic acid

    DOEpatents

    Unkefer, Pat J.; Martinez, Rodolfo A.; Glass, David R.

    2016-03-22

    A process for synthesizing 4-amino-2,4-dioxobutanoic acid involves reacting diethyl oxalate with an alkoxide in ethanol to form a reaction mixture, and afterward adding ethyl cyanoacetate to the reaction mixture and allowing a reaction to proceed under conditions suitable to form a first reaction product of the formula diethyl 2-cyano-3-hydroxy-butenedioate, and then isolating the diethyl 2-cyano-3-hydroxy-butenedioate, and afterward reacting the diethyl-2-cyano-3-hydroxy-butenedioate with an aqueous hydroxide under conditions suitable to form 4-amino-2,4-dioxobutanoic acid.

  16. Identification and characterization of trans-3-hydroxy-l-proline dehydratase and Δ1-pyrroline-2-carboxylate reductase involved in trans-3-hydroxy-l-proline metabolism of bacteria

    PubMed Central

    Watanabe, Seiya; Tanimoto, Yoshiaki; Yamauchi, Seiji; Tozawa, Yuzuru; Sawayama, Shigeki; Watanabe, Yasuo

    2014-01-01

    trans-4-Hydroxy-l-proline (T4LHyp) and trans-3-hydroxy-l-proline (T3LHyp) occur mainly in collagen. A few bacteria can convert T4LHyp to α-ketoglutarate, and we previously revealed a hypothetical pathway consisting of four enzymes at the molecular level (J Biol Chem (2007) 282, 6685–6695; J Biol Chem (2012) 287, 32674–32688). Here, we first found that Azospirillum brasilense has the ability to grow not only on T4LHyp but also T3LHyp as a sole carbon source. In A. brasilense cells, T3LHyp dehydratase and NAD(P)H-dependent Δ1-pyrroline-2-carboxylate (Pyr2C) reductase activities were induced by T3LHyp (and d-proline and d-lysine) but not T4LHyp, and no effect of T3LHyp was observed on the expression of T4LHyp metabolizing enzymes: a hypothetical pathway of T3LHyp → Pyr2C → l-proline was proposed. Bacterial T3LHyp dehydratase, encoded to LhpH gene, was homologous with the mammalian enzyme. On the other hand, Pyr2C reductase encoded to LhpI gene was a novel member of ornithine cyclodeaminase/μ-crystallin superfamily, differing from known bacterial protein. Furthermore, the LhpI enzymes of A. brasilense and another bacterium showed several different properties, including substrate and coenzyme specificities. T3LHyp was converted to proline by the purified LhpH and LhpI proteins. Furthermore, disruption of LhpI gene from A. brasilense led to loss of growth on T3LHyp, d-proline and d-lysine, indicating that this gene has dual metabolic functions as a reductase for Pyr2C and Δ1-piperidine-2-carboxylate in these pathways, and that the T3LHyp pathway is not linked to T4LHyp and l-proline metabolism. PMID:24649405

  17. Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia.

    PubMed

    Bi, Xiaoning; Baudry, Michel; Liu, Jihua; Yao, Yueqin; Fu, Lawrence; Brucher, Fernando; Lynch, Gary

    2004-11-12

    Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration- and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-alpha. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-alpha but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease. PMID:15364922

  18. Novel cis-selective and non-epimerisable C3 hydroxy azapodophyllotoxins targeting microtubules in cancer cells

    PubMed Central

    Kandil, Sahar; Wymant, Jennifer M.; Kariuki, Benson M.; Jones, Arwyn T.; McGuigan, Christopher; Westwell, Andrew D.

    2016-01-01

    Podophyllotoxin (PT) and its clinically used analogues are known to be powerful antitumour agents. These compounds contain a trans fused strained γ-lactone system, a feature that correlates to the process of epimerisation, whereby the trans γ-lactone system of ring D opens and converts to the more thermodynamically stable cis epimer. Since these cis epimers are known to be either less active or lacking antitumour activity, epimerisation is an undesirable feature from a chemotherapeutic point of view. To circumvent this problem, considerable efforts have been reported, amongst which is the synthesis of azapodophyllotoxins where the stereocentres at C2 and C3 are removed in order to preclude epimerisation. Herein we report the identification of a novel C3 hydroxy, cis-selective γ-lactone configuration of ring C in the azapodophyllotoxin scaffold, through an efficient stereoselective multicomponent reaction (MCR) involving fluorinated and non-fluorinated aldehydes. This configuration releases the highly strained trans γ-lactone system in podophyllotoxin analogues into the more thermodynamically stable cis γ-lactone motif and yet retains significantly potent activity. These compounds were evaluated against the human cancer lines MCF-7 and 22Rv1 in vitro. Fourteen out of the seventeen tested compounds exhibited sub-micromolar activity with IC50 values in the range of 0.11–0.91 μM, which is comparable and in some cases better than the activity profile of etoposide in this assay. Interestingly, we obtained strong evidence from spectroscopic and X-ray data analyses that the previously reported structure of similar analogues is not accurate. Molecular modelling performed using the podophyllotoxin binding site on β tubulin revealed a novel binding mode of these analogues. Furthermore, sub-cellular study of our compounds using immunolabelling and confocal microscopy analyses showed strong microtubule disruptive activity, particularly in dividing cells. PMID

  19. Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase reduce receptor-mediated endocytosis in opossum kidney cells.

    PubMed

    Sidaway, James E; Davidson, Robert G; McTaggart, Fergus; Orton, Terry C; Scott, Robert C; Smith, Graham J; Brunskill, Nigel J

    2004-09-01

    Renal proximal tubule cells are responsible for the reabsorption of proteins that are present in the tubular lumen. This occurs by receptor-mediated endocytosis, a process that has a requirement for some GTP-binding proteins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase used for the therapeutic reduction of cholesterol-containing plasma lipoproteins. However, they can also reduce intracellular levels of isoprenoid pyrophosphates that are derived from the product of the enzyme, mevalonate, and are required for the prenylation and normal function of GTP-binding proteins. The hypothesis that inhibition of HMG-CoA reductase in renal proximal tubule cells could reduce receptor mediated-endocytosis was therefore tested. Five different statins inhibited the uptake of FITC-labeled albumin by the proximal tubule-derived opossum kidney cell line in a dose-dependent manner and in the absence of cytotoxicity. The reduction in albumin uptake was related to the degree of inhibition of HMG-CoA reductase. Simvastatin (e.g., statin) inhibited receptor-mediated endocytosis of both FITC-albumin and FITC-beta(2)-microglobulin to similar extents but without altering the binding of albumin to the cell surface. The effect on albumin endocytosis was prevented by mevalonate and by the isoprenoid geranylgeranyl pyrophosphate but not by cholesterol. Finally, evidence that the inhibitory effect of statins on endocytosis of proteins may be caused by reduced prenylation and thereby decreased function of one or more GTP-binding proteins is provided. These data establish the possibility in principle that inhibition of HMG-CoA reductase by statins in proximal tubule cells may reduce tubular protein reabsorption. PMID:15339975

  20. Synthesis, crystal growth, structural and physicochemical studies of novel binary organic complex: 4-chloroaniline-3-hydroxy-4-methoxybenzaldehyde

    SciTech Connect

    Sharma, K.P.; Reddi, R.S.B.; Bhattacharya, S.; Rai, R.N.

    2012-06-15

    The solid-state reaction, which is solvent free and green synthesis, has been adopted to explore the novel compound. The phase diagram of 4-chloroaniline (CA) and 3-hydroxy-4-methoxybenzaldehyde (HMB) system shows the formation of a novel 1:1 molecular complex, and two eutectics on either sides of complex. Thermochemical studies of complex and eutectics have been carried out for various properties such as heat of fusion, entropy of fusion, Jackson's parameters, interfacial energy and excess thermodynamic functions. The formation of molecular complex was also studied by IR, NMR, elemental analysis and UV-Vis absorption spectra. The single crystal of molecular complex was grown and its XRD study confirms the formation of complex and identifies the crystal structure and atomic packing of crystal of complex. Transmission spectra of grown crystal of the complex show 70% transmittance efficiency with cut off wavelength 412 nm. The band gap and refractive index of the crystal of complex have also been studied. - Graphical abstarct: Exploiting phase diagram study and solvent free synthesis a novel compound was synthesized and its single crystal growth, atomic packing, energy band gap and refractive index were studied. Highlights: Black-Right-Pointing-Pointer Novel organic complex was synthesized using Green or solvent free synthesis. Black-Right-Pointing-Pointer Phase diagram study provided the information to identify the worthy composition of novel complex. Black-Right-Pointing-Pointer The single crystal of the sufficient size was grown from the ethanol solution. Black-Right-Pointing-Pointer Crystal analysis suggested that the covalent bond is formed between the two parent compounds. Black-Right-Pointing-Pointer The transmittance of the crystal was found to be 70% and it was transparent from 412 to 850 nm.

  1. A study on the anti-inflammatory effects of new derivatives of 3-hydroxy pyridine-4-one

    PubMed Central

    Hajhashemi, Valiollah; Mojiri-Froshani, Hoda; Saghaei, Lotfollah; Fassihi, Afshin

    2014-01-01

    Background: Derivatives of pyridine-4-one act as iron chelators and possess various pharmacological effects such as antifungal, antimalarial, antiviral, anti-inflammatory, and analgesic effects. The aim of our study was to evaluate the anti-inflammatory effects of the three new derivatives of pyridine-4-one. Materials and Methods: Carrageenan-induced paw edema in rats and croton oil-induced ear edema in mice were used to evaluate the anti-inflammatry effects of three 3-hydroxy-pyridine-4-one derivatives (compounds A, B, and C). Compound A (10, 20 mg/kg), compound B (200, 400 mg/kg), and compound C (100, 200 mg/kg), vehicle (1 mL/kg), and indomethacin as standard drug (10 mg/kg) were injected intraperitoneally 30 min prior to carrageenan injection and 4 h later, the paw volume was measured using a mercury plethysmograph. The maximum dose of each test compound was used in the croton oil-induced ear edema test. Results: All compounds showed significant anti-inflammatory activity in both tests. On a molar basis, compound A had the greatest potency, which may be due to the presence of a benzyl group substitution on the pyridine ring. Conclusions: Because cyclooxygenase and lipoxygenase as key enzymes of the inflammation pathway are heme-dependent, it seems that the anti-inflammatory effect of derivatives of pyridine-4-one may be related to their iron chelating properties. However, more investigations are needed to find out their exact mechanism of actions. PMID:24949305

  2. 40 CFR 180.318 - 4-(2-Methyl-4-chlorophenoxy) butyric acid; tolerance for residues.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...)butanoic acid, and its metabolite MCPA, (4-chloro-2-methylphenoxy)acetic acid, in or on the following food... acid; tolerance for residues. 180.318 Section 180.318 Protection of Environment ENVIRONMENTAL... FOOD Specific Tolerances § 180.318 4-(2-Methyl-4-chlorophenoxy) butyric acid; tolerance for...

  3. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in transplant patients: are the statins mechanistically similar?

    PubMed

    Christians, U; Jacobsen, W; Floren, L C

    1998-10-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88) inhibitors are the most effective drugs to lower cholesterol in transplant patients. However, immunosuppressants and several other drugs used after organ transplantation are cytochrome P4503A (CYP3A, EC 1.14.14.1) substrates. Pharmacokinetic interaction with some of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, specifically lovastatin and simvastatin, leads to an increased incidence of muscle skeletal toxicity in transplant patients. It is our objective to review the role of drug metabolism and drug interactions of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin. In the treatment of transplant patients, from a drug interaction perspective, pravastatin, which is not significantly metabolized by CYP enzymes, and fluvastatin, presumably a CYP2C9 substrate, compare favorably with the other statins for which the major metabolic pathways are catalyzed by CYP3A. PMID:9804052

  4. 5,7-dihydroxy-2-(3-hydroxy-4, 5-dimethoxy-phenyl)-chromen-4-one-a flavone from Bruguiera gymnorrhiza displaying anti-inflammatory properties

    PubMed Central

    Barik, Rajib; Sarkar, Ratul; Biswas, Prova; Bera, Rammohan; Sharma, Soma; Nath, Suvadeep; Karmakar, Sanmoy; Sen, Tuhinadri

    2016-01-01

    Objective: Bruguiera gymnorrhiza (BRG) (L.) Lamk (Rhizophoraceae), a mangrove species, is widely distributed in the Pacific region, eastern Africa, Indian subcontinent, and subtropical Australia. The leaves of this plant are traditionally used for treating burns and inflammatory lesions. This study isolates the bioactive compound from the methanol extract of BRG leaves and evaluates the possible mechanisms of anti-inflammatory activity involved. Materials and Methods: Bioassay-guided fractionation of BRG was performed to identify the bioactive fraction (displaying inhibition of cyclooxygenase 2 [COX2] - 5-lipoxygenase (5-LOX) activities and tumor necrosis factor-alpha (TNF-α) production at the tested concentrations of 100 and 10 μg/ml). The fractionation was performed by solvent extraction and preparative high-performance liquid chromatography. The bioactive compound was characterized by ultraviolet–visible, liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. The antioxidant potential was evaluated by electron spin resonance spectrum of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical at 250 μM. The effect of the compound was also studied on TNF-α converting enzyme and nuclear factor kappa B (NF-κB) activities at the concentrations 100, 10 and 1 μg/ml. Results: Bioassay-guided purification of BRG revealed the presence of a flavone (5,7-dihydroxy-2- [3-hydroxy-4,5-dimethoxy-phenyl]-chromen-4-one) of molecular weight 330Da. It demonstrated more than 80% inhibition against COX2, 5-LOX activities and TNF-α production at 100 μg/ml. It also displayed 40% inhibition against DPPH radical at the tested concentration along with 23.1% inhibition of NF-κB activity at 100 μg/ml. Conclusions: The isolated methoxy-flavone may play a predominant role in the anti-inflammatory properties displayed by BRG leaves. Such activity may involve multiple mechanisms, namely (a) modulation of oxidative stress (b) inhibition of arachidonic acid

  5. Inactivation of Ascaris suum by short-chain fatty acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ascaris suum eggs were inactivated in distilled water and digested sludge by butanoic, pentanoic and hexanoic acids. The fatty acids (FA) were only effective when protonated and at sufficient concentration. The conjugate bases were not effective at the concentrations evaluated. Predictions from an ...

  6. A 3-hydroxy β-end group in xanthophylls is preferentially oxidized to a 3-oxo ε-end group in mammals[S

    PubMed Central

    Nagao, Akihiko; Maoka, Takashi; Ono, Hiroshi; Kotake-Nara, Eiichi; Kobayashi, Miyuki; Tomita, Mie

    2015-01-01

    We previously found that mice fed lutein accumulated its oxidative metabolites (3′-hydroxy-ε,ε-caroten-3-one and ε,ε-carotene-3,3′-dione) as major carotenoids, suggesting that mammals can convert xanthophylls to keto-carotenoids by the oxidation of hydroxyl groups. Here we elucidated the metabolic activities of mouse liver for several xanthophylls. When lutein was incubated with liver postmitochondrial fraction in the presence of NAD+, (3′R,6′R)-3′-hydroxy-β,ε-caroten-3-one and (6RS,3′R,6′R)-3′-hydroxy-ε,ε-caroten-3-one were produced as major oxidation products. The former accumulated only at the early stage and was assumed to be an intermediate, followed by isomerization to the latter. The configuration at the C3′ and C6′ of the ε-end group in lutein was retained in the two oxidation products. These results indicate that the 3-hydroxy β-end group in lutein was preferentially oxidized to a 3-oxo ε-end group via a 3-oxo β-end group. Other xanthophylls such as β-cryptoxanthin and zeaxanthin, which have a 3-hydroxy β-end group, were also oxidized in the same manner as lutein. These keto-carotenoids, derived from dietary xanthophylls, were confirmed to be present in plasma of normal human subjects, and β,ε-caroten-3′-one was significantly increased by the ingestion of β-cryptoxanthin. Thus, humans as well as mice have oxidative activity to convert the 3-hydroxy β-end group of xanthophylls to a 3-oxo ε-end group. PMID:25502844

  7. Designing the Ideal Uranyl Ligand: a Sterically-Induced Speciation Change in Complexes with Thiophene-Bridged Bis(3-hydroxy-N-methylpyridin-2-one)

    SciTech Connect

    Szigethy, Geza; Raymond, Kenneth N.

    2009-09-11

    Structural characterization of a mononuclear uranyl complex with a tetradentate, thiophene-linked bis(3-hydroxy-N-methylpyridin-2-one) ligand reveals the most planar coordination geometry yet observed with this ligand class. The introduction of ethylsulfanyl groups onto the thiophene linker disrupts this planar, conjugated ligand arrangement, resulting in the formation of dimeric (UO{sub 2}){sub 2}L{sub 2} species in which each ligand spans two uranyl centers. Relative energy calculations reveal that this tendency toward dimer formation is the result of steric interference between ethylsulfanyl substituents and linking amides.

  8. Designing the ideal uranyl ligand: a sterically induced speciation change in complexes with thiophene-bridged bis(3-hydroxy-n-methylpyridin-2-one).

    PubMed

    Szigethy, Géza; Raymond, Kenneth N

    2009-12-21

    Structural characterization of a mononuclear uranyl complex with a tetradentate, thiophene-linked bis(3-hydroxy-N-methylpyridin-2-one) ligand reveals the most planar coordination geometry yet observed with this ligand class. The introduction of ethylsulfanyl groups onto the thiophene linker disrupts this planar, conjugated ligand arrangement, resulting in the formation of dimeric (UO(2))(2)L(2) species in which each ligand spans two uranyl centers. Relative energy calculations reveal that this tendency toward dimer formation is the result of steric interference between ethylsulfanyl substitutents and linking amides. PMID:19928845

  9. Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases.

    PubMed

    Dolder, Patrick C; Liechti, Matthias E; Rentsch, Katharina M

    2015-02-01

    Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of the present study is to develop a quantitative turboflow LC-MS/MS method that can be used for rapid quantification of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) in serum and urine in emergency toxicological cases without time-consuming extraction steps. The method was developed on an ion-trap LC-MS/MS instrument coupled to a turbulent-flow extraction system. The validation data showed no significant matrix effects and no ion suppression has been observed in serum and urine. Mean intraday accuracy and precision for LSD were 101 and 6.84%, in urine samples and 97.40 and 5.89% in serum, respectively. For O-H-LSD, the respective values were 97.50 and 4.99% in urine and 107 and 4.70% in serum. Mean interday accuracy and precision for LSD were 100 and 8.26% in urine and 101 and 6.56% in serum, respectively. For O-H-LSD, the respective values were 101 and 8.11% in urine and 99.8 and 8.35% in serum, respectively. The lower limit of quantification for LSD was determined to be 0.1 ng/ml. LSD concentrations in serum were expected to be up to 8 ng/ml. 2-Oxo-3-hydroxy LSD concentrations in urine up to 250 ng/ml. The new method was accurate and precise in the range of expected serum and urine concentrations in patients with a suspected LSD intoxication. Until now, the method has been applied in five cases with suspected LSD intoxication where the intake of the drug has been verified four times with LSD concentrations in serum in the range of 1.80-14.70 ng/ml and once with a LSD concentration of 1.25 ng/ml in urine. In serum of two patients, the O-H-LSD concentration was determined to be 0.99 and 0.45 ng/ml. In the urine of a third patient, the O-H-LSD concentration was 9.70 ng/ml. PMID:25542574

  10. New tungstenocenes containing 3-hydroxy-4-pyrone ligands: antiproliferative activity on HT-29 and MCF-7 cell lines and binding to human serum albumin studied by fluorescence spectroscopy and molecular modeling methods

    PubMed Central

    Domínguez-García, Moralba; Ortega-Zúñiga, Carlos; Meléndez, Enrique

    2012-01-01

    Three new water-soluble tungstenocene derivatives were synthesized and characterized using 3-hydroxy-4-pyrone ligands, which provide aqueous stability to the complexes. The antiproliferative activities of the complexes on HT-29 colon cancer and MCF-7 breast cancer cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and showed the new tungstenocene derivatives have higher antiproliferative action than tungstenocene dichloride (Cp2WCl2, where Cp is cyclopentadienyl). The binding interactions of the tungstenocenes with human serum albumin (HSA) were investigated using fluorescence spectroscopy and molecular modeling methods. Analysis of the fluorescence quenching spectra indicates that the tungstenocene complexes bind HSA by hydrophobic interactions and hydrogen bonding at fatty acid binding site 6 and drug binding site II. Docking studies provided a description of the hydrophobic interactions and hydrogen bonding by which the tungstenocenes become engaged with HSA. It was determined that the binding affinity of the tungstenoecenes for HSA is in the order Cp2WCl2 < [Cp2W(ethyl maltolato)]Cl < [Cp2W (maltolato)]Cl < [Cp2W(kojato)]Cl, consistent with the hydrophobic interactions and the number of hydrogen bonds involved. PMID:23212785

  11. The SUD1 Gene Encodes a Putative E3 Ubiquitin Ligase and Is a Positive Regulator of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity in Arabidopsis[C][W

    PubMed Central

    Doblas, Verónica G.; Amorim-Silva, Vítor; Posé, David; Rosado, Abel; Esteban, Alicia; Arró, Montserrat; Azevedo, Herlander; Bombarely, Aureliano; Borsani, Omar; Valpuesta, Victoriano; Ferrer, Albert; Tavares, Rui M.; Botella, Miguel A.

    2013-01-01

    The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme catalyzes the major rate-limiting step of the mevalonic acid (MVA) pathway from which sterols and other isoprenoids are synthesized. In contrast with our extensive knowledge of the regulation of HMGR in yeast and animals, little is known about this process in plants. To identify regulatory components of the MVA pathway in plants, we performed a genetic screen for second-site suppressor mutations of the Arabidopsis thaliana highly drought-sensitive drought hypersensitive2 (dry2) mutant that shows decreased squalene epoxidase activity. We show that mutations in SUPPRESSOR OF DRY2 DEFECTS1 (SUD1) gene recover most developmental defects in dry2 through changes in HMGR activity. SUD1 encodes a putative E3 ubiquitin ligase that shows sequence and structural similarity to yeast Degradation of α factor (Doα10) and human TEB4, components of the endoplasmic reticulum–associated degradation C (ERAD-C) pathway. While in yeast and animals, the alternative ERAD-L/ERAD-M pathway regulates HMGR activity by controlling protein stability, SUD1 regulates HMGR activity without apparent changes in protein content. These results highlight similarities, as well as important mechanistic differences, among the components involved in HMGR regulation in plants, yeast, and animals. PMID:23404890

  12. Production and characterization of poly(3-hydroxy butyrate-co-3 hydroxyvalerate) (PHBV) by a novel halotolerant mangrove isolate.

    PubMed

    Moorkoth, Dhanya; Nampoothiri, Kesavan Madhavan

    2016-02-01

    A halophilic mangrove isolate identified by 16S rRNA sequence as a Bacillus spp. was found to be capable of using a broad range of carbon sources including monosaccharides (glucose and fructose), disaccharides (sucrose), pentoses (xylose and arabinose), various organic acids (acetic acid, propionic acid and octanoic acid) and even the acid pre-treated liquor (APL) of sugarcane trash, a lignocellulosic biomass, for growth and the production of polyhydroxyalkanoates (PHAs) such as poly(3-hydroxybutyrate, P3HB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate, PHBV), and 4-hydroxyhexanoate, 4HHX). The study describes the innate ability of a wild-type culture for PHBV production by both propionate dependent and propionate independent pathways. The biopolymer was extracted and characterized physico-chemically. The PHBV yield from glucose was estimated to be 73% of biomass weight with a high 3-hydroxyvalerate fraction of 48mol%. Thereafter, spherical homogenous PHBV nanoparticles of ∼164nm size were prepared for future applications. PMID:26684174

  13. 2-Aza-niumyl-4-(ethyl-carbamo-yl)butano-ate: the zwitterionic form of the amino acid theanine.

    PubMed

    Kang, Shou-Kai; Chen, Yue-Hu; Qian, Shao-Song; Hu, Hao

    2010-01-01

    In the title zwitterion, C(7)H(14)N(2)O(3), the ethyl-amino and the 5-oxo groups are positionally disordered with occupancy ratios of 0.50:0.50 and 0.70:0.30, respectively. The terminal ethyl -CH(3) group undergoes considerable thermal motion. In the crystal, mol-ecules are linked via N-H⋯O hydrogen bonds, forming a two-dimensional arrangement propagating in the bc plane. PMID:21522793

  14. Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones - Attempted optimization of the orally active iron chelator, deferiprone.

    PubMed

    Xie, Yuan-Yuan; Lu, Zidong; Kong, Xiao-Le; Zhou, Tao; Bansal, Sukhi; Hider, Robert

    2016-06-10

    A range of close analogues of deferiprone have been synthesised. The group includes mono-, di- and tri-methyl-3-hydroxy-4(1H)-pyridones. These compounds were found to possess similar pFe(3+) values to that of deferiprone, with the exception of the 2.5-dimethylated derivatives. Surprisingly the NH-containing hydroxy-4(1H)-pyridones were found to be marginally more lipophilic than the corresponding N-Me containing analogues. This same group are also metabolised less efficiently by Phase 1 hydroxylating enzymes than the corresponding N-Me analogues. As result of this study, three compounds have been identified for further investigation centred on neutropenia and agranulocytosis. PMID:27014847

  15. On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme.

    PubMed

    Leopoldini, Monica; Malaj, Naim; Toscano, Marirosa; Sindona, Giovanni; Russo, Nino

    2010-10-13

    Density functional theory was applied to study the binding mode of new flavonoids as possible inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), an enzyme that catalyzes the four-electron reduction of HMGCoA to mevalonate, the committed step in the biosynthesis of sterols. The investigated flavonoid conjugates brutieridin and melitidin were recently quantified in the bergamot fruit extracts and identified to be structural analogues of statins, lipids concentration lowering drugs that inhibit HMGR. Computations allowed us to perform a detailed analysis of the geometrical and electronic features affecting the binding of these compounds, as well as that of the excellent simvastatin drug, to the active site of the enzyme and to give better insight into the inhibition process. PMID:20843083

  16. The Influence of the Linker Geometry in Bis(3-hydroxy-N-methyl-pyridin-2-one) Ligands on Solution-Phase Uranyl Affinity

    SciTech Connect

    Szigethy, Geza; Raymond, Kenneth

    2010-08-12

    Seven water-soluble, tetradentate bis(3-hydroxy-N-methyl-pyridin-2-one) (bis-Me-3,2-HOPO) ligands were synthesized that vary only in linker geometry and rigidity. Solution phase thermodynamic measurements were conducted between pH 1.6 and pH 9.0 to determine the effects of these variations on proton and uranyl cation affinity. Proton affinity decreases by introduction of the solubilizing triethylene glycol group as compared to un-substituted reference ligands. Uranyl affinity was found to follow no discernable trends with incremental geometric modification. The butyl-linked 4Li-Me-3,2-HOPO ligand exhibited the highest uranyl affinity, consistent with prior in vivo decorporation results. Of the rigidly-linked ligands, the o-phenylene linker imparted the best uranyl affinity to the bis-Me-3,2-HOPO ligand platform.

  17. Regulation of the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene. Its role in the control of ketogenesis.

    PubMed Central

    Casals, N; Roca, N; Guerrero, M; Gil-Gómez, G; Ayté, J; Ciudad, C J; Hegardt, F G

    1992-01-01

    We have explored the role of mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase in regulating ketogenesis. We had previously cloned the cDNA for mitochondrial HMG-CoA synthase and have now studied the regulation in vivo of the expression of this gene in rat liver. The amount of processed mitochondrial HMG-CoA synthase mRNA is rapidly changed in response to cyclic AMP, insulin, dexamethasone and refeeding, and is greatly increased by starvation, fat feeding and diabetes. We conclude that one point of ketogenic control is exercised at the level of genetic expression of mitochondrial HMG-CoA synthase. Images Fig. 1. Fig. 4. PMID:1348927

  18. Redox homeostasis is compromised in vivo by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency in rat cerebral cortex and liver.

    PubMed

    da Rosa, M S; Seminotti, B; Amaral, A U; Fernandes, C G; Gasparotto, J; Moreira, J C F; Gelain, D P; Wajner, M; Leipnitz, G

    2013-12-01

    3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a disorder biochemically characterized by the predominant accumulation of 3-hydroxy-3-methylglutarate (HMG), 3-methylglutarate (MGA), 3-methylglutaconate and 3-hydroxyisovalerate in tissues and biological fluids of the affected patients. Neurological symptoms and hepatopathy are commonly found in HL deficiency, especially during metabolic crises. Since the mechanisms of tissue damage in this disorder are not well understood, in the present study we evaluated the ex vivo effects of acute administration of HMG and MGA on important parameters of oxidative stress in cerebral cortex and liver from young rats. In vivo administration of HMG and MGA provoked an increase of carbonyl and carboxy-methyl-lysine formation in cerebral cortex, but not in liver, indicating that these metabolites induce protein oxidative damage in the brain. We also verified that HMG and MGA significantly decreased glutathione concentrations in both cerebral cortex and liver, implying a reduction of antioxidant defenses. Furthermore, HMG and MGA increased 2',7'-dichlorofluorescin oxidation, but did not alter nitrate and nitrite content in cerebral cortex and liver, indicating that HMG and MGA effects are mainly mediated by reactive oxygen species. HMG and MGA also increased the activities of superoxide dismutase and catalase in cerebral cortex and liver, whereas MGA decreased glutathione peroxidase activity in cerebral cortex. Our present data showing a disruption of redox homeostasis in cerebral cortex and liver caused by in vivo administration of HMG and MGA suggest that this pathomechanism may possibly contribute to the brain and liver abnormalities observed in HL-deficient patients. PMID:24127998

  19. Hydroxylation and Epoxidation of Fatty Acids by Bacillus megaterium ALA2

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacillus megaterium ALA2 produces many new oxygenated fatty acids from linoleic acid. Strain ALA2 hydroxylated palmitic acid to omega-1, omega-2, and omega-3 hydroxy palmitate. Now we found that strain ALA2 also epoxidized linoleic acid to 12,13-epoxy-9(Z)-octadecenoic acid and 9,10-epoxy-12(Z)-oc...

  20. An Open-label Phase 2 Study of UX007 (Triheptanoin) in Subjects With Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)

    ClinicalTrials.gov

    2015-12-15

    Long-chain Fatty Acid Oxidation Disorders (LC-FAOD); Carnitine Palmitoyltransferase (CPT II) Deficiency; Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency; Longchain 3-hydroxy-acyl-CoA Dehydrogenase (LCHAD) Deficiency; Trifunctional Protein (TFP) Deficiency

  1. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions.

    PubMed

    Shitara, Yoshihisa; Sugiyama, Yuichi

    2006-10-01

    3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hypercholesterolemia. Their efficacy in preventing cardiovascular events has been shown by a large number of clinical trials. However, myotoxic side effects, sometimes severe, including myopathy or rhabdomyolysis, are associated with the use of statins. In some cases, such toxicity is associated with pharmacokinetic alterations. In this review, the pharmacokinetic aspects and physicochemical properties of statins are reviewed in order to understand the mechanism governing their pharmacokinetic alterations. Among the statins, simvastatin, lovastatin and atorvastatin are metabolized by cytochrome P450 3A4 (CYP3A4) while fluvastatin is metabolized by CYP2C9. Cerivastatin is subjected to 2 metabolic pathways mediated by CYP2C8 and 3A4. Pravastatin, rosuvastatin and pitavastatin undergo little metabolism. Their plasma clearances are governed by the transporters involved in the hepatic uptake and biliary excretion. Also for other statins, which are orally administered as open acid forms (i.e. fluvastatin, cerivastatin and atorvastatin), hepatic uptake transporter(s) play important roles in their clearances. Based on such information, pharmacokinetic alterations of statins can be predicted following coadministration of other drugs or in patients with lowered activities in drug metabolism and/or transport. We also present a quantitative analysis of the effect of some factors on the pharmacokinetics of statins based on a physiologically based pharmacokinetic model. To avoid a pharmacokinetic alteration, we need to have information about the metabolizing enzyme(s) and transporter(s) involved in the pharmacokinetics of statins and, along with such information, model-based prediction is also useful. PMID:16714062

  2. Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Synthesis, pharmacological, and molecular modeling studies.

    PubMed

    Colotta, Vittoria; Catarzi, Daniela; Varano, Flavia; Lenzi, Ombretta; Filacchioni, Guido; Costagli, Chiara; Galli, Alessandro; Ghelardini, Carla; Galeotti, Nicoletta; Gratteri, Paola; Sgrignani, Jacopo; Deflorian, Francesca; Moro, Stefano

    2006-10-01

    In this paper, the study of new 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione derivatives, designed as AMPA and kainate (KA) receptor antagonists, is reported. Some derivatives bear different carboxy-containing alkyl chains on the 3-hydroxy group, while various heterocyclic rings or amide moieties are present at the 6-position of other compounds. Binding data at Gly/NMDA, AMPA, and high-affinity KA receptors showed that the presence of the free 3-hydroxy group is of paramount importance for a good affinity at all three investigated receptors, while introduction of some 6-heterocyclic moieties yielded AMPA-selective antagonists. The most significant result was the finding of the 6-(2-carboxybenzoylamino)-3-hydroxy-1H-quinazolin-2,4-dione 12, which possesses good affinity for high-affinity and low-affinity KA receptors (Ki=0.62 microM and 1.6 microM, respectively), as well as good selectivity. To rationalize the trend of affinities of the reported derivatives, an intensive molecular modeling study was carried out by docking compounds to models of the Gly/NMDA, AMPA, and KA receptors. PMID:17004715

  3. Three spinach leaf nitrate reductase-3-hydroxy-3-methylglutaryl-CoA reductase kinases that are required by reversible phosphorylation and/or Ca2+ ions.

    PubMed Central

    Douglas, P; Pigaglio, E; Ferrer, A; Halfords, N G; MacKintosh, C

    1997-01-01

    In spinach (Spinacea oleracea L.) leaf extracts, three protein kinases (PKI, PKII and PKIII) were identified each of which phosphorylated spinach nitrate reductase on serine-543, and inactivated the enzyme in the presence of nitrate reductase inhibitor, 14-3-3. PKIII was also very active in phosphorylating and inactivating Arabidopsis (Landsberg erecta) 3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 (HMGR1). PKI and PKII phosphorylated HMGR1 more slowly than PKIII, compared with their relative rates of phosphorylation of nitrate reductase. HMGR1 identical with those that are seen after phosphorylation of serine-577 by the sucrose non-fermenting (SNF1)-like PK, 3-hydroxy-3-methylglutaryl-Co A reductase kinase A (HRK-A), from cauliflower [Dale, Arró, Becerra, Morrice, Boronat, Hardie and Ferrer (1995) Eur. J. Biochem. 233, 506-513]. PKI was Ca2+-dependent when prepared in the absence of protein phosphatase (PP) inhibitors, and largely Ca2+-dependent when prepared in the presence of PP inhibitors (NaF and EGTA). The Ca2+-independent portion of PKI was inactivated by either PP2A or PP2C, while the Ca2+-dependent portion of PKI became increasingly activated during storage, which we presume was mimicking the effect of an unidentified PP. These findings indicate that PK1 is regulated by two functionally distinct phosphorylations. PKI had a molecular mass of 45 kDa on gel filtration and was active towards substrate peptides that terminated at the +2 residue from the phosphorylation site, whereas PKIII was inactive towards these peptides. PKII was Ca2+-stimulated under all conditions tested. PKIII was Ca2+-indepdented, inactivated by PP2A or PP2C, had a requirement for a hydrophobic residue in the +4 position of peptide substrates, had a molecular mass by gel filtration of approximately 140 kDa, and an antibody against the rye SNF1-related PK (RKIN1) recognized a 58 kDa subunit in fractions containing PKIII. These properties of PKIII are identical with those reported

  4. 3-Hydroxy-3-methylglutaryl coenzyme A reductase in rainbow trout: effects of fasting and statin drugs on activities and mRNA transcripts.

    PubMed

    Estey, Chelsie; Chen, Xi; Moon, Thomas W

    2008-04-01

    Human pharmaceuticals including statin drugs are found in effluents post-waste water treatment plant. In order to establish whether statin drugs could affect an aquatic species, we initially characterized in the rainbow trout the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase or HMGCoAR which is the mammalian target of statin drugs. Two HMGCoAR transcripts (-1 and -2) were isolated to trout tissues and given their prevalence in liver and brain, these two tissues were used in activity assays. HMGCoAR activities were 87.2 and 66.0 pmol/min/mg protein for liver microsomes and whole brain homogenates. Liver activities were affected by conditions promoting phosphorylation but not by a 14 day fast; brain activities were differentially altered by fasting and re-feeding. Even though activities were altered by fasting, HMGCoAR-1 (but not -2) mRNA was reduced by fasting in both the liver and hypothalamus/pituitary. Both statin drugs (cerivastatin and atorvastatin) significantly decreased HMGCoAR activities in vitro and cerivastatin when injected significantly decreased hepatic but not brain activities; some changes in mRNA levels were noted. These studies demonstrate that at the concentrations of statins used in this study, effects on HMGCoAR activities and transcripts occur. Such changes could affect cholesterol content and may alter cholesterol dynamics in this species. PMID:18280795

  5. Laser videofluorometer system for real-time characterization of high-performance liquid chromatographic eluate. [3-hydroxy-benzo(a)pyrene

    SciTech Connect

    Skoropinski, D.B.; Callis, J.B.; Danielson, J.D.S.; Christian, G.D.

    1986-11-01

    A second generation videofluorometer has been developed for real-time characterization of high-performance liquid chromatographic eluate. The instrument features a nitrogen-laser-pumped dye laser as excitation source and quarter meter polychromator/microchannel plate-intensified diode array as fluorescence detector. The dye laser cavity is tuned with a moving-iron galvanometer scanner grating drive, permitting the laser output to be changed to any wavelength in its range in less than 40 ms. Thus, the optimum excitation wavelength can be chosen for each chromatographic region. A minimum detection limit of 13 pptr has been obtained for 3-hydroxy-benzo(a)pyrene in a conventional fluorescence cuvette with a 30-s data acquisition. For the same substance eluted chromatographically, a minimum detection limit of 50 pg has been obtained, and a linear dynamic range of greater than 3 orders of magnitude observed. An extract of soil that had been contaminated with polyaromatic hydrocarbons was analyzed as a practical test of the system, permitting the quantitation of three known species, and the identification and quantitation of a previously unknown fourth compound.

  6. The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model.

    PubMed

    Andrade-Pavón, Dulce; Sánchez-Sandoval, Eugenia; Rosales-Acosta, Blanca; Ibarra, José Antonio; Tamariz, Joaquín; Hernández-Rodríguez, César; Villa-Tanaca, Lourdes

    2014-01-01

    The enzyme 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzes the conversion of HMG-Co-A into mevalonate. This step is the limiting point for the synthesis of cholesterol in mammals and ergosterol in fungi. We describe in this article the genome organization of HMGR coding genes and those deduced from different fungi, recount the evidence showing statins as HMGR inhibitors for ergosterol synthesis and its effect in yeast viability, and propose fungal HMGR (HMGRf) as a model to study the use of pharmaceutical compounds to inhibit cholesterol and ergosterol synthesis. Bibliographical search and bioinformatic analyses were performed and discussed. HMGRfs belong to the class I with a high homology in the catalytic region. The sterol biosynthetic pathway in humans and fungi share many enzymes in the initial steps (such as the HMGR enzyme), but in the last steps enzymes are different rendering the two final products: cholesterol in mammals and ergosterol in fungi. With regards to inhibitors such as statins and other compounds, these affect also fungal viability. Since HMGR from Schizosaccharomyces pombe and Ustilago maydis are very similar to the human HMGR in the catalytic regions, we propose that fungal enzymes can be used to test inhibitors for a potential use in humans. We consider that HMGRf is a good therapeutic target to design and test new antifungal compounds. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012). PMID:24270073

  7. Flavonoids from the buds of Rosa damascena inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme a reductase and angiotensin I-converting enzyme.

    PubMed

    Kwon, Eun-Kyung; Lee, Dae-Young; Lee, Hyungjae; Kim, Dae-Ok; Baek, Nam-In; Kim, Young-Eon; Kim, Hae-Yeong

    2010-01-27

    Rosa damascena has been manufactured as various food products, including tea, in Korea. A new flavonoid glycoside, kaempferol-3-O-beta-D-glucopyranosyl(1-->4)-beta-D-xylopyranoside, named roxyloside A was isolated from the buds of this plant, along with four known compounds, isoquercitrin, afzelin, cyanidin-3-O-beta-glucoside, and quercetin gentiobioside. The chemical structures of these compounds were determined by spectroscopic analyses, including FAB-MS, UV, IR, (1)H and (13)C NMR, DEPT, and 2D NMR (COSY, HSQC, and HMBC). All the isolated compounds except cyanidin-3-O-beta-glucoside exhibited high levels of inhibitory activity against 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase with IC(50) values ranging from 47.1 to 80.6 microM. Cyanidin-3-O-beta-glucoside significantly suppressed angiotensin I-converting enzyme (ACE) activity, with an IC(50) value of 138.8 microM, while the other four compounds were ineffective. These results indicate that R. damascena and its flavonoids may be effective to improve the cardiovascular system. PMID:20038104

  8. 3'-hydroxy-3,4,5,4'-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model.

    PubMed

    Piotrowska-Kempisty, Hanna; Ruciński, Marcin; Borys, Sylwia; Kucińska, Małgorzata; Kaczmarek, Mariusz; Zawierucha, Piotr; Wierzchowski, Marcin; Łażewski, Dawid; Murias, Marek; Jodynis-Liebert, Jadwiga

    2016-01-01

    In screening studies, the cytotoxic activity of four metabolites of resveratrol analogue 3,4,5,4'-tetramethoxystilbene (DMU-212) against A-2780 and SKOV-3 ovarian cancer cells was investigated. The most active metabolite, 3'-hydroxy-3,4,5,4'-tetramethoxystilbene (DMU-214), was chosen for further studies. The cytotoxicity of DMU-214 was shown to be higher than that of the parent compound, DMU-212, in both cell lines tested. Since DMU-212 was supposed to undergo metabolic activation through its conversion to DMU-214, an attempt was made to elucidate the mechanism of its anti-proliferative activity. We found that in SKOV-3 cells lacking p53, DMU-214 induced receptor-mediated apoptosis. In A-2780 cell line with expression of wild-type p53, DMU-214 modulated the expression pattern of p53-target genes driving intrinsic and extrinsic apoptosis pathways, as well as DNA repair and damage prevention. Regardless of the up-regulation of p48, p53R2, sestrins and Gaad45 genes involved in cancer cell DNA repair, we demonstrated the stronger anti-proliferative and pro-apoptotic effects of DMU-214 in A-2780 cells when compared to those in SKOV-3. Hence we verified DMU-214 activity in the xenograft model using SCID mice injected with A-2780 cells. The strong anti-proliferative activity of DMU-214 in the in vivo model allowed to suggest the tested compound as a potential therapeutic in ovarian cancer treatment. PMID:27585955

  9. Purification of a vitamin K epoxide reductase that catalyzes conversion of vitamin K 2,3-epoxide to 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone.

    PubMed Central

    Mukharji, I; Silverman, R B

    1985-01-01

    An enzyme from bovine liver microsomes that catalyzes the reduction of vitamin K 2,3-epoxide to 2- and 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone was purified 1152-fold to apparent homogeneity. Microsomes were solubilized with 3-[3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), and the enzyme was purified by chromatography on PBE-94 ion exchanger, hydroxylapatite, and DEAE-cellulose, and then gel filtration on Sephacryl S-200. The homogeneity of the final preparation was established by polyacrylamide slab gel electrophoresis in the presence of sodium dodecyl sulfate. The molecular weight of the native enzyme is 25,000 and that of denatured enzyme is 12,400, which suggests that the enzyme is a dimer with identical subunits. No chromophoric cofactors are associated with the enzyme. Dithiothreitol and CHAPS are essential for activity, but high concentrations of glycerol reduces the activity. The enzyme is not inhibited by warfarin, a potent inhibitor of the vitamin K epoxide reductase, which catalyzes the conversion of vitamin K 2,3-epoxide to vitamin K. Evidence is presented indicating that the purified enzyme is not simply a fragment of the warfarin-sensitive vitamin K epoxide reductase. Images PMID:3857611

  10. The Influence of Linker Geometry on Uranyl Complexation by Rigidly-Linked Bis(3-hydroxy-N-methyl-pyridin-2-one)

    SciTech Connect

    Szigethy, Geza; Raymond, Kenneth

    2010-04-22

    A series of bis(3-hydroxy-N-methyl-pyridin-2-one) ligands was synthesized, and their respective uranyl complexes were characterized by single crystal X-ray diffraction analyses. These structures were inspected for high-energy conformations and evaluated using a series of metrics to measure co-planarity of chelating moieties with each other and the uranyl coordination plane, as well as to measure coordinative crowding about the uranyl dication. Both very short (ethyl, 3,4-thiophene and o-phenylene) and very long ({alpha},{alpha}{prime}-m-xylene and 1,8-fluorene) linkers provide optimal ligand geometries about the uranyl cation, resulting in planar, unstrained molecular arrangements. The planarity of the rigid linkers also suggests there is a degree of pre-organization for a planar coordination mode that is ideal for uranyl-selective ligand design. Comparison of intramolecular N{sub amide}-O{sub phenolate} distances and {sup 1}H NMR chemical shifts of amide protons supports earlier results that short linkers provide the optimal geometry for intramolecular hydrogen bonding.

  11. Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver.

    PubMed

    Hwang, Seonghwan; Hartman, Isamu Z; Calhoun, Leona N; Garland, Kristina; Young, Gennipher A; Mitsche, Matthew A; McDonald, Jeffrey; Xu, Fang; Engelking, Luke; DeBose-Boyd, Russell A

    2016-06-24

    Accumulation of sterols in endoplasmic reticulum membranes stimulates the ubiquitination of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a rate-limiting step in synthesis of cholesterol. This ubiquitination marks HMGCR for proteasome-mediated degradation and constitutes one of several mechanisms for feedback control of cholesterol synthesis. Mechanisms for sterol-accelerated ubiquitination and degradation of HMGCR have been elucidated through the study of cultured mammalian cells. However, the extent to which these reactions modulate HMGCR and contribute to control of cholesterol metabolism in whole animals is unknown. Here, we examine transgenic mice expressing in the liver the membrane domain of HMGCR (HMGCR (TM1-8)), a region necessary and sufficient for sterol-accelerated degradation, and knock-in mice in which endogenous HMGCR harbors mutations that prevent sterol-induced ubiquitination. Characterization of transgenic mice revealed that HMGCR (TM1-8) is appropriately regulated in the liver of mice fed a high cholesterol diet or chow diet supplemented with the HMGCR inhibitor lovastatin. Ubiquitination-resistant HMGCR protein accumulates in the liver and other tissues disproportionately to its mRNA, indicating that sterol-accelerated degradation significantly contributes to feedback regulation of HMGCR in vivo Results of these studies demonstrate that HMGCR is subjected to sterol-accelerated degradation in the liver through mechanisms similar to those established in cultured cells. Moreover, these studies designate sterol-accelerated degradation of HMGCR as a potential therapeutic target for prevention of atherosclerosis and associated cardiovascular disease. PMID:27129778

  12. (S)-3-hydroxy-3-methylglutaryl coenzyme A reductase, a product of the mva operon of Pseudomonas mevalonii, is regulated at the transcriptional level.

    PubMed Central

    Wang, Y L; Beach, M J; Rodwell, V W

    1989-01-01

    We have cloned and sequenced a 505-base-pair (bp) segment of DNA situated upstream of mvaA, the structural gene for (S)-3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.88) of Pseudomonas mevalonii. The DNA segment that we characterized includes the promoter region for the mva operon. Nuclease S1 mapping and primer extension analysis showed that mvaA is the promoter-proximal gene of the mva operon. Transcription initiates at -56 bp relative to the first A (+1) of the translation start site. Transcription in vivo was induced by mevalonate. Structural features of the mva promoter region include an 80-bp A + T-rich region, and -12, -24 consensus sequences that resemble sequences of sigma 54 promoters in enteric organisms. The relative amplitudes of catalytic activity, enzyme protein, and mvaA mRNA are consistent with a model of regulation of this operon at the transcriptional level. Images PMID:2477360

  13. Species-specific expansion and molecular evolution of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) gene family in plants.

    PubMed

    Li, Wei; Liu, Wei; Wei, Hengling; He, Qiuling; Chen, Jinhong; Zhang, Baohong; Zhu, Shuijin

    2014-01-01

    The terpene compounds represent the largest and most diverse class of plant secondary metabolites which are important in plant growth and development. The 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR; EC 1.1.1.34) is one of the key enzymes contributed to terpene biosynthesis. To better understand the basic characteristics and evolutionary history of the HMGR gene family in plants, a genome-wide analysis of HMGR genes from 20 representative species was carried out. A total of 56 HMGR genes in the 14 land plant genomes were identified, but no genes were found in all 6 algal genomes. The gene structure and protein architecture of all plant HMGR genes were highly conserved. The phylogenetic analysis revealed that the plant HMGRs were derived from one ancestor gene and finally developed into four distinct groups, two in the monocot plants and two in dicot plants. Species-specific gene duplications, caused mainly by segmental duplication, led to the limited expansion of HMGR genes in Zea mays, Gossypium raimondii, Populus trichocarpa and Glycine max after the species diverged. The analysis of Ka/Ks ratios and expression profiles indicated that functional divergence after the gene duplications was restricted. The results suggested that the function and evolution of HMGR gene family were dramatically conserved throughout the plant kingdom. PMID:24722776

  14. Enhanced accumulation of phytosterol and triterpene in hairy root cultures of Platycodon grandiflorum by overexpression of Panax ginseng 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

    PubMed

    Kim, Yong-Kyoung; Kim, Jae Kwang; Kim, Yeon Bok; Lee, Sanghyun; Kim, Soo-Un; Park, Sang Un

    2013-02-27

    3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) catalyzes the rate-limiting step in the mevalonate pathway. To elucidate the functions of HMGR in triterpene biosynthesis, Platycodon grandiflorum was transformed with a construct expressing Panax ginseng HMGR (PgHMGR). We used PCR analysis to select transformed hairy root lines and selected six lines for further investigation. Quantitative real-time PCR showed higher expression levels of HMGR and total platycoside levels (1.5-2.5-fold increase) in transgenic lines than in controls. Phytosterols levels were also 1.1-1.6-fold higher in transgenic lines than in controls. Among these lines, line T7 produced the highest level of total platycosides (1.60 ± 0.2 mg g(-1) dry weight) and α-spinasterol (1.78 ± 0.16 mg g(-1) dry weight). These results suggest that metabolic engineering of P. grandiflorum by Agrobacterium-mediated genetic transformation may enhance production of phytosterols and triterpenoids. PMID:23298228

  15. 3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies.

    PubMed

    Colotta, Vittoria; Lenzi, Ombretta; Catarzi, Daniela; Varano, Flavia; Squarcialupi, Lucia; Costagli, Chiara; Galli, Alessandro; Ghelardini, Carla; Pugliese, Anna Maria; Maraula, Giovanna; Coppi, Elisabetta; Pellegrini-Giampietro, Domenico E; Pedata, Felicita; Sabbadin, Davide; Moro, Stefano

    2012-08-01

    Based on our 3-hydroxy-7-chloroquinazoline-2,4-dione derivatives, previously reported as antagonists at ionotropic glutamate receptors, we synthesized new 3-hydroxyquinazoline-2,4-diones bearing a trifluoromethyl group at the 7-position and different groups at position 6. Glycine/NMDA, AMPA and kainate receptor binding data showed that the 7-trifluoromethyl residue increased AMPA and kainate receptor affinity and selectivity, with respect to the 7-chlorine atom. Among the probed 6-substituents, the 6-(1,2,4-triazol-4-yl) group (compound 8) was the most advantageous for AMPA receptor affinity and selectivity. Derivative 8 demonstrated to be effective in decreasing neuronal damage produced by oxygen and glucose deprivation in organotypic rat hippocampal slices and also showed anticonvulsant effects in pentylenetetrazole-induced convulsions. The previously reported kainate receptor antagonist 6-(2-carboxybenzoyl)-amino-7-chloro-3-hydroxyquinazoline-2,4-dione 3 prevented the failure of neurotransmission induced by oxygen and glucose deprivation in the CA1 region of rat hippocampal slices. PMID:22704999

  16. Familial Hypercholesterolemia: Identification of a Defect in the Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity Associated with Overproduction of Cholesterol

    PubMed Central

    Goldstein, Joseph L.; Brown, Michael S.

    1973-01-01

    The homozygous form of the autosomal dominant disorder, familial hypercholesterolemia, is characterized by the presence in children of profound hypercholesterolemia, cutaneous planar xanthomas, and rapidly progressive coronary vascular disease that usually results in death before age 30 years. Cultured skin fibroblasts from three unrelated subjects with this disorder showed 40- to 60-fold higher activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34), the rate-controlling enzyme in cholesterol biosynthesis, when compared with fibroblasts of seven control subjects. Enhanced enzyme activity resulted from a complete absence of normal feedback suppression by low-density lipoproteins, which led to a marked overproduction of cholesterol by the mutant cells. The demonstration of apparently identical kinetic properties of the reductase activity of control and mutant cells, coupled with the evidence that this enzyme is normally regulated not by allosteric effectors but by alterations in enzyme synthesis and degradation, suggests that the primary genetic abnormality does not involve the structural gene for the enzyme itself, but a hitherto unidentified gene whose product is necessary for mediation of feedback control by lipoproteins. The fibroblasts of two obligate heterozygotes, the parents of one of the homozygotes, showed a pattern of enzyme regulation intermediate between that of controls and homozygotes. PMID:4355366

  17. Regulation of synthesis and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase by low density lipoprotein and 25-hydroxycholesterol in UT-1 cells.

    PubMed Central

    Faust, J R; Luskey, K L; Chin, D J; Goldstein, J L; Brown, M S

    1982-01-01

    UT-1 cells are a clone of Chinese hamster ovary cells that were selected to grow in the presence of compactin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]. These cells have 100- to 1,000-fold more immunoprecipitable reductase than normal. The enzyme activity is rapidly decreased when low density lipoprotein (LDL) or 25-hydroxycholesterol is added to the culture medium. In this current study, a quantitative immunoprecipitation assay was used to determine whether LDL and 25-hydroxycholesterol inhibit the synthesis or stimulate the degradation of reductase in UT-1 cells. Each of these agents inhibited the incorporation of [35S]methionine into immunoprecipitable reductase by more than 98%. Pulse-chase experiments showed that reductase was degraded with a half-life of 10-13 hr in UT-1 cells and that the rate of degradation of preformed enzyme was increased 3-fold by the addition of either LDL or 25-hydroxycholesterol. We conclude that the predominant mechanism by which LDL and 25-hydroxycholesterol decrease reductase activity in UT-1 cells is a profound suppression of synthesis of the enzyme. Images PMID:6957860

  18. Effect of tris(3-hydroxy-4-pyridinonate) iron(III) complexes on iron uptake and storage in soybean (Glycine max L.).

    PubMed

    Santos, Carla S; Carvalho, Susana M P; Leite, Andreia; Moniz, Tânia; Roriz, Mariana; Rangel, António O S S; Rangel, Maria; Vasconcelos, Marta W

    2016-09-01

    Iron deficiency chlorosis (IDC) is a serious environmental problem affecting the growth of several crops in the world. The application of synthetic Fe(III) chelates is still one of the most common measures to correct IDC and the search for more effective Fe chelates remains an important issue. Herein, we propose a tris(3-hydroxy-4-pyridinonate) iron(III) complex, Fe(mpp)3, as an IDC corrector. Different morphological, biochemical and molecular parameters were assessed as a first step towards understanding its mode of action, compared with that of the commercial fertilizer FeEDDHA. Plants treated with the pyridinone iron(III) complexes were significantly greener and had increased biomass. The total Fe content was measured using ICP-OES and plants treated with pyridinone complexes accumulated about 50% more Fe than those treated with the commercial chelate. In particular, plants supplied with compound Fe(mpp)3 were able to translocate iron from the roots to the shoots and did not elicit the expression of the Fe-stress related genes FRO2 and IRT1. These results suggest that 3,4-HPO iron(III) chelates could be a potential new class of plant fertilizing agents. PMID:27156133

  19. Vibrational spectroscopic (FT-IR and FT-Raman) studies, natural bond orbital analysis and molecular electrostatic potential surface of 3-hydroxy-6-methyl-2-nitropyridine

    NASA Astrophysics Data System (ADS)

    Karnan, M.; Balachandran, V.; Murugan, M.

    2012-10-01

    The optimized molecular structure and corresponding vibrational assignments of 3-hydroxy-6-methyl-2-nitropyridine have been investigated using density functional theory (DFT) B3LYP method with 6-311++G(d,p), 6-311++G(2d,2p) and 6-311++G(3d,3p) basis sets. Investigation of the relative orientation of the hydroxyl group with respect to the nitro group has shown that two conformers (O-cis) and (O-trans) exist. The vibrational analysis of the stable conformer of the title compound is performed by means of infrared absorption and Raman spectroscopy in combination with theoretical simulations. The molecular stability and bond strength were investigated by applying the natural bond orbital (NBO) analysis. Information about the size, shape, charge density distribution and site of chemical reactivity of the molecule has been obtained by mapping electron density isosurface with electrostatic potential (ESP). The isotropic chemical shift computed by 1H and 13C nuclear magnetic resonance (NMR) chemical shifts of the HMNP calculated using the gauge invariant atomic orbital (GIAO) method also shows good agreement with experimental observations.

  20. Conformational flexibility and absolute stereochemistry of (3R)-3-hydroxy-4-aryl-β-lactams investigated by chiroptical properties and TD-DFT calculations.

    PubMed

    Tedesco, Daniele; Zanasi, Riccardo; Guerrini, Andrea; Bertucci, Carlo

    2012-09-01

    The effect of conformational flexibility on the chiroptical properties of a series of synthetic (3R)-3-hydroxy-4-aryl-β-lactams of known stereochemistry (1-6) was investigated by means of electronic circular dichroism (ECD) measurements and time-dependent density functional theory (TD-DFT) calculations. The application of the β-lactam sector rules allowed a correct stereochemical characterization of these compounds, with the exception of a thienyl-substituted derivative (cis-). TD-DFT calculations yielded accurate predictions of experimental ECD spectra and [α](D) values, allowing us to assign the correct absolute configuration to all the investigated compounds. A detailed analysis of the β-lactam ring equilibrium geometry on optimized conformers identified regular patterns for the arrangement of atoms around the amide chromophore, confirming the validity of the β-lactam sector rules. However, relevant variations in theoretical chiroptical properties were found for compounds bearing a heterocyclic substituent at C4 or a phenyl substituent at C3, whose conformers deviate from these regular geometric patterns. This behavior explains the failure of the β-lactam sector rules in cis-. This study showed the importance of conformational flexibility for the determination of chiroptical properties and highlighted the strengths and weaknesses of the different methods for the stereochemical characterization of chiral molecules in solution. PMID:22544665

  1. Isolation of pig mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene promoter: characterization of a peroxisome proliferator-responsive element.

    PubMed Central

    Ortiz, J A; Mallolas, J; Nicot, C; Bofarull, J; Rodríguez, J C; Hegardt, F G; Haro, D; Marrero, P F

    1999-01-01

    Low expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene during development correlates with an unusually low hepatic ketogenic capacity and lack of hyperketonaemia in piglets. Here we report the isolation and characterization of the 5' end of the pig mitochondrial HMG-CoA synthase gene. The 581 bp region proximal to the transcription start site permits transcription of a reporter gene, confirming the function of the promoter. The pig mitochondrial HMG-CoA synthase promoter is trans-activated by the peroxisomal proliferator-activated receptor (PPAR), and a functional response element for PPAR (PPRE) has been localized in the promoter region. Pig PPRE is constituted by an imperfect direct repeat (DR-1) and a downstream sequence, both of which are needed to confer PPAR-sensitivity to a thymidine kinase promoter and to form complexes with PPAR.retinoid X receptor heterodimers. A role of PPAR trans-activation in starvation-associated induction of gene expression is suggested. PMID:9882632

  2. Butyric acid in irritable bowel syndrome.

    PubMed

    Załęski, Andrzej; Banaszkiewicz, Aleksandra; Walkowiak, Jarosław

    2013-01-01

    Butyric acid (butanoic acid) belongs to a group of short-chain fatty acids and is thought to play several beneficial roles in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as a main source of energy. Moreover, butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflammatory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric acid in IBS. PMID:24868283

  3. Butyric acid in irritable bowel syndrome

    PubMed Central

    Załęski, Andrzej; Walkowiak, Jarosław

    2013-01-01

    Butyric acid (butanoic acid) belongs to a group of short-chain fatty acids and is thought to play several beneficial roles in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as a main source of energy. Moreover, butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflammatory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric acid in IBS. PMID:24868283

  4. Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8.

    PubMed

    Gardinier, Kevin M; Gernert, Douglas L; Porter, Warren J; Reel, Jon K; Ornstein, Paul L; Spinazze, Patrick; Stevens, F Craig; Hahn, Patric; Hollinshead, Sean P; Mayhugh, Daniel; Schkeryantz, Jeff; Khilevich, Albert; De Frutos, Oscar; Gleason, Scott D; Kato, Akihiko S; Luffer-Atlas, Debra; Desai, Prashant V; Swanson, Steven; Burris, Kevin D; Ding, Chunjin; Heinz, Beverly A; Need, Anne B; Barth, Vanessa N; Stephenson, Gregory A; Diseroad, Benjamin A; Woods, Tim A; Yu, Hong; Bredt, David; Witkin, Jeffrey M

    2016-05-26

    Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients. PMID:27067148

  5. Endocytic Adaptor Epidermal Growth Factor Receptor Substrate 15 (Eps15) Is Involved in the Trafficking of Ubiquitinated α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors*

    PubMed Central

    Lin, Amy; Man, Heng-Ye

    2014-01-01

    AMPA-type glutamate receptors (AMPARs) play a critical role in mediating fast excitatory synaptic transmission in the brain. Alterations in receptor expression, distribution, and trafficking have been shown to underlie synaptic plasticity and higher brain functions, including learning and memory, as well as brain dysfunctions such as drug addiction and psychological disorders. Therefore, it is essential to elucidate the molecular mechanisms that regulate AMPAR dynamics. We have shown previously that mammalian AMPARs are subject to posttranslational modification by ubiquitin, with AMPAR ubiquitination enhancing receptor internalization and reducing AMPAR cell surface expression. Here we report a crucial role for epidermal growth factor receptor substrate 15 (Eps15), an endocytic adaptor, in ubiquitination-dependent AMPAR internalization. We find that suppression or overexpression of Eps15 results in changes in AMPAR surface expression. Eps15 interacts with AMPARs, which requires Nedd4-mediated GluA1 ubiquitination and the ubiquitin-interacting motif of Eps15. Importantly, we find that Eps15 plays an important role in AMPAR internalization. Knockdown of Eps15 suppresses the internalization of GluA1 but not the mutant GluA1 that lacks ubiquitination sites, indicating a role of Eps15 for the internalization of ubiquitinated AMPARs. These results reveal a novel molecular mechanism employed specifically for the trafficking of the ubiquitin-modified AMPARs. PMID:25023288

  6. Dynamic Regulation of N-Methyl-d-aspartate (NMDA) and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors by Posttranslational Modifications.

    PubMed

    Lussier, Marc P; Sanz-Clemente, Antonio; Roche, Katherine W

    2015-11-27

    Many molecular mechanisms underlie the changes in synaptic glutamate receptor content that are required by neuronal networks to generate cellular correlates of learning and memory. During the last decade, posttranslational modifications have emerged as critical regulators of synaptic transmission and plasticity. Notably, phosphorylation, ubiquitination, and palmitoylation control the stability, trafficking, and synaptic expression of glutamate receptors in the central nervous system. In the current review, we will summarize some of the progress made by the neuroscience community regarding our understanding of phosphorylation, ubiquitination, and palmitoylation of the NMDA and AMPA subtypes of glutamate receptors. PMID:26453298

  7. Preparation of 4-amino-2,4-dioxobutanoic acid

    DOEpatents

    Unkefer, Pat J.; Martinez, Rodolfo A.; Glass, David R.

    2015-06-02

    A process for synthesizing 4-amino-2,4-dioxobutanoic acid involves reacting diethyl oxalate with sodium ethoxide in ethanol to form a reaction mixture, and afterward adding ethyl cyanoacetate to the reaction mixture and allowing a reaction to proceed under conditions suitable to form a first reaction product of the formula diethyl-2-cyano-3-hydroxy-butenedioate, and then isolating the diethyl-2-cyano-3-hydroxybutenedioate, and afterward reacting the diethyl-2-cyano-3-hydroxy-butenedioate with aqueous sodium hydroxide under conditions suitable to form 4-amino-2,4-dioxobutanoic acid.

  8. New beauveriolides produced by amino acid-supplemented fermentation of Beauveria sp. FO-6979.

    PubMed

    Matsuda, Daisuke; Namatame, Ichiji; Tomoda, Hiroshi; Kobayashi, Susumu; Zocher, Rainer; Kleinkauf, Horst; Omura, Satoshi

    2004-01-01

    Five new beauveriolides were isolated from the acetone extracts of Beauveria sp. FO-6979 mycelia fermented in amino acid-supplemented media. The structures were elucidated by spectroscopic studies including NMR experiments and chemical degradation. All the beauveriolides are cyclodepsipeptides consisting of one 3-hydroxy-4-methyl fatty acid, two L-amino acids and one D-amino acid in common. Beauveriolide VII with the structure of cyclo-[3-hydroxy-4-methyloctanoyl-L-phenylalanyl-L-alanyl-D-valyl] inhibited lipid droplet formation and cholesteryl ester synthesis in macrophages, but the other beauveriolides showed only slight or almost no effect on lipid droplet formation. PMID:15032479

  9. The effects of the 3-hydroxy, 3-methylglutaryl coenzyme A reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease.

    PubMed

    Smit, J W; van Erpecum, K J; Renooij, W; Stolk, M F; Edgar, P; Doornewaard, H; Vanberge-Henegouwen, G P

    1995-06-01

    3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce biliary cholesterol saturation index (CSI) in duodenal bile in hypercholesterolemic patients and might be useful for gallstone dissolution. However, preliminary data suggest that these drugs are not effective in this respect. We therefore studied 33 patients with radiolucent gallstones in an opacifying gallbladder who were scheduled for elective cholecystectomy. Patients were treated with 40 mg pravastatin day-1 or placebo during the 3 weeks before surgery. Six patients could not be evaluated. Baseline characteristics (age, sex, body mass index, serum cholesterol, and the solitary/multiple gallstone ratio) were similar in both groups. Serum cholesterol fell by 39% in the pravastatin group (P < .001) and remained unchanged in the placebo group. Biliary cholesterol (9.5 +/- 1.3 vs. 14.3 +/- 1.5 mmol/L, P = .026), and phospholipid concentrations (24.8 +/- 3.9 vs. 36.7 +/- 3.9 mmol/L, P = .043) were lower in the pravastatin group. Although bile salt concentrations were lower in the pravastatin group (114 +/- 21 vs. 152 +/- 15 mmol/L), this difference was not significant. CSI was not different between both groups (142 +/- 27% [pravastatin] vs. 113 +/- 6% [placebo], P = NS). Cholesterol crystals were present in fresh bile in 7 of 13 patients in the pravastatin group and in 11 of 14 controls (P = NS). Nucleation time was comparable between the 2 groups (13 +/- 3 vs. 9 +/- 3 days, P = NS). Bile salt species and molecular species of phospholipids determined with high-performance liquid chromatography did not differ either between both groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7768495

  10. Bivalent transition metal complexes of o-hydroxyacetophenone [N-(3-hydroxy-2-naphthoyl)] hydrazone: Spectroscopic, antibacterial, antifungal activity and thermogravimetric studies

    NASA Astrophysics Data System (ADS)

    Zaky, R. R.; Ibrahim, K. M.; Gabr, I. M.

    2011-10-01

    Schiff base complexes of Cu(II), Ni(II) and Zn(II) with the o-hydroxyacetophenone [N-(3-hydroxy-2-naphthoyl)] hydrazone (H 2o-HAHNH) containing N and O donor sites have been synthesized. Both ligand and its metal complexes were characterized by different physicochemical methods, elemental analysis, molar conductivity ( 1H NMR, 13C NMR, IR, UV-visible, ESR, MS spectra) and also thermal analysis (TG and DTG) techniques. The discussion of the outcome data of the prepared complexes indicates that the ligand behave as a bidentate and/or tridentate ligand. The electronic spectra of the complexes as well as their magnetic moments suggest octahedral geometries for all isolated complexes. The room temperature solid state ESR spectrum of the Cu(II) complex shows d x2- y2 as a ground state, suggesting tetragonally distorted octahedral geometry around Cu(II) centre. The molar conductance measurements proved that the complexes are non-electrolytes. The kinetic thermodynamic parameters such as: E#, Δ H#, Δ G#, Δ S# are calculated from the DTG curves, for the [Ni(H O-HAHNH) 2] and [Zn(H 2 O-HAHNH)(OAc) 2]·H 2O complexes using the Coats-Redfern equation. Also, the antimicrobial properties of all compounds were studied using a wide spectrum of bacterial and fungal strains. The [Cu(H o-HAHNH)(OAc)(H 2O) 2] complex was the most active against all strains, including Aspergillus sp., Stemphylium sp. and Trichoderma sp. Fungi; E. coli and Clostridium sp. Bacteria.

  11. Proliferation and Morphogenesis of the Endoplasmic Reticulum Driven by the Membrane Domain of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Plant Cells1[OPEN

    PubMed Central

    Ferrero, Sergi; Grados-Torrez, Ricardo Enrique; Antolín-Llovera, Meritxell; López-Iglesias, Carmen; Cortadellas, Nuria; Ferrer, Joan Carles

    2015-01-01

    The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) has a key regulatory role in the mevalonate pathway for isoprenoid biosynthesis and is composed of an endoplasmic reticulum (ER)-anchoring membrane domain with low sequence similarity among eukaryotic kingdoms and a conserved cytosolic catalytic domain. Organized smooth endoplasmic reticulum (OSER) structures are common formations of hypertrophied tightly packed ER membranes devoted to specific biosynthetic and secretory functions, the biogenesis of which remains largely unexplored. We show that the membrane domain of plant HMGR suffices to trigger ER proliferation and OSER biogenesis. The proliferating membranes become highly enriched in HMGR protein, but they do not accumulate sterols, indicating a morphogenetic rather than a metabolic role for HMGR. The N-terminal MDVRRRPP motif present in most plant HMGR isoforms is not required for retention in the ER, which was previously proposed, but functions as an ER morphogenic signal. Plant OSER structures are morphologically similar to those of animal cells, emerge from tripartite ER junctions, and mainly build up beside the nuclear envelope, indicating conserved OSER biogenesis in high eukaryotes. Factors other than the OSER-inducing HMGR construct mediate the tight apposition of the proliferating membranes, implying separate ER proliferation and membrane association steps. Overexpression of the membrane domain of Arabidopsis (Arabidopsis thaliana) HMGR leads to ER hypertrophy in every tested cell type and plant species, whereas the knockout of the HMG1 gene from Arabidopsis, encoding its major HMGR isoform, causes ER aggregation at the nuclear envelope. Our results show that the membrane domain of HMGR contributes to ER morphogenesis in plant cells. PMID:26015445

  12. Geranylgeranyl Pyrophosphate Is a Potent Regulator of HRD-dependent 3-Hydroxy-3-methylglutaryl-CoA Reductase Degradation in Yeast*

    PubMed Central

    Garza, Renee M.; Tran, Peter N.; Hampton, Randolph Y.

    2009-01-01

    3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), the rate-limiting enzymes of sterol synthesis, undergoes feedback-regulated endoplasmic reticulum degradation in both mammals and yeast. The yeast Hmg2p isozyme is subject to ubiquitin-mediated endoplasmic reticulum degradation by the HRD pathway. We had previously shown that alterations in cellular levels of the 15-carbon sterol pathway intermediate farnesyl pyrophosphate (FPP) cause increased Hmg2p ubiquitination and degradation. We now present evidence that the FPP-derived, 20-carbon molecule geranylgeranyl pyrophosphate (GGPP) is a potent endogenous regulator of Hmg2p degradation. This work was launched by the unexpected observation that GGPP addition directly to living yeast cultures caused high potency and specific stimulation of Hmg2p degradation. This effect of GGPP was not recapitulated by FPP, GGOH, or related isoprenoids. GGPP-caused Hmg2p degradation met all the criteria for the previously characterized endogenous signal. The action of added GGPP did not require production of endogenous sterol molecules, indicating that it did not act by causing the build-up of an endogenous pathway signal. Manipulation of endogenous GGPP by several means showed that naturally made GGPP controls Hmg2p stability. Analysis of the action of GGPP indicated that the molecule works upstream of retrotranslocation and can directly alter the structure of Hmg2p. We propose that GGPP is the FPP-derived regulator of Hmg2p ubiquitination. Intriguingly, the sterol-dependent degradation of mammalian HMGR is similarly stimulated by the addition of GGOH to intact cells, implying that a dependence on 20-carbon geranylgeranyl signals may be a common conserved feature of HMGR regulation that may lead to highly specific therapeutic approaches for modulation of HMGR. PMID:19776008

  13. Proliferation and Morphogenesis of the Endoplasmic Reticulum Driven by the Membrane Domain of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Plant Cells.

    PubMed

    Ferrero, Sergi; Grados-Torrez, Ricardo Enrique; Leivar, Pablo; Antolín-Llovera, Meritxell; López-Iglesias, Carmen; Cortadellas, Nuria; Ferrer, Joan Carles; Campos, Narciso

    2015-07-01

    The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) has a key regulatory role in the mevalonate pathway for isoprenoid biosynthesis and is composed of an endoplasmic reticulum (ER)-anchoring membrane domain with low sequence similarity among eukaryotic kingdoms and a conserved cytosolic catalytic domain. Organized smooth endoplasmic reticulum (OSER) structures are common formations of hypertrophied tightly packed ER membranes devoted to specific biosynthetic and secretory functions, the biogenesis of which remains largely unexplored. We show that the membrane domain of plant HMGR suffices to trigger ER proliferation and OSER biogenesis. The proliferating membranes become highly enriched in HMGR protein, but they do not accumulate sterols, indicating a morphogenetic rather than a metabolic role for HMGR. The N-terminal MDVRRRPP motif present in most plant HMGR isoforms is not required for retention in the ER, which was previously proposed, but functions as an ER morphogenic signal. Plant OSER structures are morphologically similar to those of animal cells, emerge from tripartite ER junctions, and mainly build up beside the nuclear envelope, indicating conserved OSER biogenesis in high eukaryotes. Factors other than the OSER-inducing HMGR construct mediate the tight apposition of the proliferating membranes, implying separate ER proliferation and membrane association steps. Overexpression of the membrane domain of Arabidopsis (Arabidopsis thaliana) HMGR leads to ER hypertrophy in every tested cell type and plant species, whereas the knockout of the HMG1 gene from Arabidopsis, encoding its major HMGR isoform, causes ER aggregation at the nuclear envelope. Our results show that the membrane domain of HMGR contributes to ER morphogenesis in plant cells. PMID:26015445

  14. Diurnal variation in the fraction of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the active form in the mammary gland of the lactating rat.

    PubMed Central

    Smith, R A; Middleton, B; West, D W

    1986-01-01

    'Expressed' and 'total' activities of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) were measured in freeze-clamped samples of mammary glands from lactating rats at intervals throughout the 24 h light/dark cycle. 'Expressed' activities were measured in microsomal fractions isolated and assayed in the presence of 100 mM-KF. 'Total' activities were determined in microsomal preparations from the same homogenates but washed free of KF and incubated with exogenously added sheep liver phosphoprotein phosphatase before assay. Both 'expressed' and 'total' activities of HMG-CoA reductase underwent a diurnal cycle, which had a major peak 6 h into the light phase and a nadir 15 h later, i.e. 9 h into the dark period. Both activities showed a secondary peak of activity (around 68% of the maximum activity) at the time of changeover from dark to light, with a trough in the value of the 'expressed' activity that was close to the nadir value. 'Expressed' activity was lower than 'total' at all time points, indicating the presence of enzyme molecules inactivated by covalent phosphorylation. Nevertheless the 'expressed'/'total' activity ratio was comparatively constant and varied only between 43% and 75%. Immunotitration of enzyme activity, with antiserum raised in sheep against purified rat liver HMG-CoA reductase, confirmed the presence of both active and inactive forms of the enzyme and indicated that at the peak and nadir the variation in 'expressed' HMG-CoA reductase activity resulted from changes in the total number of enzyme molecules rather than from covalent modification. The sample obtained after 3 h of the light phase exhibited an anomalously low 'total' HMG-CoA reductase activity, which could be increased when Cl- replaced F- in the homogenization medium. The result suggests that at that time the activity of the enzyme could be regulated by mechanisms other than covalent phosphorylation or degradation. PMID:3814075

  15. Origin of the Proton-transfer Step in the Cofactor-free (1H)-3-Hydroxy-4-oxoquinaldine 2,4-Dioxygenase

    PubMed Central

    Hernandez-Ortega, Aitor; Quesne, Matthew G.; Bui, Soi; Heuts, Dominic P. H. M.; Steiner, Roberto A.; Heyes, Derren J.; de Visser, Sam P.; Scrutton, Nigel S.

    2014-01-01

    Dioxygenases catalyze a diverse range of chemical reactions that involve the incorporation of oxygen into a substrate and typically use a transition metal or organic cofactor for reaction. Bacterial (1H)-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase (HOD) belongs to a class of oxygenases able to catalyze this energetically unfavorable reaction without any cofactor. In the quinaldine metabolic pathway, HOD breaks down its natural N-heteroaromatic substrate using a mechanism that is still incompletely understood. Experimental and computational approaches were combined to study the initial step of the catalytic cycle. We have investigated the role of the active site His-251/Asp-126 dyad, proposed to be involved in substrate hydroxyl group deprotonation, a critical requirement for subsequent oxygen reaction. The pH profiles obtained under steady-state conditions for the H251A and D126A variants show a strong pH effect on their kcat and kcat/Km constants, with a decrease in kcat/Km of 5500- and 9-fold at pH 10.5, respectively. Substrate deprotonation studies under transient-state conditions show that this step is not rate-limiting and yield a pKa value of ∼7.2 for WT HOD. A large solvent isotope effect was found, and the pKa value was shifted to ∼8.3 in D2O. Crystallographic and computational studies reveal that the mutations have a minor effect on substrate positioning. Computational work shows that both His-251 and Asp-126 are essential for the proton transfer driving force of the initial reaction. This multidisciplinary study offers unambiguous support to the view that substrate deprotonation, driven by the His/Asp dyad, is an essential requirement for its activation. PMID:24482238

  16. 3-hydroxy-3-methyl glutaryl coenzyme A reductase: an essential actor in the biosynthesis of cantharidin in the blister beetle Epicauta chinensis Laporte.

    PubMed

    Lü, S; Jiang, M; Huo, T; Li, X; Zhang, Y

    2016-02-01

    Cantharidin (C(10)H(12)O(4)) is a monoterpene defensive toxin in insects involved in chemical defence as well as in courtship and mating behaviours. It is relatively well known in the medical literature because of its high anticancer activity and as an effective therapy for molluscum contagiosum. However, little is known about its biosynthesis pathway in vivo, and no enzyme involved in cantharidin biosynthesis has been identified. The purpose of this study was to identify the crucial enzyme that is involved in the biosynthesis of cantharidin. Using the homology cloning method, a 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) gene, the rate-limiting enzyme in the mevalonate pathway, was cloned from the blister beetle Epicauta chinensis. Quantitative reverse transcription PCR and gas chromatography methods revealed that the HMGR transcripts had a positive correlation with cantharidin production in the beetles (R = 0.891). RNA interference (RNAi) knockdown of HMGR mRNA expression was achieved by microinjection of a specific double-stranded RNA with more than 90% RNAi efficiency, and an apparent decrease of cantharidin production was observed. Furthermore, the HMGR mRNA was greatly upregulated by exogenous juvenile hormone III (JH III), and cantharidin production was also raised in males; however, when injecting the JH III with RNAi of HMGR mRNA at the same time, cantharidin production did not rise. These results demonstrate that HMGR is an essential enzyme in cantharidin biosynthesis in the blister beetle E. chinensis, which further verifies previous research results demonstrating that cantharidin is synthesized de novo by the mevalonate pathway in blister beetles. PMID:26566751

  17. In vitro activities of 3-hydroxy-1,5,6-trimethoxy-2-methyl-9,10-anthraquinone against non-small cell lung carcinoma.

    PubMed

    Feng, Shi-Xiu; Guan, Qiunong; Chen, Tao; Du, Caigan

    2012-07-01

    Medicinal herbs are the preferred candidates for drug discovery against human diseases including cancer. The roots of Prismatomeris connata have been used in traditional herbal medicine to treat many health problems, particularly pneumoconiosis. This study was to test the anti-tumor activity of 3-hydroxy-1,5,6-trimethoxy-2-methyl-9,10-anthraquinone (PCON6), a major anthraquinone derivative from C. connata, against lung cancer. Cell viability in cultures was assessed by MTT assay. Cell death or apoptosis was determined with annexin-V and 7-aminoactinomycin D staining. Cell cycle was analyzed by both propidium iodide DNA staining and BrdU incorporation assay. Here we showed that in a panel of fifteen different tumor cells lines, a group of four non-small cell lung carcinoma (NSCLC) cell lines exhibited a relatively higher sensitivity to PCON6 growth inhibition than the rest of most non-lung cancer cell lines (p = 0.0461). Further studies demonstrated that the suppression of NSCLC H520 cell growth by PCON6 was associated with its induction of apoptosis at 20 μM (p = 0.0008), and of cell accumulation at S phase cell cycle (p < 0.05) that was further supported by a decrease in cdc2 protein expression. This preliminary study suggests that natural compound PCON6 has relatively selective cytotoxicity against NSCLC growth and represent a concept of developing a novel drug therapy specific for NSCLC based on the roots of C. connata or PCON6. PMID:22864748

  18. Rapid proteasomal elimination of 3-hydroxy-3-methylglutaryl-CoA reductase by interferon-γ in primary macrophages requires endogenous 25-hydroxycholesterol synthesis

    PubMed Central

    Lu, Hongjin; Talbot, Simon; Robertson, Kevin A.; Watterson, Steven; Forster, Thorsten; Roy, Douglas; Ghazal, Peter

    2015-01-01

    Interferons (IFNs) play a central role in immunity and emerging evidence suggests that IFN-signalling coordinately regulates sterol biosynthesis in macrophages, via Sterol Regulatory Element-Binding Protein (SREBP) dependent and independent pathways. However, the precise mechanisms and kinetic steps by which IFN controls sterol biosynthesis are as yet not fully understood. Here, we elucidate the molecular circuitry governing how IFN controls the first regulated step in the mevalonate-sterol pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), through the synthesis of 25-Hydroxycholesterol (25-HC) from cholesterol by the IFN-inducible Cholesterol-25-Hydroxylase (CH25H). We show for the first 30-min of IFN stimulation of macrophages the rate of de novo synthesis of the Ch25h transcript is markedly increased but by 120-min becomes transcriptionally curtailed, coincident with induction of the Activating Transcription Factor 3 (ATF3) repressor. We demonstrate ATF3 induction by Toll-like receptors is strictly dependent on IFN-signalling. While the SREBP-pathway dependent rates of de novo transcription of Hmgcr are relatively unchanged in the first 90-min of IFN treatment, we find HMGCR enzyme levels undergo a rapid proteasomal-mediated degradation, defining a previously unappreciated SREBP-independent mechanism for IFN-action. These events precede a sustained marked reduction in Hmgcr RNA levels involving SREBP-dependent mechanisms. We demonstrate that HMGCR proteasomal-degradation by IFN strictly requires the synthesis of endogenous 25-HC and functionally couples HMGCR to CH25H to coordinately suppress sterol biosynthesis. In conclusion, we quantitatively delineate proteomic and transcriptional levels of IFN-mediated control of HMGCR, the primary enzymatic step of the mevalonate-sterol biosynthesis pathway, providing a foundational framework for mathematically modelling the therapeutic outcome of immune-metabolic pathways. PMID:25759117

  19. Synthesis and biological evaluation of phenolic 4,5-dihydroisoxazoles and 3-hydroxy ketones as estrogen receptor alpha and beta agonists.

    PubMed

    Poutiainen, Pekka K; Venäläinen, Tuomas A; Peräkylä, Mikael; Matilainen, Juha M; Väisänen, Sami; Honkakoski, Paavo; Laatikainen, Reino; Pulkkinen, Juha T

    2010-05-15

    In this work, 52 diphenyl-4,5-dihydroisoxazoles and -3-hydroxy ketones were prepared and their estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) activities were explored in order to systematize and maximize their biological activity. The biological activity was firstly screened by using ERE reporter assay to find out how aromatic hydroxylation and methylation of the chiral centers of the compounds affect the ability of ER to mediate biological responses. For selected 19 compounds, the relative binding affinities (RBA, relative to 3,17beta-estradiol) and ability to induce transcription of primary E2 target gene pS2 in human MCF-7 breast cancer cells were determined. In the reporter assay, many compounds showed even stronger activity than E2 and some of them showed RBA larger than 1%. The highest RBAs were determined for the enantiomers of 1-hydroxy-6-(4-hydroxy-phenyl)-1-phenyl-hexan-3-one (50a and 50b). Isomer 50a showed high binding affinity both to ERalpha (with RBA approximately 200%) and ERbeta (with RBA approximately 60%), while the RBAs of 50b were ca. 40% of those. Some of the other compounds (with RBA approximately 1-16%) showed also notable ERalpha binding selectivity. When four most promising ligands (50a, 50b, 45a, and 45b) were studied with respect to their ability to induce the transcription of primary E2 target gene pS2, the compounds acted as agonists or partial agonists. Computer modeling was used to predict receptor binding conformations and to rationalize the RBA differences of the compounds. PMID:20430632

  20. Biosynthesis of poly(3-hydroxybutyrate-co-3-hydroxy-4-methylvalerate) by recombinant Escherichia coli expressing leucine metabolism-related enzymes derived from Clostridium difficile.

    PubMed

    Saika, Azusa; Watanabe, Yoriko; Sudesh, Kumar; Tsuge, Takeharu

    2014-06-01

    An obligate anaerobic bacterium Clostridium difficile has a unique metabolic pathway to convert leucine to 4-methylvalerate, in which 4-methyl-2-pentenoyl-CoA (4M2PE-CoA) is an intermediate of this pathway. 4M2PE-CoA is also able to be converted to 3-hydroxy-4-methylvalerate (3H4MV), a branched side chain monomer unit, for synthesis of polyhydroxyalkanoate (PHA) copolymer. In this study, to synthesize 3H4MV-containing PHA copolymer from leucine, the leucine metabolism-related enzymes (LdhA and HadAIBC) derived from C. difficile and PHA biosynthesis enzymes (PhaPCJAc and PhaABRe) derived from Aeromonas caviae and Ralstonia eutropha were co-expressed in the codon usage-improved Escherichia coli. Under microaerobic culture conditions, this E. coli was able to synthesize P(3HB-co-12.2 mol% 3H4MV) from glucose with the supplementation of 1 g/L leucine. This strain also produced P(3HB-co-12.6 mol% 3H4MV) using the culture supernatant of leucine overproducer E. coli strain NS1391 as the medium for PHA production, achieving 3H4MV copolymer synthesis only from glucose. Furthermore, we tested the feasibility of the 3H4MV copolymer synthesis in E. coli strain NS1391 from glucose. The recombinant E. coli NS1391 was able to synthesize P(3HB-co-3.0 mol% 3H4MV) from glucose without any leucine supplementation. This study demonstrates the potential of the new metabolic pathway for 3H4MV synthesis using leucine metabolism-related enzymes from C. difficile. PMID:24484910

  1. Inhibition of 3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections

    PubMed Central

    Lorenzo-Morales, Jacob; Machin, Rubén P.; López-Arencibia, Atteneri; García-Castellano, José Manuel; de Fuentes, Isabel; Loftus, Brendan; Maciver, Sutherland K.; Valladares, Basilio; Piñero, José E.

    2013-01-01

    Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba. 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease. PMID:23114753

  2. Improvement of benzylisoquinoline alkaloid productivity by overexpression of 3'-hydroxy-N-methylcoclaurine 4'-O-methyltransferase in transgenic Coptis japonica plants.

    PubMed

    Inui, Takayuki; Kawano, Noriaki; Shitan, Nobukazu; Yazaki, Kazufumi; Kiuchi, Fumiyuki; Kawahara, Nobuo; Sato, Fumihiko; Yoshimatsu, Kayo

    2012-01-01

    Coptis japonica (Cj) rhizomes are used as a crude drug for gastroenteritis, since they accumulate antimicrobial berberine. Berberine also shows various useful bioactivities, including cholesterol-lowering activity. Unfortunately, Cj is a slow-growing plant and more than 5 years are required to obtain a crude drug suitable for the Japanese Pharmacopoeia. To improve alkaloid productivity, we overexpressed the 3'-hydroxy-N-methylcoclaurine 4'-O-methyltransferase (4'OMT) gene in Cj. We established the transgenic plant (named CjHE4') by introducing one copy of Cj4'OMT by Agrobacterium-mediated transformation. The successful overexpression of 4'OMT was confirmed in all tissues of CjHE4' by real-time polymerase chain reaction (PCR) analysis. HPLC analysis revealed that the berberine content of CjHE4' leaves and roots cultivated for 4 months was increased to 2.7- and 2.0-fold, respectively, compared with non-transgenic wild-type (CjWT), and these inductions of alkaloids were stable for at least 20 months. Furthermore, in CjHE4' cultivated for 20 months, the berberine content in medicinal parts, stems and rhizomes was significantly increased (1.6-fold). As a consequence, increased amounts of alkaloids in CjHE4' resulted in the improvement of berberine yields (1.5-fold), whereas CjHE4' showed slower growth than CjWT. These results indicated that 4'OMT is one of the key-step enzymes in berberine biosynthesis and is useful for metabolic engineering in Cj. PMID:22687397

  3. 3-Hydroxy-4,5-dimethyl-2(5H)-furanone levels in fortified Madeira wines: relationship to sugar content.

    PubMed

    Câmara, José Sousa; Marques, José C; Alves, María A; Silva Ferreira, Antonio C

    2004-11-01

    The maturation of Madeira wines usually involves exposure to relatively high temperatures and humidity levels >70%, which affect the aroma and flavor composition and lead to the formation of the typical and characteristic bouquet of these wines. To estimate the levels of sotolon [3-hydroxy-4,5-dimethyl-2(5H)-furanone] and their behavior over time, 86 aged Madeira wines samples (1-25 years old), with different sugar concentrations, respectively, 90 g L(-)(1) for Boal, 110 g L(-)(1) for Malvazia, 25 g L(-)(1) for Sercial, and 65 g L(-)(1) for Verdelho varieties, were analyzed. Isolation was performed by liquid-liquid extraction with dichloromethane followed by chromatographic analysis by GC-MS. The reproducibility of the method was found to be 4.9%. The detection and quantification limits were 1.2 and 2.0 microg L(-)(1), respectively. The levels of sotolon found ranged from not detected to 2000 microg L(-)(1) for wines between 1 and 25 years old. It was observed that during aging, the concentration of sotolon increased with time in a linear fashion (r = 0.917). The highest concentration of sotolon was found in wines with the highest residual sugar contents, considering the same time of storage. The results show that there is a strong correlation between sotolon and sugar derivatives: furfural, 5-methylfurfural, 5-hydroxymethylfurfural, and 5-ethoxymethylfurfural. These compounds are also well correlated with wine aging. These findings indicate that the kinetics of sotolon formation is closely related with residual sugar contents, suggesting that this molecule may come from a component like sugar. PMID:15506814

  4. Functional Analysis of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Encoding Genes in Triterpene Saponin-Producing Ginseng1[C][W

    PubMed Central

    Kim, Yu-Jin; Lee, Ok Ran; Oh, Ji Yeon; Jang, Moon-Gi; Yang, Deok-Chun

    2014-01-01

    Ginsenosides are glycosylated triterpenes that are considered to be important pharmaceutically active components of the ginseng (Panax ginseng ‘Meyer’) plant, which is known as an adaptogenic herb. However, the regulatory mechanism underlying the biosynthesis of triterpene saponin through the mevalonate pathway in ginseng remains unclear. In this study, we characterized the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) concerning ginsenoside biosynthesis. Through analysis of full-length complementary DNA, two forms of ginseng HMGR (PgHMGR1 and PgHMGR2) were identified as showing high sequence identity. The steady-state mRNA expression patterns of PgHMGR1 and PgHMGR2 are relatively low in seed, leaf, stem, and flower, but stronger in the petiole of seedling and root. The transcripts of PgHMGR1 were relatively constant in 3- and 6-year-old ginseng roots. However, PgHMGR2 was increased five times in the 6-year-old ginseng roots compared with the 3-year-old ginseng roots, which indicates that HMGRs have constant and specific roles in the accumulation of ginsenosides in roots. Competitive inhibition of HMGR by mevinolin caused a significant reduction of total ginsenoside in ginseng adventitious roots. Moreover, continuous dark exposure for 2 to 3 d increased the total ginsenosides content in 3-year-old ginseng after the dark-induced activity of PgHMGR1. These results suggest that PgHMGR1 is associated with the dark-dependent promotion of ginsenoside biosynthesis. We also observed that the PgHMGR1 can complement Arabidopsis (Arabidopsis thaliana) hmgr1-1 and that the overexpression of PgHMGR1 enhanced the production of sterols and triterpenes in Arabidopsis and ginseng. Overall, this finding suggests that ginseng HMGRs play a regulatory role in triterpene ginsenoside biosynthesis. PMID:24569845

  5. Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier

    PubMed Central

    Diao, Xing-xing; Zhong, Kan; Li, Xiu-li; Zhong, Da-fang; Chen, Xiao-yan

    2015-01-01

    Aim: To investigate the mechanisms underlying the isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP (3-OH-NBP) and 10-hydroxy-NBP (10-OH-NBP), across the blood brain barrier (BBB). Methods: After oral administration of NBP (20 mg/kg) to rats, the pharmacokinetics of two major hydroxylated metabolites, 3-OH-NBP and 10-OH-NBP, in plasma and brains were investigated. Plasma and brain protein binding of 3-OH-NBP and 10-OH-NBP was also assessed. To evaluate the influences of major efflux transporters, rats were pretreated with the P-gp inhibitor tariquidar (10 mg/kg, iv) and BCRP inhibitor pantoprazole (40 mg/kg, iv), then received 3-OH-NBP (12 mg/kg, iv) or 10-OH-NBP (3 mg/kg, iv). The metabolic profile of NBP was investigated in rat brain homogenate. Results: After NBP administration, the plasma exposure of 3-OH-NBP was 4.64 times that of 10-OH-NBP, whereas the brain exposure of 3-OH-NBP was only 11.8% of 10-OH-NBP. In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively. In the rats pretreated with tariquidar and pantoprazole, the unbound partition coefficient Kp,uu of 3-OH-NBP was significantly increased, while that of 10-OH-NBP showed a slight but not statistically significant increase. Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP. Conclusion: The isomer-selective distribution of 10-OH-NBP and 3-OH-NBP across the BBB of rats is mainly attributed to the differences in plasma and brain protein binding and the efflux transport of 3-OH-NBP. The abundant 10-OH-NBP is not generated in rat brains. PMID:26567730

  6. Avian 3-hydroxy-3-methylglutaryl-CoA lyase: sensitivity of enzyme activity to thiol/disulfide exchange and identification of proximal reactive cysteines.

    PubMed Central

    Hruz, P. W.; Miziorko, H. M.

    1992-01-01

    Catalysis by purified avian 3-hydroxy-3-methylglutaryl-CoA lyase is critically dependent on the reduction state of the enzyme, with less than 1% of optimal activity being observed with the air-oxidized enzyme. The enzyme is irreversibly inactivated by sulfhydryl-directed reagents with the rate of this inactivation being highly dependent upon the redox state of a critical cysteine. Methylation of reduced avian lyase with 1 mM 4-methylnitrobenzene sulfonate results in rapid inactivation of the enzyme with a k(inact) of 0.178 min-1. The oxidized enzyme is inactivated at a sixfold slower rate (k(inact) = 0.028 min-1). Inactivation of the enzyme with the reactive substrate analog 2-butynoyl-CoA shows a similar dependence upon the enzyme's redox state, with a sevenfold difference in k(inact) observed with oxidized vs. reduced forms of the enzyme. Chemical cross-linking of the reduced enzyme with stoichiometric amounts of the bifunctional reagents 1,3-dibromo-2-propanone (DBP) or N,N'-ortho-phenylene-dimaleimide (PDM) coincides with rapid inactivation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of enzyme treated with bifunctional reagent reveals a band of twice the molecular weight of the lyase monomer, indicating that an intersubunit cross-link has been formed. Differential labeling of native and cross-linked protein with [1-14C]iodoacetate has identified as the primary cross-linking target a cysteine within the sequence VSQAACR, which maps at the carboxy-terminus of the cDNA-deduced sequence of the avian enzyme (Mitchell, G.A., et al., 1991, Am. J. Hum. Genet. 49, 101). In contrast, bacterial HMG-CoA lyase, which contains no corresponding cysteine, is not cross-linked by comparable treatment with bifunctional reagent. These results provide evidence for a potential regulatory mechanism for the eukaryotic enzyme via thiol/disulfide exchange and identify a cysteinyl residue with the reactivity and juxtaposition required for participation in disulfide

  7. Overproduction of a Mr 92,000 protomer of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in compactin-resistant C100 cells

    PubMed Central

    Hardeman, Edna C.; Jenke, Hans-Stephan; Simoni, Robert D.

    1983-01-01

    We describe a cell line, designated C100, that displays a 100-fold increase in the major regulatory enzyme of the cholesterol biosynthetic pathway, 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMG-CoA; mevalonate:NADP+ oxido-reductase (CoA-acylating), EC 1.1.1.34]. Immunoprecipitation of [35S]methionine-labeled enzyme from C100 microsomal membranes prepared in the presence of the protease inhibitors phenyl-methylsulfonyl fluoride and leupeptin revealed two up regulated proteins: a major band of Mr 92,000 and a minor band of Mr 63,000. We conclude that the Mr 92,000 protein is probably the intact form of HMG-CoA reductase protomer based on the following criteria. (i) It is a highly up regulated microsomal membrane protein that coincides with the increase in HMG-CoA reductase specific activity in this cell line. (ii) It is recognized by a specific HMG-CoA reductase antiserum under a variety of stringencies. (iii) Isolation and solubilization of [35S]methionine-labeled C100 microsomal membranes in the absence of protease inhibitors resulted in the disappearance of the Mr 92,000 protein and the appearance of two proteins of Mr 52,000 and 38,000. (iv) Analysis of cells labeled for 30 min with [35S]methionine, well under the half-life of HMG-CoA reductase, revealed only the Mr 92,000 protein to be present in total cell extract. (v) The previously reported single immunoprecipitation polypeptide for HMG-CoA reductase of Mr 62,000 [Chin, D. J., Luskey, K. L., Anderson, R. G. W., Faust, J. R., Goldstein, J. L. & Brown, M. S. (1982) Proc. Natl. Acad. Sci. USA 79, 1185-1189] can be isolated and appears to be the result of both proteolysis and sample preparation for NaDodSO4 gel electrophoresis. Analysis of C100 cells labeled with [35S]methionine for 24 hr indicates that the predominant steady-state form of the enzyme is the Mr 92,000, rather than the Mr 63,000, protein, further suggesting that the two proteins do not have a classical precursor-product relationship. Images

  8. Control of 3-Hydroxy-3-Methylglutaryl-CoA Reductase Activity in Cultured Human Fibroblasts by Very Low Density Lipoproteins of Subjects with Hypertriglyceridemia

    PubMed Central

    Gianturco, Sandra H.; Gotto, Antonio M.; Jackson, Richard L.; Patsch, Josef R.; Sybers, Harley D.; Taunton, O. David; Yeshurun, Daniel L.; Smith, Louis C.

    1978-01-01

    Very low density lipoproteins (VLDL) and low density lipoproteins (LDL) from human normolipemic plasma, and the VLDL, the intermediate density lipoprotein (IDL), and LDL from patients with Type III hyperlipoproteinemic plasma were tested for their abilities to suppress the activity of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase in cultured human fibroblasts from normal subjects and a Type III patient. Regulation of cholesterol synthesis in the fibroblasts of a patient with Type III hyperlipoproteinemia appears to be normal. VLDL from normal subjects, isolated by angle head ultracentrifugation (d < 1.006) or by gel filtration on BioGel A-5m, were about 5 times less effective than LDL in suppressing HMG-CoA reductase activity, based on protein content, in agreement with previous reports with normal fibroblasts. Zonal centrifugation of normal VLDL isolated by both methods showed that the VLDL contained IDL. Normal VLDL from the angle head rotor, refractionated by the zonal method, had little, if any, ability to suppress the HMG-CoA reductase activity in either normal or Type III fibroblasts. VLDL, IDL, and LDL fractionated by zonal ultracentrifugation from Type III plasma gave half-maximum inhibition at 0.2-0.5 μg of protein/ml, indistinguishable from the suppression caused by normal LDL. Type III VLDL did not suppress HMG-CoA reductase in mutant LDL receptor-negative fibroblasts. Zonally isolated VLDL obtained from one Type IV and one Type V patient gave half-maximal suppression at 5 and 0.5 μg of protein/ml, respectively. Molecular diameters and apoprotein compositions of the zonally isolated normal and Type III VLDL were similar; the major difference in composition was that Type III VLDL contained more cholesteryl esters and less triglyceride than did normal VLDL. The compositions and diameters of the Type IV and Type V VLDL were similar to normal VLDL. These findings show that the basic defect in Type III hyperlipoproteinemia is qualitatively

  9. Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein.

    PubMed Central

    Hampton, R Y; Gardner, R G; Rine, J

    1996-01-01

    3-hydroxy-3-methylglutaryl-CoA reductase (HMG-R), a key enzyme of sterol synthesis, is an integral membrane protein of the endoplasmic reticulum (ER). In both humans and yeast, HMG-R is degraded at or in the ER. The degradation of HMG-R is regulated as part of feedback control of the mevalonate pathway. Neither the mechanism of degradation nor the nature of the signals that couple the degradation of HMG-R to the mevalonate pathway is known. We have launched a genetic analysis of the degradation of HMG-R in Saccharomyces cerevisiae using a selection for mutants that are deficient in the degradation of Hmg2p, an HMG-R isozyme. The underlying genes are called HRD (pronounced "herd"), for HMG-CoA reductase degradation. So far we have discovered mutants in three genes: HRD1, HRD2, and HRD3. The sequence of the HRD2 gene is homologous to the p97 activator of the 26S proteasome. This p97 protein, also called TRAP-2, has been proposed to be a component of the mature 26S proteasome. The hrd2-1 mutant had numerous pleiotropic phenotypes expected for cells with a compromised proteasome, and these phenotypes were complemented by the human TRAP-2/p97 coding region. In contrast, HRD1 and HRD3 genes encoded previously unknown proteins predicted to be membrane bound. The Hrd3p protein was homologous to the Caenorhabditis elegans sel-1 protein, a negative regulator of at least two different membrane proteins, and contained an HRD3 motif shared with several other proteins. Hrd1p had no full-length homologues, but contained an H2 ring finger motif. These data suggested a model of ER protein degradation in which the Hrd1p and Hrd3p proteins conspire to deliver HMG-R to the 26S proteasome. Moreover, our results lend in vivo support to the proposed role of the p97/TRAP-2/Hrd2p protein as a functionally important component of the 26S proteasome. Because the HRD genes were required for the degradation of both regulated and unregulated substrates of ER degradation, the HRD genes are the

  10. Preparation of 4-amino-2,4-dioxobutanoic acid

    DOEpatents

    Unkefer, Pat J.; Martinez, Rodolfo A.; Glass, David R.

    2016-03-22

    A process for synthesizing 4-amino-2,4-dioxobutanoate involves reacting a dialkyl oxalate with an alkoxide in ethanol to form a reaction mixture, and afterward adding an alkyl cyano acetate to the reaction mixture and allowing a reaction to proceed under conditions suitable to form a first reaction product of the formula diethyl 2-cyano-3-hydroxy-butenedioate, and then isolating the diethyl 2-cyano-3-hydroxy-butenedioate, and afterward reacting the diethyl-2-cyano-3-hydroxy-butenedioate with an aqueous hydroxide under conditions suitable to form 4-amino-2,4-dioxobutanoate. The 4-amino-2,4-dioxobutanoate may be acidified into 4-amino-2,4-dioxobutanoic acid.

  11. Crystallization and preliminary X-ray analysis of 1H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase from Arthrobacter nitroguajacolicus Rü61a: a cofactor-devoid dioxygenase of the α/β-hydrolase-fold superfamily

    SciTech Connect

    Steiner, Roberto A.; Frerichs-Deeken, Ursula; Fetzner, Susanne

    2007-05-01

    Preliminary crystallographic data are reported for 1H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase (HOD) from A. nitroguajacolicus Rü61a. 1H-3-Hydroxy-4-oxoquinaldine 2,4-dioxygenase (HOD) is a cofactor-devoid dioxygenase that is involved in the anthranilate pathway of quinaldine degradation. HOD has been proposed to belong to the α/β-hydrolase-fold superfamily of enzymes. N-terminally His{sub 6}-tagged HOD has been crystallized by the hanging-drop vapour-diffusion method using sodium/potassium tartrate as a precipitant and CuCl{sub 2} as an additive. The structure was solved by the single anomalous dispersion (SAD) technique using data collected to 3.5 Å resolution at the Cu absorption peak wavelength. The crystals belong to the primitive tetragonal space group P4{sub 3}2{sub 1}2, with unit-cell parameters a = b = 153.788, c = 120.872 Å.

  12. Synthesis and discovery of phytofurans: metabolites of α-linolenic acid peroxidation.

    PubMed

    Cuyamendous, C; Leung, K S; Durand, T; Lee, J C-Y; Oger, C; Galano, J-M

    2015-11-01

    Phytofurans are novel metabolites produced by non-enzymatic peroxidation of α-linolenic acid. An unprecedented Payne rearrangement-cyclization of a C2-symmetric bis-epoxide permitted construction of the core 3-hydroxy-2,5-disubstituted tetrahydrofuran. LC-MS/MS investigation provided evidence for the presence of phytofurans in nuts and seeds for the first time. PMID:26364843

  13. Iron-chelating and anti-lipid peroxidation properties of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in long-term iron loading β-thalassemic mice

    PubMed Central

    Kulprachakarn, Kanokwan; Chansiw, Nittaya; Pangjit, Kanjana; Phisalaphong, Chada; Fucharoen, Suthat; Hider, Robert C.; Santitherakul, Sineenart; Srichairatanakool, Somdet

    2014-01-01

    Objective To evaluate the iron-chelating properties and free-radical scavenging activities of 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) treatment in chronic iron-loaded β-thalassemic (BKO) mice. Methods The BKO mice were fed with a ferrocene-rich diet and were orally administered with CM1 [50 mg/(kg.day)] for 6 months. Blood levels of non-transferrin bound iron, labile plasma iron, ferritin (Ft) and malondialdehyde were determined. Results The BKO mice were fed with an iron diet for 8 months which resulted in iron overload. Interestingly, the mice showed a decrease in the non-transferrin bound iron, labile plasma iron and malondialdehyde levels, but not the Ft levels after continuous CM1 treatment. Conclusions CM1 could be an effective oral iron chelator that can reduce iron overload and lipid peroxidation in chronic iron overload β-thalassemic mice. PMID:25183338

  14. Inhibition of squalene synthase but not squalene cyclase prevents mevalonate-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase synthesis at a posttranscriptional level.

    PubMed

    Peffley, D M; Gayen, A K

    1997-01-15

    Previously, we found that mevalonate-derived products together with an oxysterol regulated reductase synthesis at a posttranscriptional level. To determine which products were responsible for this regulation, either the squalene synthase inhibitor zaragozic acid A or the squalene cyclase inhibitor 4,4,10-beta-trimethyl-trans-decal-3beta-ol (TMD) was added to lovastatin-treated Syrian hamster cells in conjunction with mevalonate. Mevalonate alone decreased reductase synthesis 50% compared with lovastatin-treated cells. In contrast, when both zaragozic acid A and mevalonate were added to lovastatin-treated cells, there was no change in reductase synthesis. With either treatment, reductase mRNA levels did not change compared with lovastatin-treated cells. When both 25-hydroxycholesterol and mevalonate were added to lovastatin-treated cells, reductase synthesis and mRNA levels were decreased 95 and 50%, respectively. The 10-fold difference between changes in reductase synthesis and mRNA levels under these conditions reflects a specific effect of mevalonate-derived isoprenoids on reductase synthesis at the translational level. In contrast, coincubation of cells with mevalonate plus 25-hydroxycholesterol in the presence of zaragozic acid decreased reductase synthesis and mRNA levels 60 and 50%, respectively, compared with lovastatin-treated cells. Moreover, degradation of reductase was increased approximately 7-fold in cells treated with mevalonate alone but only 3-fold in cells treated with mevalonate and zaragozic acid A. These results indicate that isoprenoid products between mevalonate and squalene affect reductase at a posttranslational level by increasing degradation but do not regulate reductase synthesis at a posttranscriptional level. In contrast, when both TMD and mevalonate were added to lovastatin-treated cells, reductase synthesis was decreased approximately 50% with no corresponding decrease in reductase mRNA levels, similar to mevalonate only. Reductase

  15. Human lens coloration and aging. Evidence for crystallin modification by the major ultraviolet filter, 3-hydroxy-kynurenine O-beta-D-glucoside.

    PubMed

    Hood, B D; Garner, B; Truscott, R J

    1999-11-12

    The human lens becomes increasingly yellow with age and thereby reduces our perception of blue light. This coloration is associated with lens proteins (crystallins), but its molecular basis was unknown. Here we show that the coloration occurs because of the interaction of crystallins with a UV filter compound, 3-hydroxykynurenine glucoside (3-OHKG). Crystallin modification results from deamination of the 3-OHKG amino acid side chain, yielding an unsaturated ketone that is susceptible to nucleophilic attack by cysteine, histidine, and lysine residues. This novel protein modification contributes to age-related lens coloration and may play a role in human nuclear cataractogenesis. PMID:10551806

  16. Bioproduction, statistical optimization and characterization of microbial plastic (poly 3-hydroxy butyrate) employing various hydrolysates of water hyacinth (Eichhornia crassipes) as sole carbon source.

    PubMed

    Radhika, D; Murugesan, A G

    2012-10-01

    Saccharified water hyacinth hydrolysates (acid and enzyme hydrolysate) were used for the efficient production of poly (3-hydroxybutyrate) (PHB) via the Cupriavidus necator bacteria. The bacterium significantly utilizes the enzymatic hydrolyzate which gave the maximum PHB concentration (4.3 ± 0.4 g L(-1)), this was greatly exceeded the value of 2 ± 0.1 g L(-1) obtained from the acid hydrolysate amended media. Moreover, for the optimal PHB production, response surface methodology was used through central composite rotary design method which gave improved PHB concentration in microbial cells. After 72 h, 35 g L(-1) of reducing sugar contained water hyacinth hydrolysate and 1.5 g L(-1) of (NH(4))(2)SO(4) supplementation in laboratory scale fermentor gave 12 g L(-1) of dry cell weight and 7 g L(-1) of PHB. The produced PHB was characterized under FTIR, GPC and DSC instruments to find out the number average molecular mass, polydispersity index and melting temperature were 1.7 × 10(5)kDa, 1.9 and 170°C respectively. PMID:22858470

  17. Molecular insight into amyloid oligomer destabilizing mechanism of flavonoid derivative 2-(4' benzyloxyphenyl)-3-hydroxy-chromen-4-one through docking and molecular dynamics simulations.

    PubMed

    Kumar, Akhil; Srivastava, Swati; Tripathi, Shubhandra; Singh, Sandeep Kumar; Srikrishna, Saripella; Sharma, Ashok

    2016-06-01

    Aggregation of amyloid peptide (Aβ) has been shown to be directly related to progression of Alzheimer's disease (AD). Aβ is neurotoxic and its deposition and aggregation ultimately lead to cell death. In our previous work, we reported flavonoid derivative (compound 1) showing promising result in transgenic AD model of Drosophila. Compound 1 showed prevention of Aβ-induced neurotoxicity and neuroprotective efficacy in Drosophila system. However, mechanism of action of compound 1 and its effect on the amyloid is not known. We therefore performed molecular docking and atomistic, explicit-solvent molecular dynamics simulations to investigate the process of Aβ interaction, inhibition, and destabilizing mechanism. Results showed different preferred binding sites of compound 1 and good affinity toward the target. Through the course of 35 ns molecular dynamics simulation, conformations_5 of compound 1 intercalates into the hydrophobic core near the salt bridge and showed major structural changes as compared to other conformations. Compound 1 showed interference with the salt bridge and thus reducing the inter strand hydrogen bound network. This minimizes the side chain interaction between the chains A-B leading to disorder in oligomer. Contact map analysis of amino acid residues between chains A and B also showed lesser interaction with adjacent amino acids in the presence of compound 1 (conformations_5). The study provides an insight into how compound 1 interferes and disorders the Aβ peptide. These findings will further help to design better inhibitors for aggregation of the amyloid oligomer. PMID:26208790

  18. Bacterial poly(hydroxyalkanoates) as a source of chiral hydroxyalkanoic acids.

    PubMed

    Ren, Qun; Grubelnik, Andreas; Hoerler, Mirjam; Ruth, Katinka; Hartmann, René; Felber, Helene; Zinn, Manfred

    2005-01-01

    Polyhydroxyalkanoates (PHA) are polyesters of various hydroxyalkanoates accumulated in numerous bacteria. All of the monomeric units of PHA are enantiomerically pure and in R-configuration. R-Hydroxyalkanoic acids can be widely used as chiral starting materials in fine chemical, pharmaceutical and medical industries. In this study, we established an efficient method for the production of chiral hydroxyalkanoic acid monomers from PHA. Pseudomonas putida cells containing PHA were resuspended in phosphate buffer at different pH. We observed that the optimal initial pH for intracellular PHA degradation and monomer release was at pH 8-11 with pH 11 as the best. At initial pH 11, PHA containing 3-hydroxyoctanoic acid and 3-hydroxyhexanoic acid was degraded with an efficiency of over 90% (w/w) in 9 h, and the yield of the corresponding monomers was also over 90%. Under the same conditions, unsaturated monomers were also effectively produced from PHA containing 3-hydroxy-6-heptenoic acid, 3-hydroxy-8-nonenoic acid, and 3-hydroxy-10-undecenoic acid. The monomers (e.g., 3-hydroxyoctanoic acid) were further isolated using solid phase extraction and purified on reversed phase semipreparative liquid chromatography. We confirmed that the purified 3-hydroxyoctanoic acid monomer has exclusively the R-configuration. PMID:16004474

  19. Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidene)alkanoic Acids and Related Derivatives.

    PubMed

    Maggio, Benedetta; Raffa, Demetrio; Raimondi, Maria Valeria; Cascioferro, Stella; Plescia, Fabiana; Schillaci, Domenico; Cusimano, Maria Grazia; Leonchiks, Ainars; Zhulenkovs, Dmitrijs; Basile, Livia; Daidone, Giuseppe

    2016-01-01

    A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM. PMID:26907235

  20. Hydrogen-bonded supra­molecular motifs in pyrimethaminium 4-methyl­benzoate, pyrimethaminium 3-hydroxy­picolinate and pyri­meth­aminium 2,4-di­chloro­benzoate

    PubMed Central

    Thanigaimani, Kaliyaperumal; Muthiah, Packianathan Thomas

    2010-01-01

    In 2,4-diamino-5-(4-chloro­phenyl)-6-ethyl­pyrimidin-1-ium (pyri­methaminium, PMNH) 4-methyl­benzoate, C12H14ClN4 +·C8H7O2 −, (I), pyrimethaminium 3-hydroxy­picolinate, C12H14ClN4 +·C6H4NO3 −, (II), and pyrimethaminium 2,4-dichloro­benzoate, C12H14ClN4 +·C7H3Cl2O2 −, (III), the PMNH cations inter­act with the carboxyl­ate groups of the corresponding anion via nearly parallel N—H⋯O hydrogen bonds, forming R 2 2(8) ring motifs. A description of the observed arrays of quadruple hydrogen bonds in (I) and (II) in terms of hydrogen donors and acceptors (the DA model), their graph-set motifs and the resulting supra­molecular ladder is given. In (III), supra­molecular chains along the b axis and helical chains along the a axis are formed via N—H⋯O hydrogen bonds involving the 2-amino and 4-amino groups of the PMNH cation, respectively. Weak Cl⋯Cl inter­actions are also found in (III). PMID:20203404

  1. Chicken ovalbumin upstream-promoter transcription factor (COUP-TF) could act as a transcriptional activator or repressor of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene.

    PubMed Central

    Rodríguez, J C; Ortiz, J A; Hegardt, F G; Haro, D

    1997-01-01

    The chicken ovalbumin upstream-promoter transcription factor (COUP-TF) has a dual effect on the regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene. COUP-TF could act as a transcriptional activator or repressor of this gene through different DNA sequences. COUP-TF induces expression of a reporter gene linked to the mitochondrial HMG-CoA synthase gene promoter in human hepatoma HepG2 cells, but represses it in a Leydig tumour cell line (R2C); in both these cell lines the expression of the mitochondrial HMG-CoA synthase gene mimics that of liver and testis. The activation is promoted by a fragment of the gene from coordinates -62 to +28, which contains a GC box and a TATA box, and where no COUP-TF binding site was observed by in vitro DNA binding studies. On the other hand, the COUP-TF inhibitory effect is mainly due to repression of peroxisome-proliferator-activated receptor-dependent activation of the gene, interacting with the region from -104 to -92. To our knowledge this work represents the second example of a target gene for COUP-TF I that could be either activated or repressed by the action of this receptor through different DNA sequences of the same gene. PMID:9291136

  2. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency

    PubMed Central

    AOYAMA, YUKA; YAMAMOTO, TOSHIYUKI; SAKAGUCHI, NAOMI; ISHIGE, MIKA; TANAKA, TOJU; ICHIHARA, TOMOKO; OHARA, KATSUAKI; KOUZAN, HIROKO; KINOSADA, YASUTOMI; FUKAO, TOSHIYUKI

    2015-01-01

    Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency is an autosomal recessive disorder affecting the leucine catabolic pathway and ketone body synthesis, and is clinically characterized by metabolic crises with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. In the present study, we initially used PCR with genomic followed by direct sequencing to investigate the molecular genetic basis of HMGCL deficiency in two patients clinically diagnosed with the condition. Although we identified a mutation in each patient, the inheritance patterns of these mutations were not consistent with disease causation. Therefore, we investigated HMGCL using multiplex ligation-dependent probe amplification (MLPA) to determine the copy numbers of all exons. A heterozygous deletion that included exons 2–4 was identified in one of the patients. MLPA revealed that the other patient had two copies for all HMGCL exons. Paternal uniparental isodisomy of chromosome 1 was confirmed in this patient by microarray analysis. These findings indicate that MLPA is useful for the identification of genomic aberrations and mutations other than small-scale nucleotide alterations. To the best of our knowledge, this is the first study describing HMGCL deficiency caused by uniparental disomy. PMID:25872961

  3. Crystal structure, FT-IR, FT-Raman, 1H NMR and computational study of ethyl 2-{[(Z)3-(4-chlorophenyl)-3-hydroxy-2-propene-1-thione] amino} acetate

    NASA Astrophysics Data System (ADS)

    Prasanth, S.; Varughese, Mary; Joseph, Nirmala; Mathew, Paulson; Manojkumar, T. K.; Sudarsanakumar, C.

    2015-02-01

    The molecular structure of a thioamide derivative ethyl 2-{[(Z)3-(4-chlorophenyl)-3-hydroxy-2-propene-1-thione] amino} acetate was determined by X-ray diffraction. The proton NMR (1H NMR), Fourier Transform Infra-Red (FT-IR) and Fourier Transform Raman (FT-Raman) spectra of the compound were recorded and analyzed. The conjugated enol form of the compound was crystallized in the monoclinic space group P21/c, with unit cell dimensions a = 12.514(2) Å, b = 5.403(5) Å, c = 21.233(3) Å, β = 94.597(4)°. The structure was solved by direct methods and refined to the R value of 0.0462. The thioamide moiety in the compound adopts the Z-conformation and the Csbnd N bond shows a high rotational barrier. The geometry in the gas phase was optimized by B3LYP and RHF quantum mechanical calculations using Gaussian 09 programme and the vibrational frequencies were calculated. The experimental and theoretical data are in good agreement.

  4. A new mechanism of 6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one dihydrochloride (TAS-103) action discovered by target screening with drug-immobilized affinity beads.

    PubMed

    Yoshida, Makoto; Kabe, Yasuaki; Wada, Tadashi; Asai, Akira; Handa, Hiroshi

    2008-03-01

    6-((2-(Dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)-quinolin-7-one dihydrochloride (TAS-103) is a quinoline derivative that displays antitumor activity in murine and human tumor models. TAS-103 has been reported to be a potent topoisomerase II poison. However, other studies have indicated that cellular susceptibility to TAS-103 is not correlated with topoisomerase II expression. Because the direct target of TAS-103 remained unclear, we searched for a TAS-103 binding protein using high-performance affinity latex beads. We obtained a component of the signal recognition particle (SRP) as a TAS-103 binding protein. This component is a 54-kDa subunit (SRP54) of SRP, which mediates the proper delivery of secretory proteins in cells. We fractioned 293T cell lysates using gel-filtration chromatography and performed a coimmunoprecipitation assay using 293T cells expressing FLAG-tagged SRP54. The results revealed that TAS-103 disrupts SRP complex formation and reduces the amount of SRP14 and SRP19. TAS-103 treatment and RNAi-mediated knockdown of SRP54 or SRP14 promoted accumulation of the exogenously expressed chimeric protein interleukin-6-FLAG inside cells. In conclusion, we identified signal recognition particle as a target of TAS-103 by using affinity latex beads. This provides new insights into the mechanism underlying the effects of chemotherapies comprising TAS-103 and demonstrates the usefulness of the affinity beads. PMID:18089836

  5. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

    PubMed

    Aoyama, Yuka; Yamamoto, Toshiyuki; Sakaguchi, Naomi; Ishige, Mika; Tanaka, Toju; Ichihara, Tomoko; Ohara, Katsuaki; Kouzan, Hiroko; Kinosada, Yasutomi; Fukao, Toshiyuki

    2015-06-01

    Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency is an autosomal recessive disorder affecting the leucine catabolic pathway and ketone body synthesis, and is clinically characterized by metabolic crises with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. In the present study, we initially used PCR with genomic followed by direct sequencing to investigate the molecular genetic basis of HMGCL deficiency in two patients clinically diagnosed with the condition. Although we identified a mutation in each patient, the inheritance patterns of these mutations were not consistent with disease causation. Therefore, we investigated HMGCL using multiplex ligation-dependent probe amplification (MLPA) to determine the copy numbers of all exons. A heterozygous deletion that included exons 2-4 was identified in one of the patients. MLPA revealed that the other patient had two copies for all HMGCL exons. Paternal uniparental isodisomy of chromosome 1 was confirmed in this patient by microarray analysis. These findings indicate that MLPA is useful for the identification of genomic aberrations and mutations other than small-scale nucleotide alterations. To the best of our knowledge, this is the first study describing HMGCL deficiency caused by uniparental disomy. PMID:25872961

  6. Divergence in cholesterol biosynthetic rates and 3-hydroxy-3-methylglutaryl-CoA reductase activity as a consequence of granulocyte versus monocyte-macrophage differentiation in HL-60 cells.

    PubMed Central

    Yachnin, S; Toub, D B; Mannickarottu, V

    1984-01-01

    Addition of dimethyl sulfoxide or phorbol myristate acetate (PMA) to HL-60 cell cultures induces granulocytic or monocyte-macrophage differentiation, respectively, in HL-60 cells. Dimethyl sulfoxide-induced granulocyte differentiation in HL-60 cells is associated with a decrease in cellular 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity and with a decrease in the incorporation of [14C]acetate and mevalonate into products of the cholesterol biosynthetic pathway. PMA-induced monocyte-macrophage differentiation in HL-60 cells is associated with a rapid and profound fall in cell proliferation but nonetheless is accompanied by a dose-dependent increase in cellular HMG-CoA reductase activity and [14C]acetate incorporation into the cholesterol biosynthetic pathway. In addition, PMA induces an increase in [14C]mevalonate incorporation into cholesterol and its precursors, suggesting that post-HMG-CoA reductase events in cholesterol biosynthesis are also enhanced. Mature peripheral blood human monocytes possess an active cholesterol biosynthetic pathway, whereas mature human granulocytes are almost entirely lacking in the ability to synthesize post-squalene products. Our results with HL-60 cells indicate that this divergence in sterol-synthesizing ability between two cell lineages, which normally also derive from a common stem cell, can be observed as an early event in the differentiation process. PMID:6583685

  7. Co(II), Cd(II), Hg(II) and U(VI)O2 complexes of o-hydroxyacetophenone[N-(3-hydroxy-2-naphthoyl)] hydrazone: Physicochemical study, thermal studies and antimicrobial activity

    NASA Astrophysics Data System (ADS)

    Zaky, R. R.; Yousef, T. A.; Ibrahim, K. M.

    2012-11-01

    The o-Hydroxy acetophenone [N-(3-hydroxy-2-naphthoyl)] hydrazone (H2o-HAHNH) has been prepared and its structure is confirmed by elemental analysis, IR, 1H NMR and 13C NMR spectroscopy. It has been used to produce diverse complexes with Co(II), Cd(II), Hg(II) and U(VI)O2 ions. The isolated complexes have been investigated by elemental analysis, magnetic measurements, molar conductivity, thermal (TG, DTG) and spectral (1H NMR, 13C NMR, IR, UV-visible, MS) studies. Infrared spectra suggested H2o-HAHNH acts as a bidentate and/or tridentate ligand. The electronic spectrum of [Co(Ho-HAHNH)2] complex as well as its magnetic moments suggesting octahedral geometry around Co(II) center. The TG analyses suggest high stability for most complexes followed by thermal decomposition in different steps. Moreover, the kinetic and thermodynamic parameters (Ea, A, ΔH∗, ΔS∗ and ΔG∗) for the different decomposition steps of the [Co(Ho-HAHNH)2] and [Cd(Ho-HAHNH)2] complexes were calculated using the Coats-Redfern and Horowitz-Metzger methods. Moreover, the antibacterial and antifungal activities of the isolated compounds were studied using a wide spectrum of bacterial and fungal strains.

  8. Regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase expression by Zingiber officinale in the liver of high-fat diet-fed rats.

    PubMed

    Nammi, Srinivas; Kim, Moon S; Gavande, Navnath S; Li, George Q; Roufogalis, Basil D

    2010-05-01

    Zingiber officinale has been used to control lipid disorders and reported to possess remarkable cholesterol-lowering activity in experimental hyperlipidaemia. In the present study, the effect of a characterized and standardized extract of Zingiber officinale on the hepatic lipid levels as well as on the hepatic mRNA and protein expression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was investigated in a high-fat diet-fed rat model. Rats were treated with an ethanol extract of Zingiber officinale (400 mg/kg) extract along with a high-fat diet for 6 weeks. The extract of Zingiber officinale significantly decreased hepatic triglyceride and tended to decrease hepatic cholesterol levels when administered over 6 weeks to the rats fed a high-fat diet. We found that in parallel, the extract up-regulated both LDL receptor mRNA and protein level and down-regulated HMG-CoA reductase protein expression in the liver of these rats. The metabolic control of body lipid homeostasis is in part due to enhanced cholesterol biosynthesis and reduced expression of LDL receptor sites following long-term consumption of high-fat diets. The present results show restoration of transcriptional and post-transcriptional changes in low-density lipoprotein and HMG CoA reductase by Zingiber officinale administration with a high-fat diet and provide a rational explanation for the effect of ginger in the treatment of hyperlipidaemia. PMID:20002065

  9. H2O-mediated isatin spiro-epoxide ring opening with NaCN: Synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation.

    PubMed

    Sharma, Pankaj; Senwar, Kishna Ram; Jeengar, Manish Kumar; Reddy, T Srinivasa; Naidu, V G M; Kamal, Ahmed; Shankaraiah, Nagula

    2015-11-01

    A simple method for isatin spiro-epoxide ring-opening by sodium cyanide in water to obtain a variety of isatin hydroxy nitriles has been developed. Further, these intermediates have been converted into new 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids via azide-nitrile cycloaddition reaction in a sealed tube. These compounds were evaluated for their in vitro anticancer activity on five human cancer cell lines i.e. breast (BT549 and MDA MB-231), prostate (PC-3 and DU-145) and ovarian (PA-1). The compounds 6d and 6r showed potent anticancer activity against DU-145 cell line with IC50 values in the range of 7.01 ± 0.91 and 4.26 ± 0.09 μM respectively. The compounds 6d, 6g, 6q and 6r were also tested on human normal prostate epithelial (RWPE-1) cells and found to be safer with lesser cytotoxicity. The morphology and long term clonogenic survival of DU-145 cells were severely affected by compound 6r. Cell cycle analysis revealed that the compounds arrest the cells in G2/M phase. Acridine orange/ethidium bromide (AO/EB) staining, DAPI staining, annexin-V binding assay and DNA fragmentation analysis showed that cell proliferation was inhibited through induction of apoptosis. Moreover, one of the compounds 6r treatment led to collapse of the mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS) in DU-145 cells. PMID:26413726

  10. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate transforming growth factor-β signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase

    PubMed Central

    Park, Ho-Jin; Galper, Jonas B.

    1999-01-01

    Transforming growth factor-β (TGFβ) signaling has been shown to play a role in cardiac development as well as in the pathogenesis of cardiovascular disease. Prior studies have suggested a relationship between cholesterol metabolism and TGFβ signaling. Here we demonstrate that induction of the cholesterol metabolic pathway by growth of embryonic chicken atrial cells in medium supplemented with lipoprotein-depleted serum coordinately decreased the expression of the TGFβ type II receptor (TGFβRII), TGFβ1, and TGFβ signaling as measured by plasminogen activator inhibitor-1 (PAI-1) promoter activity. Inhibition of the cholesterol metabolic pathway by the hydrophobic 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors, simvastatin and atorvastatin, reversed the effect of lipoprotein-depleted serum and up-regulated TGFβRII expression, whereas the hydrophilic HMGCoA reductase inhibitor, pravastatin, had no effect. Simvastatin stimulated the expression of TGFβRII, TGFβ1, and PAI-1 at the level of transcription. Experiments using specific inhibitors of different branches of the cholesterol metabolic pathway demonstrated that simvastatin exerted its effect on TGFβ signaling by inhibition of the geranylgeranylation pathway. C3 exotoxin, which specifically inactivates geranylgeranylated Rho GTPases, mimicked the effect of simvastatin on PAI-1 promoter activity. Cotransfection of cells with a PAI-1 promoter-reporter and a dominant-negative RhoA mutant increased PAI-1 promoter activity, whereas cotransfection with a dominant-active RhoA mutant decreased PAI-1 promoter activity. These data support the conclusion that TGFβ signaling is regulated by RhoA GTPase and demonstrate a relationship between cholesterol metabolism and TGFβ signaling. Our data suggest that in patients treated with HMGCoA reductase inhibitors, these agents may exert effects independent of cholesterol lowering on TGFβ signaling in the heart. PMID:10500210

  11. Increased accumulation of the cardio-cerebrovascular disease treatment drug tanshinone in Salvia miltiorrhiza hairy roots by the enzymes 3-hydroxy-3-methylglutaryl CoA reductase and 1-deoxy-D-xylulose 5-phosphate reductoisomerase.

    PubMed

    Shi, Min; Luo, Xiuqin; Ju, Guanhua; Yu, Xiaohong; Hao, Xiaolong; Huang, Qiang; Xiao, Jianbo; Cui, Lijie; Kai, Guoyin

    2014-09-01

    Tanshinone is widely used for treatment of cardio-cerebrovascular diseases with increasing demand. Herein, key enzyme genes SmHMGR (3-hydroxy-3-methylglutaryl CoA reductase) and SmDXR (1-deoxy-D-xylulose 5-phosphate reductoisomerase) involved in the tanshinone biosynthetic pathway were introduced into Salvia miltiorrhiza (Sm) hairy roots to enhance tanshinone production. Over-expression of SmHMGR or SmDXR in hairy root lines can significantly enhance the yield of tanshinone. Transgenic hairy root lines co-expressing HMGR and DXR (HD lines) produced evidently higher levels of total tanshinone (TT) compared with the control and single gene transformed lines. The highest tanshinone production was observed in HD42 with the concentration of 3.25 mg g(-1) DW. Furthermore, the transgenic hairy roots showed higher antioxidant activity than control. In addition, transgenic hairy root harboring HMGR and DXR (HD42) exhibited higher tanshinone content after elicitation by yeast extract and/or Ag(+) than before. Tanshinone can be significantly enhanced to 5.858, 6.716, and 4.426 mg g(-1) DW by YE, Ag(+), and YE-Ag(+) treatment compared with non-induced HD42, respectively. The content of cryptotanshinone and dihydrotanshinone was effectively elevated upon elicitor treatments, whereas there was no obvious promotion effect for the other two compounds tanshinone I and tanshinone IIA. Our results provide a useful strategy to improve tanshinone content as well as other natural active products by combination of genetic engineering with elicitors. PMID:24913677

  12. Role of lipoprotein-X in the pathogenesis of cholestatic hypercholesterolemia. Uptake of lipoprotein-X and its effect on 3-hydroxy-3-methylglutaryl coenzyme A reductase and chylomicron remnant removal in human fibroblasts, lymphocytes, and in the rat.

    PubMed Central

    Walli, A K; Seidel, D

    1984-01-01

    Cholestasis is accompanied by the appearance of lipoprotein-X (LP-X) in plasma. This lipoprotein has a high content of unesterified cholesterol and phospholipids and appears to be ineffective in suppressing the enhanced hepatic cholesterogenesis of cholestasis. Its role as a possible causative factor for cholestatic hypercholesterolemia was investigated. When 125I-LP-X was injected into rats, it disappeared rapidly from the circulation. Calculated on the basis of gram wet weight, spleen took up more LP-X than liver. Prior ligation of the bile duct reduced the uptake in spleen. Experiments with isolated perfused rat liver showed that nonparenchymal cells (NPC) took up over eightfold more 125I-LP-X than hepatic parenchymal cells (PC). Incubation of PC, NPC, human lymphocyte suspensions, or fibroblast cultures with LP-X showed that NPC bound more LP-X than PC or fibroblasts. Lymphocytes took up 20-fold more LP-X than PC and the activity of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase was depressed by LP-X. Lymphocytes isolated from cholestatic patients showed low activity of this enzyme. The activity was increased by LP-X in isolated perfused livers, but suppressed in isolated microsomes. LP-X competitively inhibited the uptake of chylomicron remnants in isolated perfused livers and hepatocytes. In contrast, degradation of LDL by perfused livers, which were isolated from ethinyl estradiol-treated rats or human fibroblast cultures, remained unchanged in the presence of LP-X. The results indicate that cholesterol transported by LP-X is mainly taken up by the cells of the reticuloendothelial system. It increases the activity of hepatic HMG-CoA reductase and suppresses remnant uptake, thus emphasizing a major role of LP-X in cholestatic hypercholesterolemia. Images PMID:6470142

  13. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, potentiate the anti-angiogenic effects of bevacizumab by suppressing angiopoietin2, BiP, and Hsp90α in human colorectal cancer

    PubMed Central

    Lee, S J; Lee, I; Lee, J; Park, C; Kang, W K

    2014-01-01

    Background: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are commonly prescribed because of their therapeutic and preventive effects on cardiovascular diseases. Even though they have been occasionally reported to have antitumour activity, it is unknown whether statins have anti-angiogenic effect in human colorectal cancer (CRC). Methods: A total of 11 human CRC cell lines were used to test the effects of bevacizumab, statins, and bevacizumab plus statins on human umbilical vein endothelial cell (HUVEC) viability and invasion in vitro. To determine the molecular mechanism of statins as anti-angiogenic agents, we performed an angiogenesis antibody array and proteomics analysis and confirmed the results using immunoblot assay, HUVEC invasion rescue assay, and siRNA assay. The antitumoural effects of bevacizumab and statins were evaluated in xenograft models. Results: A conventional dose of statins (simvastatin 0.2 μM, lovastatin 0.4 μM, atorvastatin 0.1 μM, and pravastatin 0.4 μM) in combination with bevacizumab directly reduced the cell viability, migration, invasion, and tube formation of HUVECs. The culture media of the CRC cells treated with bevacizumab or statins were also found to inhibit HUVEC invasion by suppressing angiogenic mediators, such as angiopoietin2, binding immunoglobulin protein (BiP), and Hsp90α. The combined treatment with bevacizumab and simvastatin significantly reduced the growth and metastases of xenograft tumours compared with treatment with bevacizumab alone. Conclusions: The addition of simvastatin at a dose used in patients with cardiovascular diseases (40–80 mg once daily) may potentiate the anti-angiogenic effects of bevacizumab on CRC by suppressing angiopoietin2, BiP, and Hsp90α in cancer cells. A clinical trial of simvastatin in combination with bevacizumab in patients with CRC is needed. PMID:24945998

  14. Synthesis of α,ω-polyfluorinated α-amino acid derivatives and δ,δ-difluoronorvaline.

    PubMed

    Ulbrich, Dirk; Daniliuc, Constantin G; Haufe, Günter

    2016-03-01

    Intending to synthesize ω,ω-difluoroalkyl amino acid derivatives by oxidative desulfurization-fluorination reactions of suitable arylthio-2-phthalimido butanoates and pentanoates, in addition to small amounts of the target products, mainly α,ω-polyfluorinated amino acid derivatives were formed by additional sulfur-assisted α-fluorination. This novel structural motif was verified spectroscopically as well as by X-ray analysis. A plausible mechanism of formation is suggested. Using a different approach, δ,δ-difluoronorvaline hydrochloride was synthesized with at least 36% enantiomeric excess via deoxofluorination of the corresponding aldehyde. PMID:26857261

  15. Novel Regulation of the Synthesis of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Subunit GluA1 by Carnitine Palmitoyltransferase 1C (CPT1C) in the Hippocampus.

    PubMed

    Fadó, Rut; Soto, David; Miñano-Molina, Alfredo J; Pozo, Macarena; Carrasco, Patricia; Yefimenko, Natalia; Rodríguez-Álvarez, José; Casals, Núria

    2015-10-16

    The regulation of AMPA-type receptor (AMPAR) abundance in the postsynaptic membrane is an important mechanism involved in learning and memory formation. Recent data suggest that one of the constituents of the AMPAR complex is carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform located in the endoplasmic reticulum of neurons. Previous results had demonstrated that CPT1C deficiency disrupted spine maturation in hippocampal neurons and impaired spatial learning, but the role of CPT1C in AMPAR physiology had remained mostly unknown. In the present study, we show that CPT1C binds GluA1 and GluA2 and that the three proteins have the same expression profile during neuronal maturation. Moreover, in hippocampal neurons of CPT1C KO mice, AMPAR-mediated miniature excitatory postsynaptic currents and synaptic levels of AMPAR subunits GluA1 and GluA2 are significantly reduced. We show that AMPAR expression is dependent on CPT1C levels because total protein levels of GluA1 and GluA2 are decreased in CPT1C KO neurons and are increased in CPT1C-overexpressing neurons, whereas other synaptic proteins remain unaltered. Notably, mRNA levels of AMPARs remained unchanged in those cultures, indicating that CPT1C is post-transcriptionally involved. We demonstrate that CPT1C is directly involved in the de novo synthesis of GluA1 and not in protein degradation. Moreover, in CPT1C KO cultured neurons, GluA1 synthesis after chemical long term depression was clearly diminished, and brain-derived neurotrophic factor treatment was unable to phosphorylate the mammalian target of rapamycin (mTOR) and stimulate GluA1 protein synthesis. These data newly identify CPT1C as a regulator of AMPAR translation efficiency and therefore also synaptic function in the hippocampus. PMID:26338711

  16. Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons.

    PubMed

    Qin, Xike; Jiang, Yongjun; Tse, Yiu Chung; Wang, Yunling; Wong, Tak Pan; Paudel, Hemant K

    2015-12-01

    The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR-induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR-mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. PMID:26475861

  17. Glutamate Stimulates Local Protein Synthesis in the Axons of Rat Cortical Neurons by Activating α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors and Metabotropic Glutamate Receptors*

    PubMed Central

    Hsu, Wei-Lun; Chung, Hui-Wen; Wu, Chih-Yueh; Wu, Huei-Ing; Lee, Yu-Tao; Chen, En-Chan; Fang, Weilun; Chang, Yen-Chung

    2015-01-01

    Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. By analyzing the metabolic incorporation of azidohomoalanine, a methionine analogue, in newly synthesized proteins, we find that glutamate treatments up-regulate protein translation not only in intact rat cortical neurons in culture but also in the axons emitting from cortical neurons before making synapses with target cells. The process by which glutamate stimulates local translation in axons begins with the binding of glutamate to the ionotropic AMPA receptors and metabotropic glutamate receptor 1 and members of group 2 metabotropic glutamate receptors on the plasma membrane. Subsequently, the activated mammalian target of rapamycin (mTOR) signaling pathway and the rise in Ca2+, resulting from Ca2+ influxes through calcium-permeable AMPA receptors, voltage-gated Ca2+ channels, and transient receptor potential canonical channels, in axons stimulate the local translation machinery. For comparison, the enhancement effects of brain-derived neurotrophic factor (BDNF) on the local protein synthesis in cortical axons were also studied. The results indicate that Ca2+ influxes via transient receptor potential canonical channels and activated the mTOR pathway in axons also mediate BDNF stimulation to local protein synthesis. However, glutamate- and BDNF-induced enhancements of translation in axons exhibit different kinetics. Moreover, Ca2+ and mTOR signaling appear to play roles carrying different weights, respectively, in transducing glutamate- and BDNF-induced enhancements of axonal translation. Thus, our results indicate that exposure to transient increases of glutamate and more lasting increases of BDNF would stimulate local protein synthesis in migrating axons en route to their targets in the developing brain. PMID:26134564

  18. Characterization of the Antiallergic Drugs 3-[2-(2-Phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic Acid and Ethyl 3-Hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as Full Aryl Hydrocarbon Receptor Agonists

    PubMed Central

    Morales, José Luis; Krzeminski, Jacek; Amin, Shantu; Perdew, Gary H.

    2008-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates most of the toxic effects of numerous chlorinated (e.g., TCDD) and nonchlorinated polycyclic aromatic compounds (e.g., benzo[a]pyrene). Studies in AhR null mice suggested that this receptor may also play a role in the modulation of immune responses. Recently, two drugs, namely, M50354 and M50367 (ethyl ester derivative of M50354), were described as AhR ligands with high efficacy toward reducing atopic allergic symptoms in an AhR-dependent manner by skewing T helper cell differentiation toward a TH1 phenotype [Negishi et al. (2005) J. Immunol. 175 (11), 7348–7356]. Surprisingly, these drugs were shown to have minimal activity toward inducing classical dioxin responsive element-driven AhR-mediated CYP1A1 transcription. We synthesized and reevaluated the ability of these drugs to regulate AhR activity. In contrast to previously published data, both M50354 and M50367 were found to be potent inducers of several AhR target genes, namely, CYP1A1, CYP1B1, and UGT1A2. M50367 was a more effective agonist than M50354, perhaps accounting for its higher bioavailability in vivo. However, M50354 was capable of displacing an AhR-specific radioligand more effectively than M50367. This is consistent with M50354 being the active metabolite of M50367. In conclusion, two selective inhibitors of TH2 differentiation are full AhR agonists. PMID:18179178

  19. Crystal Structures of Two Bacterial 3-Hydroxy-3-methylglutaryl-CoA Lyases Suggest a Common Catalytic Mechanism among a Family of TIM Barrel Metalloenzymes Cleaving Carbon-Carbon Bonds

    SciTech Connect

    Forouhar,F.; Hussain, M.; Farid, R.; Benach, J.; Abashidze, M.; Edstrom, W.; Vorobiev, S.; Montelione, G.; Hunt, J.; et al.

    2006-01-01

    The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the terminal steps in ketone body generation and leucine degradation. Mutations in this enzyme cause a human autosomal recessive disorder called primary metabolic aciduria, which typically kills victims because of an inability to tolerate hypoglycemia. Here we present crystal structures of the HMG-CoA lyases from Bacillus subtilis and Brucella melitensis at 2.7 and 2.3 {angstrom} resolution, respectively. These enzymes share greater than 45% sequence identity with the human orthologue. Although the enzyme has the anticipated triose-phosphate isomerase (TIM) barrel fold, the catalytic center contains a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel, contrary to the predictions of homology models. Surprisingly, the residues forming this cation-binding site and most of their interaction partners are shared with three other TIM barrel enzymes that catalyze diverse carbon-carbon bond cleavage reactions believed to proceed through enolate intermediates (4-hydroxy-2-ketovalerate aldolase, 2-isopropylmalate synthase, and transcarboxylase 5S). We propose the name 'DRE-TIM metallolyases' for this newly identified enzyme family likely to employ a common catalytic reaction mechanism involving an invariant Asp-Arg-Glu (DRE) triplet. The Asp ligates the divalent cation, while the Arg probably stabilizes charge accumulation in the enolate intermediate, and the Glu maintains the precise structural alignment of the Asp and Arg. We propose a detailed model for the catalytic reaction mechanism of HMG-CoA lyase based on the examination of previously reported product complexes of other DRE-TIM metallolyases and induced fit substrate docking studies conducted using the crystal structure of human HMG-CoA lyase (reported in the accompanying paper by Fu, et al. (2006) J. Biol. Chem. 281, 7526-7532). Our model is consistent with extensive mutagenesis results and

  20. Ethanol extract of Zhongtian hawthorn lowers serum cholesterol in mice by inhibiting transcription of 3-hydroxy-3-methylglutaryl-CoA reductase via nuclear factor-kappa B signal pathway.

    PubMed

    Hu, Hai-Jie; Luo, Xue-Gang; Dong, Qing-Qing; Mu, Ai; Shi, Guo-Long; Wang, Qiu-Tong; Chen, Xiao-Ying; Zhou, Hao; Zhang, Tong-Cun; Pan, Li-Wen

    2016-03-01

    Hawthorn is a berry-like fruit from the species of Crataegus. In China, it has another more famous name, Shan-Zha, which has been used to improve digestion as a traditional Chinese medicine or food for thousands of years. Moreover, during the last decades, hawthorn has received more attention because of its potential to treat cardiovascular diseases. However, currently, only fruits of C. pinnatifida and C. pinnatifida var. major are included as Shan-Zha in the Chinese Pharmacopoeia. In this study, our results showed that the ethanol extract of Zhongtian hawthorn, a novel grafted cultivar of C. cuneata (wild Shan-Zha), could markedly reduce body weight and levels of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, and liver cholesterol of hyperlipidemia mice. It could suppress the stimulation effect of high-fat diet on the transcription of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and p65, and counteract the downregulation of CYP7A1 and LDLR. In addition, the results of luciferase reporter assay and Western blot showed that the transcriptional activity of HMGCR promoter was inhibited by Zhongtian hawthorn ethanol extract in a dose-dependent manner, while overexpression of p65 could reverse this transcriptional repression effect. These results suggested that Zhongtian hawthorn could provide health benefits by counteracting the high-fat diet-induced hypercholesteolemic and hyperlipidemic effects in vivo, and the mechanism underlying this event was mainly dependent on the suppressive effect of Zhongtian hawthorn ethanol extract on the transcription of HMGCR via nuclear factor-kappa B (NF-κB) signal pathway. Therefore, this novel cultivar of hawthorn cultivar which has much bigger fruits, early bearing, high yield, cold resistance, and drought resistance, might be considered as a good alternative to Shan-Zha and has great value in the food and medicine industry. In addition, to our best knowledge, this is also the first report that the

  1. Characterization of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors

    PubMed Central

    Malherbe, P; Masciadri, R; Norcross, R D; Knoflach, F; Kratzeisen, C; Zenner, M-T; Kolb, Y; Marcuz, A; Huwyler, J; Nakagawa, T; Porter, R H P; Thomas, A W; Wettstein, J G; Sleight, A J; Spooren, W; Prinssen, E P

    2008-01-01

    Background and purpose: As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to characterize derivatives of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) as enhancers of GABAB receptors. Experimental approach: Enhancing properties of rac-BHFF were assessed in the Chinese hamster ovary (CHO)-Gα16-hGABAB(1a,2a) cells by Fluorometric Imaging Plate Reader and GTPγ[35S]-binding assays, and in rat hippocampal slices by population spike (PS) recordings. In vivo activities of rac-BHFF were assessed using the loss of righting reflex (LRR) and stress-induced hyperthermia (SIH) models. Key results: In GTPγ[35S]-binding assays, 0.3 μM rac-BHFF or its pure enantiomer (+)-BHFF shifted the GABA concentration–response curve to the left, an effect that resulted in a large increase in both GABA potency (by 15.3- and 87.3-fold) and efficacy (149% and 181%), respectively. In hippocampal slices, rac-BHFF enhanced baclofen-induced inhibition of PS of CA1 pyramidal cells. In an in vivo mechanism-based model in mice, rac-BHFF increased dose-dependently the LRR induced by baclofen with a minimum effective dose of 3 mg kg−1 p.o. rac-BHFF (100 mg kg−1 p.o.) tested alone had no effect on LRR nor on spontaneous locomotor activity, but exhibited anxiolytic-like activity in the SIH model in mice. Conclusions and implications: rac-BHFF derivatives may serve as valuable pharmacological tools to elucidate the pathophysiological roles played by GABAB receptors in the central and peripheral nervous systems. PMID:18536733

  2. Chronic Intermittent Ethanol Exposure Alters Stress Effects on (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) Immunolabeling of Amygdala Neurons in C57BL/6J Mice.

    PubMed

    Maldonado-Devincci, Antoniette M; Kampov-Polevoi, Alexander; McKinley, Raechel E; Morrow, Danielle H; O'Buckley, Todd K; Morrow, A Leslie

    2016-01-01

    The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) is decreased in various brain regions of C57BL/6J mice following exposure to an acute stressor or chronic intermittent ethanol (CIE) exposure and withdrawal. It is well established that there are complex interactions between stress and ethanol drinking, with mixed literature regarding the effects of stress on ethanol intake. However, there is little research examining how chronic ethanol exposure alters stress responses. The present work examined the impact of CIE exposure and withdrawal on changes in brain levels of 3α,5α-THP, as well as hormonal and behavioral responses to forced swim stress (FSS). Adult male C57BL/6J mice were exposed to four cycles of CIE to induce ethanol dependence. Following 8 h or 72 h withdrawal, mice were subjected to FSS for 10 min, and 50 min later brains were collected for immunohistochemical analysis of cellular 3α,5α-THP. Behavioral and circulating corticosterone responses to FSS were quantified. Following 8 h withdrawal, ethanol exposure potentiated the corticosterone response to FSS. Following 72 h withdrawal, this difference was no longer observed. Following 8 h withdrawal, stress-exposed mice showed no differences in immobility, swimming or struggling behavior. However, following 72 h withdrawal, ethanol-exposed mice showed less immobility and greater swimming behavior compared to air-exposed mice. Interestingly, cellular 3α,5α-THP levels were increased in the lateral amygdala 8 h and 72 h post-withdrawal in stressed ethanol-exposed mice compared to ethanol-exposed/non-stressed mice. In the paraventricular nucleus of the hypothalamus, stress exposure decreased 3α,5α-THP levels compared to controls following 72 h withdrawal, but no differences were observed 8 h post-withdrawal. There were no differences in cellular 3α,5α-THP levels in the nucleus accumbens shell at either withdrawal time point. These data suggest that

  3. Chronic Intermittent Ethanol Exposure Alters Stress Effects on (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) Immunolabeling of Amygdala Neurons in C57BL/6J Mice

    PubMed Central

    Maldonado-Devincci, Antoniette M.; Kampov-Polevoi, Alexander; McKinley, Raechel E.; Morrow, Danielle H.; O’Buckley, Todd K.; Morrow, A. Leslie

    2016-01-01

    The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) is decreased in various brain regions of C57BL/6J mice following exposure to an acute stressor or chronic intermittent ethanol (CIE) exposure and withdrawal. It is well established that there are complex interactions between stress and ethanol drinking, with mixed literature regarding the effects of stress on ethanol intake. However, there is little research examining how chronic ethanol exposure alters stress responses. The present work examined the impact of CIE exposure and withdrawal on changes in brain levels of 3α,5α-THP, as well as hormonal and behavioral responses to forced swim stress (FSS). Adult male C57BL/6J mice were exposed to four cycles of CIE to induce ethanol dependence. Following 8 h or 72 h withdrawal, mice were subjected to FSS for 10 min, and 50 min later brains were collected for immunohistochemical analysis of cellular 3α,5α-THP. Behavioral and circulating corticosterone responses to FSS were quantified. Following 8 h withdrawal, ethanol exposure potentiated the corticosterone response to FSS. Following 72 h withdrawal, this difference was no longer observed. Following 8 h withdrawal, stress-exposed mice showed no differences in immobility, swimming or struggling behavior. However, following 72 h withdrawal, ethanol-exposed mice showed less immobility and greater swimming behavior compared to air-exposed mice. Interestingly, cellular 3α,5α-THP levels were increased in the lateral amygdala 8 h and 72 h post-withdrawal in stressed ethanol-exposed mice compared to ethanol-exposed/non-stressed mice. In the paraventricular nucleus of the hypothalamus, stress exposure decreased 3α,5α-THP levels compared to controls following 72 h withdrawal, but no differences were observed 8 h post-withdrawal. There were no differences in cellular 3α,5α-THP levels in the nucleus accumbens shell at either withdrawal time point. These data suggest that

  4. The regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity, cholesterol esterification and the expression of low-density lipoprotein receptors in cultured monocyte-derived macrophages.

    PubMed Central

    Knight, B L; Patel, D D; Soutar, A K

    1983-01-01

    Human blood monocytes cultured in medium containing 20% whole serum showed the greatest activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and [14C]acetate incorporation into non-saponifiable lipids around the 7th day after seeding, the period of greatest growth. Although there was enough low-density lipoprotein (LDL) in the medium to saturate the LDL receptors that were expressed by normal cells at that time, HMG-CoA reductase activity and acetate incorporation were as high in normal cells as in cells from familial-hypercholesterolaemic (FH) patients. Both the addition of extra LDL, which interacted with the cells by non-saturable processes, and receptor-mediated uptake of acetylated LDL significantly reduced reductase activity and increased incorporation of [14C]oleate into cholesteryl esters in normal cells and cells from FH patients ('FH cells'), and reduced the expression of LDL receptors in normal cells. Pre-incubation for 20h in lipoprotein-deficient medium apparently increased the number of LDL receptors expressed by normal cells but reduced the activity of HMG-CoA reductase in both normal and FH cells. During subsequent incubations the same rate of degradation of acetylated LDL and of non-saturable degradation of LDL by FH cells was associated with the same reduction in HMG-CoA reductase activity, although LDL produced a much smaller stimulation of oleate incorporation into cholesteryl esters. In normal cells pre-incubated without lipoproteins, receptor-mediated uptake of LDL could abolish reductase activity and the expression of LDL receptors. The results suggested that in these cells, receptor-mediated uptake of LDL might have a greater effect on reductase activity and LDL receptors than the equivalent uptake of acetylated LDL. It is proposed that endogenous synthesis is an important source of cholesterol for growth of normal cells, and that the site at which cholesterol is deposited in the cells may determine the nature and extent of the

  5. Synthesis of isonicotinoylhydrazones from anacardic acid and their in vitro activity against Mycobacterium smegmatis.

    PubMed

    Swamy, B Narayana; Suma, T K; Rao, G Venkateswara; Reddy, G Chandrasekara

    2007-03-01

    Isonicotinoylhydrazones were synthesized from a natural product anacardic acid, a major constituent of cashew nut shell liquid. The unsaturated side chain in anacardic acid and its 5-nitro derivative were converted into C(8')-aldehydes by oxidative cleavage. C(8')-aldehydes are then coupled with isoniazid (an anti-TB drug) to obtain N-isonicotinoyl-N'-8-[(2'-carbohydroxy-3'-hydroxy) phenyl] octanal hydrazone (5) and N-isonicotinoyl-N'-8-[(2'-carbohydroxy-3'-hydroxy-6-nitro) phenyl] octanal hydrazone (6). These isonicotinoylhydrazones of anacardic aldehydes showed potent antimycobacterial activity against Mycobacterium smegmatis mc(2)155. The synergistic studies of 5 and 6 with isoniazid showed more inhibitory activities than isoniazid alone. Compounds 5 and 6 also showed activity against Mycobacterium tuberculosis H(37)Rv. PMID:17112641

  6. Gestational age dependency in the prenatal toxicity and in the disposition kinetics of the novel anticonvulsant HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) after subcutaneous administration in pregnant rats.

    PubMed

    Gómez-Martínez, Lisbeth E

    2007-01-01

    HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) is a novel anticonvulsant with promising anticonvulsant profile, which is being actively researched. The potential maternal and embryo/fetal toxicities of HEPP were evaluated in pregnant rats following subcutaneous (s.c.) administration during organogenesis (gestation days 6 through 14, GDs 6-14) and the fetal period (GDs 14-21). Single- and multiple-dose pharmacokinetics were also evaluated at the same periods in order to establish possible correlations with some maternal or embryo/fetal toxicity end points. Embryotoxicity was mainly indicated by a significant dose-concentration dependency in the increase in resorptions, high percentage of fully resorbed litters, and decrease in embryo body weights during the GD6-14 dosing period. No gross external alterations were observed in live fetuses. There was no indication of maternal toxicity; but a marked increase in maternal body weight was evident following dosing from GD14 to GD21. The maternal plasma profile following single subcutaneous dose of 50 mg/kg on both GD14 and GD21 showed a monoexponential elimination pattern. Statistically significant differences between treatments (GD14 versus GD21) were observed in elimination (k(el) = 0.12 versus 0.15 h(-1)), absorption (k(a) = 2.01 versus 3.14 h(-1)), maximum plasma concentration time points (T(max) = 1.49 versus 1.01 h); maximum plasma concentration (C(max) = 40.23 versus 36.31 microg/ml) and areas under the concentration-time curve (AUCs(0-infinity) = 421.88 versus 274 microg h/ml. Based on comparisons of C(max), T(max), and AUCs(0-infinity) between the actual data and single intraperitoneal (i.p.) data previously published, the s.c. administration exhibited slower disposition and higher absorbed amount. After multiple-dose administrations of 50 and 100 mg/kg every 12 h (07:00 and 19:00 h), steady-state plasma levels were lower than the computer prediction, and only slight accumulation was observed. In both dosing

  7. Oxygenation by COX-2 (cyclo-oxygenase-2) of 3-HETE (3-hydroxyeicosatetraenoic acid), a fungal mimetic of arachidonic acid, produces a cascade of novel bioactive 3-hydroxyeicosanoids

    PubMed Central

    2005-01-01

    Cyclo-oxygenases-1/2 (COX-1/2) catalyse the oxygenation of AA (arachidonic acid) and related polyunsaturated fatty acids to endoperoxide precursors of prostanoids. COX-1 is referred to as a constitutive enzyme involved in haemostasis, whereas COX-2 is an inducible enzyme expressed in inflammatory diseases and cancer. The fungus Dipodascopsis uninucleata has been shown by us to convert exogenous AA into 3(R)-HETE [3(R)-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid]. 3R-HETE is stereochemically identical with AA, except that a hydroxy group is attached at its C-3 position. Molecular modelling studies with 3-HETE and COX-1/2 revealed a similar enzyme–substrate structure as reported for AA and COX-1/2. Here, we report that 3-HETE is an appropriate substrate for COX-1 and -2, albeit with a lower activity of oxygenation than AA. Oxygenation of 3-HETE by COX-2 produced a novel cascade of 3-hydroxyeicosanoids, as identified with EI (electron impact)–GC–MS, LC–MS–ES (electrospray) and LC–MS–API (atmospheric pressure ionization) methods. Evidence for in vitro production of 3-hydroxy-PGE2 (3-hydroxy-prostaglandin E2) was obtained upon infection of HeLa cells with Candida albicans at an MOI (multiplicity of infection) of 100. Analogous to interaction of AA and aspirin-treated COX-2, 3-HETE was transformed by acetylated COX-2 to 3,15-di-HETE (3,15-dihydroxy-HETE), whereby C-15 showed the (R)-stereochemistry. 3-Hydroxy-PGs are potent biologically active compounds. Thus 3-hydroxy-PGE2 induced interleukin-6 gene expression via the EP3 receptor (PGE2 receptor 3) in A549 cells, and raised cAMP levels via the EP4 receptor in Jurkat cells. Moreover, 3R,15S-di-HETE triggered the opening of the K+ channel in HTM (human trabecular meshwork) cells, as measured by the patch–clamp technique. Since many fatty acid disorders are associated with an ‘escape’ of 3-hydroxy fatty acids from the β-oxidation cycle, the production of 3-hydroxyeicosanoids may be critical in

  8. [Effect of excitant amino acid antagonists on glutamate receptors in the locust and on convulsions induced by glutamate, aspartate, kynurenine and quinolinic acid in mice].

    PubMed

    Ryzhov, I V; Slepokurov, M V; Lapin, I P; Mandel'shtam, Iu E; Aleksandrov, V G

    1986-03-01

    All excitatory amino acid antagonists studied: diethyl esters of aspartic (DEEA) and glutamic (DEEG) acids, 2-amino-3-phosphono-propionic acid (APPA) and 2-amino-4-phosphono-butanoic acid (APBA), diminished the amplitude of excitatory postsynaptic potentials (EPP) of the locust (Locusta migratoria migratorioides) muscle fibers and arbitrary blocked glutamate (GLU) and aspartate (ASP) responses. Kynurenine (KYN) and quinolinic (QUI) acid had no effect on EPP even at a concentration of 2 X 10(-2) M. The antagonists were not strictly selective against intracerebroventricularly administered endogenous convulsants: GLU, ASP, KYN and QUI and in simulation of experimental seizures in mice. The antagonists structurally similar to ASP prevented ASP- and KYN-induced seizures in lower doses than GLU derivatives. Anti-KYN, but not anti-QUI DEEA, DEEG, APPA and APBA efficacy suggests that KYN and QUI act on different structures or binding sites. PMID:2869799

  9. Thermochemistry of C-O, (CO)-O, and (CO)-C bond breaking in fatty acid methyl esters

    SciTech Connect

    Osmont, Antoine; Yahyaoui, Mohammed; Catoire, Laurent; Goekalp, Iskender; Swihart, Mark T.

    2008-10-15

    Density functional theory quantum chemical calculations corrected with empirical atomic increments have been used to examine C-O, (CO)-O, and (CO)-C bond scission enthalpies in gas-phase fatty acid methyl esters (FAMEs) present in biodiesel derived from rapeseed oil methyl ester and soybean oil methyl ester. Mechanistic information, currently not available elsewhere for these large species, is obtained based on thermochemical considerations and compared to thermochemical considerations reported for methyl butanoate, a small methyl ester sometimes used as a model for FAMEs. These results are compared to previously reported C-C and C-H bond scissions in these FAMEs, derived using this same protocol. (author)

  10. Cyano substituent effects on enol and enethiol acidity and basicity

    NASA Astrophysics Data System (ADS)

    Luna, Alberto; Mó, Otilia; Yáñez, Manuel; Guillemin, Jean-Claude; Gal, Jean-François; Maria, Pierre-Charles

    2007-11-01

    The gas-phase basicity and acidity of 3-hydroxy-2-propenenitrile (3-hydroxyacrylonitrile) and its sulfur-containing analogue, 3-mercapto-2-propenenitrile, have been determined by means of high-level G3B3 ab initio calculations and, in the case of the latter compound, compared with the experimental values obtained by means of FT-ICR mass spectrometry techniques, and with previous reported values for the NC-CHCH-X (X = CH3, NH2, SiH3, PH2) analogues. For both compounds the Z-isomer is the dominant species in the gas-phase. Protonation takes place in both cases at the cyano group. The loss of the proton from the substituent, was found to be systematically much more favorable than the deprotonation at the HCCH group. 3-Hydroxy-2-propenenitrile is predicted to be a stronger base by ca. 5 kJ mol-1 than its thio analogue, but a weaker acid by 26 kJ mol-1. Both compounds are stronger acids than the corresponding unsubstituted vinyl compounds, because cyano substitution stabilizes much more the deprotonated species than the corresponding neutral compound. There is a clear disagreement between our theoretical estimates for both the gas-phase basicity and the gas-phase acidity of 3-mercapto-2-propenenitrile and the corresponding experimental values, which is consistent with its isomerization to yield isothiazole.

  11. Contrast of volatile fatty acid driven and inorganic acid or base driven phosphorus release and uptake in enhanced biological phosphorus removal.

    PubMed

    Randall, Andrew A

    2012-04-01

    Addition of an inorganic acid or base was detrimental to net phosphorus removals in short-term batch experiments, suggesting there might be system upset when pH changes. In contrast, addition of volatile fatty acids (VFAs) increased anaerobic phosphorus release and aerobic phosphorus uptake while maintaining or improving net phosphorus removals. The effect of pH change differed if the acid or base added was inorganic versus organic. Volatile fatty acids that resulted in poly-3-hydroxy-butyrate rather than poly-3-hydroxy-valerate resulted in greater net phosphorus removals, and this corresponded to differences in consumption of reducing equivalents. Acetic acid resulted in improved net phosphorus removal compared to sodium acetate, suggesting that acid forms of VFAs might be superior as supplemental VFAs. It is hypothesized that anaerobic phosphorus release following addition of inorganic acid is primarily a result of phosphorus and proton (H+) symport (excretion from the cell) for pH homeostasis, whereas addition of VFAs results in phosphorus and H+ release to maintain the proton motive force. PMID:22834218

  12. Adsorption and degradation of phenoxyalkanoic acid herbicides in soils: A review.

    PubMed

    Paszko, Tadeusz; Muszyński, Paweł; Materska, Małgorzata; Bojanowska, Monika; Kostecka, Małgorzata; Jackowska, Izabella

    2016-02-01

    The primary aim of the present review on phenoxyalkanoic acid herbicides-2-(2,4-dichlorophenoxy) acetic acid (2,4-D), 2-(4-chloro-2-methylphenoxy) acetic acid (MCPA), (2R)-2-(2,4-dichlorophenoxy) propanoic acid (dichlorprop-P), (2R)-2-(4-chloro-2-methylphenoxy) propanoic acid (mecoprop-P), 4-(2,4-dichlorophenoxy) butanoic acid (2,4-DB), and 4-(4-chloro-2-methylphenoxy) butanoic acid (MCPB)-was to compare the extent of their adsorption in soils and degradation rates to assess their potential for groundwater contamination. The authors found that adsorption decreased in the sequence of 2,4-DB > 2,4-D > MCPA > dichlorprop-P > mecoprop-P. Herbicides are predominantly adsorbed as anions-on organic matter and through a water-bridging mechanism with adsorbed Fe cations-and their neutral forms are adsorbed mainly on organic matter. Adsorption of anions of 2,4-D, MCPA, dichlorprop-P, and mecoprop-P is inversely correlated with their lipophilicity values, and modeling of adsorption of the compounds based on this relationship is possible. The predominant dissipation mechanism of herbicides in soils is bacterial degradation. The contribution of other mechanisms, such as degradation by fungi, photodegradation, or volatilization from soils, is much smaller. The rate of bacterial degradation decreased in the following order: 2,4-D > MCPA > mecoprop-P > dichlorprop-P. It was found that 2,4-D and MCPA have the lowest potential for leaching into groundwater and that mecoprop-P and dichlorprop-P have slightly higher potential. Because of limited data on adsorption and degradation of 2,4-DB and MCPB, estimation of their leaching potential was not possible. PMID:26292078

  13. Degradation of ascorbic acid in ethanolic solutions.

    PubMed

    Hsu, Hsin-Yun; Tsai, Yi-Chin; Fu, Chi-Chang; Wu, James Swi-Bea

    2012-10-24

    Ascorbic acid occurs naturally in many wine-making fruits. The industry also uses ascorbic acid as an antioxidant and color stabilizer in the making of alcoholic beverages including white wine, wine cooler, alcopop, and fruit liqueur. However, the degradation of ascorbic acid itself may cause browning and the deterioration of color quality. This study was aimed to monitor the degradation of ascorbic acid, the formation of degradation products, and the browning in storage of ascorbic acid containing 0-40% (v/v) ethanolic solutions buffered at pH 3.2 as models of alcoholic beverages. The results show that ascorbic acid degradation in the ethanolic solutions during storage follows first-order reaction, that the degradation and browning rates increase with the increase of ethanol concentration, that the activation energy for the degradation of ascorbic acid is in the range 10.35-23.10 (kcal/mol), that 3-hydroxy-2-pyrone is an indicator and a major product of ascorbic acid degradation, and that aerobic degradation pathway dominants over anaerobic pathway in ascorbic acid degradation in ethanolic solutions. PMID:22994409

  14. 40 CFR 721.10273 - 3′H-Cyclopropa[7,22][5,6]fullerene-C70-D5h(6)-3′-butanoic acid, 3′-phenyl-, methyl ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... processing, except for mechanical processing. (2) The significant new uses are: (i) Protection in the...), engineering control measures (e.g., enclosure or confinement of the operation, general and local ventilation..., voltage or other characteristics of the device, a compound that improves the mechanical properties...

  15. 40 CFR 721.10271 - 3′H-Cyclopropa[1,9][5,6]fullerene-C60-Ih-3′-butanoic acid, 3′-phenyl-, methyl ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... processing, except for mechanical processing. (2) The significant new uses are: (i) Protection in the...), engineering control measures (e.g., enclosure or confinement of the operation, general and local ventilation..., voltage or other characteristics of the device, a compound that improves the mechanical properties...

  16. 40 CFR 721.10272 - 3′H-Cyclopropa[8,25][5,6]fullerene-C70-D5h(6)-3′-butanoic acid, 3′-phenyl-,methyl ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... properties of lubricants and plastics, or use as an acceptor molecule in a polymer coating in an encapsulated organic photovoltaic electronic device) and (q). (iii) Release to water. Requirements as specified...

  17. 40 CFR 721.10272 - 3′H-Cyclopropa[8,25][5,6]fullerene-C70-D5h(6)-3′-butanoic acid, 3′-phenyl-,methyl ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... properties of lubricants and plastics, or use as an acceptor molecule in a polymer coating in an encapsulated organic photovoltaic electronic device) and (q). (iii) Release to water. Requirements as specified...

  18. 40 CFR 721.10271 - 3′H-Cyclopropa[1,9][5,6]fullerene-C60-Ih-3′-butanoic acid, 3′-phenyl-, methyl ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false 3â²H-Cyclopropa fullerene-C60-Ih-3â²... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10271 3′H-Cyclopropa fullerene-C60-Ih... to reporting. (1) The chemical substance identified as 3′H-Cyclopropa...

  19. 40 CFR 721.10273 - 3′H-Cyclopropa[7,22][5,6]fullerene-C70-D5h(6)-3′-butanoic acid, 3′-phenyl-, methyl ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... lubricants and plastics, or use as an acceptor molecule in a polymer coating in an encapsulated organic photovoltaic electronic device) and (q). (iii) Release to water. Requirements as specified in §...

  20. Elevated Levels of Mercapturic Acids of Acrolein and Crotonaldehyde in the Urine of Chinese Women in Singapore Who Regularly Cook at Home

    PubMed Central

    Hecht, Stephen S.; Koh, Woon-Puay; Wang, Renwei; Chen, Menglan; Carmella, Steven G.; Murphy, Sharon E.; Yuan, Jian-Min

    2015-01-01

    Lung cancer is unusually common among non-smoking women in Southeastern Asia but the causes of this frequently fatal disease are not well understood. Several epidemiology studies indicate that inhalation of fumes from high temperature Chinese style cooking with a wok may be a cause. Only one previous study investigated uptake of potential toxicants and carcinogens by women who cook with a wok. We enrolled three-hundred twenty-eight non-smoking women from Singapore for this study. Each provided a spot urine sample and answered a questionnaire concerning their cooking habits and other factors. The urine samples were analyzed by liquid chromatography-tandem mass spectrometry for mercapturic acid metabolites of acrolein (3-hydroxypropylmercapturic acid), crotonaldehyde (3-hydroxy-1-methylpropylmercapturic acid), and benzene (S-phenylmercapturic acid), accepted biomarkers of uptake of these toxic and carcinogenic compounds. We observed statistically significant effects of wok cooking frequency on levels of 3-hydroxypropylmercapturic acid and 3-hydroxy-1-methylpropylmercapturic acid, but not S-phenylmercapturic acid. Women who cooked greater than 7 times per week had a geometric mean of 2600 (95% CI, 2189-3090) pmol/mg creatinine 3-hydroxypropylmercapturic acid compared to 1901 (95% CI, 1510-2395) pmol/mg creatinine when cooking less than once per week (P for trend 0.018). The corresponding values for 3-hydroxy-1-methylpropylmercapturic acid were 1167 (95% CI, 1022-1332) and 894 (95% CI, 749-1067) pmol/mg creatinine (P for trend 0.008). We conclude that frequent wok cooking leads to elevated exposure to the toxicants acrolein and crotonaldehyde, but not benzene. Kitchens should be properly ventilated to decrease exposure to potentially toxic and carcinogenic fumes produced during Chinese style wok cooking. PMID:25807518

  1. Elevated levels of mercapturic acids of acrolein and crotonaldehyde in the urine of Chinese women in Singapore who regularly cook at home.

    PubMed

    Hecht, Stephen S; Koh, Woon-Puay; Wang, Renwei; Chen, Menglan; Carmella, Steven G; Murphy, Sharon E; Yuan, Jian-Min

    2015-01-01

    Lung cancer is unusually common among non-smoking women in Southeastern Asia but the causes of this frequently fatal disease are not well understood. Several epidemiology studies indicate that inhalation of fumes from high temperature Chinese style cooking with a wok may be a cause. Only one previous study investigated uptake of potential toxicants and carcinogens by women who cook with a wok. We enrolled three-hundred twenty-eight non-smoking women from Singapore for this study. Each provided a spot urine sample and answered a questionnaire concerning their cooking habits and other factors. The urine samples were analyzed by liquid chromatography-tandem mass spectrometry for mercapturic acid metabolites of acrolein (3-hydroxypropylmercapturic acid), crotonaldehyde (3-hydroxy-1-methylpropylmercapturic acid), and benzene (S-phenylmercapturic acid), accepted biomarkers of uptake of these toxic and carcinogenic compounds. We observed statistically significant effects of wok cooking frequency on levels of 3-hydroxypropylmercapturic acid and 3-hydroxy-1-methylpropylmercapturic acid, but not S-phenylmercapturic acid. Women who cooked greater than 7 times per week had a geometric mean of 2600 (95% CI, 2189-3090) pmol/mg creatinine 3-hydroxypropylmercapturic acid compared to 1901 (95% CI, 1510-2395) pmol/mg creatinine when cooking less than once per week (P for trend 0.018). The corresponding values for 3-hydroxy-1-methylpropylmercapturic acid were 1167 (95% CI, 1022-1332) and 894 (95% CI, 749-1067) pmol/mg creatinine (P for trend 0.008). We conclude that frequent wok cooking leads to elevated exposure to the toxicants acrolein and crotonaldehyde, but not benzene. Kitchens should be properly ventilated to decrease exposure to potentially toxic and carcinogenic fumes produced during Chinese style wok cooking. PMID:25807518

  2. Emissions of volatile fatty acids from feed at dairy facilities

    NASA Astrophysics Data System (ADS)

    Alanis, Phillip; Ashkan, Shawn; Krauter, Charles; Campbell, Sean; Hasson, Alam S.

    2010-12-01

    Recent studies suggest that dairy operations may be a major source of non-methane volatile organic compounds in dairy-intensive regions such as Central California, with short chain carboxylic acids (volatile fatty acids or VFAs) as the major components. Emissions of four VFAs (acetic acid, propanoic acid, butanoic acid and hexanoic acid) were measured from two feed sources (silage and total mixed rations (TMR)) at six Central California Dairies over a fifteen-month period. Measurements were made using a combination of flux chambers, solid phase micro-extraction fibers coupled to gas chromatography mass spectrometry (SPME/GC-MS) and infra-red photoaccoustic detection (IR-PAD for acetic acid only). The relationship between acetic acid emissions, source surface temperature and four sample composition factors (acetic acid content, ammonia-nitrogen content, water content and pH) was also investigated. As observed previously, acetic acid dominates the VFA emissions. Fluxes measured by IR-PAD were systematically lower than SPME/GC-MS measurements by a factor of two. High signals in field blanks prevented emissions from animal waste sources (flush lane, bedding, open lot) from being quantified. Acetic acid emissions from feed sources are positively correlated with surface temperature and acetic acid content. The measurements were used to derive a relationship between surface temperature, acetic acid content and the acetic acid flux. The equation derived from SPME/GC-MS measurements predicts estimated annual average acetic acid emissions of (0.7 + 1/-0.4) g m -2 h -1 from silage and (0.2 + 0.3/-0.1) g m -2 h -1 from TMR using annually averaged acetic acid content and meteorological data. However, during the summer months, fluxes may be several times higher than these values.

  3. Tyrosine-Based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) Prodrugs: Synthesis, Stability, Antiviral Activity and in Vivo Transport Studies

    PubMed Central

    Zakharova, Valeria M.; Serpi, Michaela; Krylov, Ivan S.; Peterson, Larryn W.; Breitenbach, Julie M.; Borysko, Katherine Z.; Drach, John C.; Collins, Mindy; Hilfinger, John M.; Kashemirov, Boris A.; McKenna, Charles E.

    2011-01-01

    Eight novel single amino acid (6–11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPCa, 4) and its cyclic adenine analog ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC50 values for the prodrugs vs vaccinia, cowpox, human cytomegalo- and herpes simplex type 1 viruses were similar to those for the parent drugs ((S)-HPMPC, 2, (S)-HPMPA, 1; IC50 0.3 – 30 µM); there were no cytoxicity with KB or HFF cells at ≤ 100 µM. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30 – 1732 min) with differences of 3–10× between phostonate diastereomers. The tyrosine-alkylamide derivatives of 3 and 4 were the most stable. (L)-Tyr-NHiBu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39 % vs <5 %). PMID:21812420

  4. Measurement of non-enteric emission fluxes of volatile fatty acids from a California dairy by solid phase micro-extraction with gas chromatography/mass spectrometry

    NASA Astrophysics Data System (ADS)

    Alanis, Phillip; Sorenson, Mark; Beene, Matt; Krauter, Charles; Shamp, Brian; Hasson, Alam S.

    Dairies are a major source of volatile organic compounds (VOCs) in California's San Joaquin Valley; a region that experiences high ozone levels during summer. Short-chain carboxylic acids, or volatile fatty acids (VFAs), are believed to make up a large fraction of VOC emissions from these facilities, although there are few studies to substantiate this. In this work, a method using a flux chamber coupled to solid phase micro-extraction (SPME) fibers followed by analysis using gas chromatography/mass spectrometry was developed to quantify emissions of six VFAs (acetic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid and 3-methyl butanoic acid) from non-enteric sources. The technique was then used to quantify VFA fluxes from a small dairy located on the campus of California State University Fresno. Both animal feed and animal waste are found to be major sources of VFAs, with acetic acid contributing 70-90% of emissions from the sources tested. Measured total acid fluxes during spring (with an average temperature of 20 °C) were 1.84 ± 0.01, 1.06 ± 0.08, (1.3 ± 0.5) × 10 -2, (1.7 ± 0.2) × 10 -2 and (1.2 ± 0.5) × 10 -2 g m -2 h -1 from silage, total mixed rations, flushing lane, open lot and lagoon sources, respectively. VFA emissions from the sources tested total 390 ± 80 g h -1. The data indicate high fluxes of VFAs from dairy facilities, but differences in the design and operation of dairies in the San Joaquin Valley as well as seasonal variations mean that additional measurements must be made to accurately determine emissions inventories for the region.

  5. Synthesis, Characterization, and Antifungal Activity of Phenylpyrrole-Substituted Tetramic Acids Bearing Carbonates.

    PubMed

    Xu, Wen-Qin; Chen, Min; Wang, Kun-Yao; Ren, Zheng-Jiao; Lu, Ai-Min; Yang, Chun-Long

    2016-01-01

    For the aim of discovering new fungicide, a series of phenylpyrrole-substituted tetramic acid derivatives bearing carbonates 6a-q were designed and synthesized via 4-(2,4-dioxopyrrolidin-3-ylidene)-4-(phenylamino)butanoic acids 4a-k and the cyclized products 1',3,4,5'-tetrahydro-[2,3'-bipyrrolylidene]-2',4',5(1H)-triones 5a-k. The compounds were characterized using IR, ¹H- and (13)C-NMR spectroscopy, mass spectrometry (EI-MS), and elemental analysis. The structure of 6b was confirmed by X-ray diffraction crystallography. The title compounds 6a-q were bioassayed in vitro against the phytopathogenic fungi Fusarium graminearum, Botrytis cinerea and Rhizoctonia solani at a concentration of 100 μg/mL, respectively. Most compounds displayed good inhibitory activity. PMID:27007370

  6. Statins in therapy: understanding their hydrophilicity, lipophilicity, binding to 3-hydroxy-3-methylglutaryl-CoA reductase, ability to cross the blood brain barrier and metabolic stability based on electrostatic molecular orbital studies.

    PubMed

    Fong, Clifford W

    2014-10-01

    The atomic electrostatic potentials calculated by the CHELPG method have been shown to be sensitive indicators of the gas phase and solution properties of the statins. Solvation free energies in water, n-octanol and n-octane have been determined using the SMD solvent model. The percentage hydrophilicity and hydrophobicity (or lipophilicity) of the statins in solution have been determined using (a) the differences in solvation free energies between n-octanol and n-octane as a measure of hydrophilicity, and the solvation energy in octane as a measure of hydrophobicity (b) the sum of the atomic electrostatic charges on the hydrogen bonding and polar bonding nuclei of the common pharmacophore combined with a solvent measure of hydrophobicity, and (c) using the buried surface areas after statin binding to HMGCR to calculate the hydrophobicity of the bound statins. The data suggests that clinical definitions of statins as either "hydrophilic" or "lipophilic" based on experimental partition coefficients are misleading. An estimate of the binding energy between rosuvastatin and HMGCR has been made using: (a) a coulombic electrostatic interaction model, (b) the calculated desolvation and resolvation of the statin in water, and (c) the first shell transfer solvation energy as a proxy for the restructuring of the water molecules immediately adjacent to the active binding site of HMGCR prior to binding. Desolvation and resolvation of the statins before and after binding to HMGCR are major determinants of the energetics of the binding process. An analysis of the amphiphilic nature of lovastatin anion, acid and lactone and fluvastatin anion and their abilities to cross the blood brain barrier has indicated that this process may be dominated by desolvation and resolvation effects, rather than the statin molecular size or statin-lipid interactions within the bilayer. The ionization energy and electron affinity of the statins are sensitive physical indicators of the ease that the

  7. Biochemical characterization of thermostable ω-transaminase from Sphaerobacter thermophilus and its application for producing aromatic β- and γ-amino acids.

    PubMed

    Mathew, Sam; Nadarajan, Saravanan Prabhu; Chung, Taeowan; Park, Hyun Ho; Yun, Hyungdon

    2016-06-01

    An (S)-ω-transaminase from the thermophilic eubacterium Sphaerobacter thermophilus was expressed and functionally characterized. The enzyme showed good stability at high temperature and in the presence of various substrates. Substrate specificity analysis showed that the enzyme had activity towards a broad range of substrates including amines, β- and γ-amino acids. The purified enzyme showed a specific activity of 3.3U/mg towards rac-β-phenylalanine at 37°C. The applicability of this enzyme as an attractive biocatalyst was demonstrated by synthesizing optically pure β- and γ-amino acids. Among the various beta and gamma amino acids produced via asymmetric synthesis, (S)-4-amino-4-(4-methoxyphenyl)-butanoic acid showed highest analytical yield (82%) with excellent enantiomeric excess (>99%). PMID:27178795

  8. Antimutagenic action of the triterpene betulinic acid isolated from Scoparia dulcis (Scrophulariaceae).

    PubMed

    de Freitas, P L; Dias, A C S; Moreira, V R; Monteiro, S G; Pereira, S R F

    2015-01-01

    The mutagenic and antimutagenic activities of triterpene betulinic acid {3b-3-hydroxy-lup-20(29)-en-28-oic} isolated from the roots of Scoparia dulcis (Scrophulariaceae) were analyzed using the somatic mutation and recombination test (SMART) in the wings of Drosophila melanogaster. The mutagenic potential of betulinic acid was evaluated at 3 different concentrations (1.64, 3.28, and 6.57 mM). Antimutagenic activity evaluation was performed by co-treatment trials in which the flies received betulinic acid at 3 different concentrations in addition to 10 mM pro-mutagenic urethane. The results demonstrated that betulinic acid was not capable of causing DNA damage. However, the frequency of small single spots, large spots, and twin spots was significantly reduced. In the high bioactivation cross, betulinic acid was significantly active and exerted enhanced antimutagenic activity, possibly as a desmutagen. PMID:26345907

  9. Effect of short-chain fatty acids on the formation of amylose microparticles by amylosucrase.

    PubMed

    Lim, Min-Cheol; Park, Kyu-Hwan; Choi, Jong-Hyun; Lee, Da-Hee; Letona, Carlos Andres Morales; Baik, Moo-Yeol; Park, Cheon-Seok; Kim, Young-Rok

    2016-10-20

    Amylose microparticles can be produced by self-assembly of amylose molecules through an amylosucrase-mediated synthesis. Here we investigated the role of short-chain fatty acids in the formation of amylose microparticles and the fate of these fatty acids at the end of the reaction. The rate of self-assembly and production yields of amylose microparticles were significantly enhanced in the presence of fatty acids. The effect was dependent on the length of the fatty acid carbon tail; butanoic acid (C4) was the most effective, followed by hexanoic acid (C6) and octanoic acid (C8). The amylose microparticles were investigated by carrying out SEM, XRD, Raman, NMR, FT-IR and DSC analysis. The size, morphology and crystal structure of the resulting amylose microparticles were comparable with those of amylose microparticles produced without fatty acids. The results indicated the carboxyl group of the fatty acid to be responsible for promoting the self-assembly of amylose chains to form microparticles. The fatty acids were eventually removed from the microstructure through the tight association of amylose double helices to form the amylose microparticles. PMID:27474606

  10. Aroma-active components of nonfat dry milk.

    PubMed

    Karagül-Yüceer, Y; Drake, M A; Cadwallader, K R

    2001-06-01

    Application of aroma extract dilution analysis (AEDA) on the volatile components of low-, medium-, and high-heat-treated nonfat dry milks (NDM) revealed aroma-active compounds in the log(3) flavor dilution (log(3) FD) factor range of 1 to 6. The following compounds contributed the highest log(3) FD factors to overall NDM flavor: 2,5-dimethyl-4-hydroxy-3(2H)-furanone [(Furaneol), burnt sugar-like]; butanoic acid (rancid); 3-(methylthio)propanal [(methional), boiled potato-like]; o-aminoacetophenone (grape-like); delta-decalactone (sweet); (E)-4,5-epoxy-(E)-2-decenal (metallic); pentanoic acid (sweaty); 4,5-dimethyl-3-hydroxy-2(5H)-furanone [(sotolon), curry]; 3-methoxy-4-hydroxybenzaldehyde [(vanillin), vanilla]; 2-acetyl-1-pyrroline and 2-acetyl-2-thiazoline (popcorn-like); hexanoic acid (vinegar-like); phenylacetic acid (rose-like); octanoic acid (waxy); nonanal (fatty); and 1-octen-3-one (mushroom-like). The odor intensities of Furaneol, butanoic acid, methional, o-aminoacetophenone, sotolon, vanillin, (E)-4,5-epoxy-(E)-2-decenal, and phenylacetic acid were higher in high-heat-treated samples than others. However, the odor intensities of lactones, 2-acetyl-1-pyrroline, and 2-acetyl-2-thiazoline were not affected by heat treatment. Sensory evaluation results also revealed that heat-generated flavors have a major impact on the flavor profile of NDM. PMID:11409991

  11. Genetic engineering of Ganoderma lucidum for the efficient production of ganoderic acids.

    PubMed

    Xu, Jun-Wei; Zhong, Jian-Jiang

    2015-01-01

    Ganoderma lucidum is a well-known traditional medicinal mushroom that produces ganoderic acids with numerous interesting bioactivities. Genetic engineering is an efficient approach to improve ganoderic acid biosynthesis. However, reliable genetic transformation methods and appropriate genetic manipulation strategies remain underdeveloped and thus should be enhanced. We previously established a homologous genetic transformation method for G. lucidum; we also applied the established method to perform the deregulated overexpression of a homologous 3-hydroxy-3-methyl-glutaryl coenzyme A reductase gene in G. lucidum. Engineered strains accumulated more ganoderic acids than wild-type strains. In this report, the genetic transformation systems of G. lucidum are described; current trends are also presented to improve ganoderic acid production through the genetic manipulation of G. lucidum. PMID:26588475

  12. Carboxylic acids in secondary aerosols from oxidation of cyclic monoterpenes by ozone

    SciTech Connect

    Glasius, M.; Lahaniati, M.; Calogirou, A.; Di Bella, D.; Jensen, N.R.; Hjorth, J.; Kotzias, D.; Larsen, B.R.

    2000-03-15

    A series of smog chamber experiments have been conducted in which five cyclic monoterpenes were oxidized by ozone. The evolved secondary aerosol was analyzed by GC-MS and HPLC-MS for nonvolatile polar oxidation products with emphasis on the identification of carboxylic acids. Three classes of compounds were determined at concentration levels corresponding to low percentage molar yields: i.e., dicarboxylic acids, oxocarboxylic acids, and hydroxyketocarboxylic acids. Carboxylic acids are highly polar and have lower vapor pressures than their corresponding aldehydes and may thus play an important role in secondary organic aerosol formation processes. The most abundant carboxylic acids were the following: cis-pinic acid AB1(cis-3-carboxy-2,2-dimethylcyclobutylethanoic acid) from {alpha} and {beta}-pinene; cis-pinonic acid A3 (cis-3-acetyl-2,2-dimethylcyclobutylethanoic acid) and cis-10-hydroxypinonic acid Ab6 (cis-2,2-dimethyl-3-hydroxyacetylcyclobutyl-ethanoic acid) from {alpha}-pinene and {beta}-pinene; cis-3-caric acid C1 (cis-2,2-dimethyl-1,3-cyclopropyldiethanoic acid), cis-3-caronic acid C3 (2,2-dimethyl-3-(2-oxopropyl)cyclopropanylethanoic acid), and cis-10-hydroxy-3-caronic acid C6 (cis-2,2-dimethyl-3(hydroxy-2-oxopropyl)cyclopropanylethanoic acid) from 3-carene; cis-sabinic acid S1 (cis-2-carboxy-1-isopropylcyclopropylethanoic acid) from sabinene; limonic acid L1 (3-isopropenylhexanedioic acid), limononic acid L3 (3-isopropenyl-6-oxo-heptanoic acid), 7-hydroxy-limononic acid L6 (3-isopropenyl-7-hydroxy-6-oxoheptanoic acid), and 7-hydroxylimononic acid Lg{prime} (7-hydroxy-3-isopropenyl-6-oxoheptanoic acid) from limonene.

  13. Potential gastroprotective effect of novel cyperenoic acid/quinone derivatives in human cell cultures.

    PubMed

    Theoduloz, Cristina; Carrión, Ivanna Bravo; Pertino, Mariano Walter; Valenzuela, Daniela; Schmeda-Hirschmann, Guillermo

    2012-11-01

    The stem bark of Tabebuia species and the rhizomes of Jatropha isabelii are used in Paraguayan traditional medicine to treat gastric lesions and as anti-inflammatory agents. The sesquiterpene cyperenoic acid obtained from J. isabelii has been shown to display a gastroprotective effect in animal models of induced gastric ulcers while the quinone lapachol shows several biological effects associated with the use of the crude drug. The aim of this work was to prepare hybrid molecules presenting a terpene and a quinone moiety and to obtain an assessment of the gastroprotective activity of the new compounds using human cell cultures (MRC-5 fibroblasts and AGS epithelial gastric cells). Eight compounds, including the natural products and semisynthetic derivatives were assessed for proliferation of MRC-5 fibroblasts, protection against sodium taurocholate-induced damage, prostaglandin E2 content, and stimulation of cellular-reduced glutathione synthesis in AGS cells. The following antioxidant assays were performed: DPPH discoloration, scavenging of the superoxide anion, and inhibition of induced lipoperoxidation in erythrocyte membranes. 3-Hydroxy-β-lapachone (3) and cyperenoic acid (4) stimulated fibroblast proliferation. Lapachol (1), dihydroprenyl lapachol (2), 3-hydroxy-β-lapachone (3), and lapachoyl cyperenate (6) protected against sodium taurocholate-induced damage in AGS cells. Lapachol (1) and dihydroprenyl lapachoyl cyperenate (7) significantly stimulated prostaglandin E2 synthesis in AGS cells. Compounds 3, 4, and 7 raised reduced glutathione levels in AGS cells. The hybrid compounds presented activities different than those of the starting sesquiterpene or quinones. PMID:23047252

  14. Selective production of fungal beauveriolide I or III by fermentation in amino acid-supplemented media.

    PubMed

    Namatame, Ichiji; Matsuda, Daisuke; Tomoda, Hiroshi; Yamaguchi, Yuichi; Masuma, Rokuro; Kobayashi, Susumu; Omura, Satoshi

    2002-12-01

    Beauveriolides I and III, cyclic depsipeptides composed of L-Phe, L-Ala, D-Leu and (3S,4S)-3-hydroxy-4-methyloctanoic acid, and L-Phe, L-Ala, L-allo-Ile and (3S,4S)-3-hydroxy-4-methyloctanoic acid, respectively, were previously isolated from the culture broth of fungal Beauveria sp. FO-6979 as inhibitors of macrophage foam cell formation. To improve the production of these compounds by fermentation, the culture conditions were studied. The production of both beauveriolides was increased five to ten folds by fermentation in the culture media containing tryptone. Further study revealed that addition of L-Leu/L-Ile, but not D-Leu/D-allo-Ile, to the culture medium yielded a high and selective production of beauveriolide I or III. As a result, regardless of their separation difficulty due to the similar physico-chemical properties, a large amount of beauveriolide I or III was prepared from the culture broth obtained from L-Leu- or L-Ile-supplemented fermentation, respectively, by one step purification using silica gel column chromatography. PMID:12617514

  15. Predicting the Sorption of Aromatic Acids to Noncarbonized and Carbonized Sorbents.

    PubMed

    Sigmund, Gabriel; Sun, Huichao; Hofmann, Thilo; Kah, Melanie

    2016-04-01

    Approaches based on the octanol-water partition coefficient are commonly used to describe sorption of neutral organic compounds in environmental systems, but they are not suitable for organic acids, which can dissociate to form anions. We here investigate the applicability of an alternative approach based on the pH-dependent distribution ratio (DOW) to describe sorption of aromatic acids to sorbents representing different degrees of carbonization. Sorption isotherms for four structurally similar acids ((2,4-dichlorophenoxy)acetic acid (2,4-D), 4-chloro-2-15 methylphenoxy)acetic acid (MCPA), 4-(2,4-dichlorophenoxy)butanoic16 acid (2,4-DB), and 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan)) were measured for 15 sorbents: fresh and carbonized wood shavings, pig manure, sewage sludge, carbon nanotubes, and activated carbon. Dissociation greatly affected the sorption of all acids. Sorption coefficients measured in the high pH range indicated that sorption of the anions ranged over several orders of magnitude and should not be neglected. Sorption trends for all sorbates and carbonized sorbents could be very well described by a single regression equation that included DOW of the sorbate and the specific surface area of the sorbent (R(2) > 0.89). PMID:26949216

  16. The effect of oil sands process-affected water and model naphthenic acids on photosynthesis and growth in Emiliania huxleyi and Chlorella vulgaris.

    PubMed

    Beddow, Jessica; Johnson, Richard J; Lawson, Tracy; Breckels, Mark N; Webster, Richard J; Smith, Ben E; Rowland, Steven J; Whitby, Corinne

    2016-02-01

    Naphthenic acids (NAs) are among the most toxic organic pollutants present in oil sands process waters (OSPW) and enter marine and freshwater environments through natural and anthropogenic sources. We investigated the effects of the acid extractable organic (AEO) fraction of OSPW and individual surrogate NAs, on maximum photosynthetic efficiency of photosystem II (PSII) (FV/FM) and cell growth in Emiliania huxleyi and Chlorella vulgaris as representative marine and freshwater phytoplankton. Whilst FV/FM in E. huxleyi and C. vulgaris was not inhibited by AEO, exposure to two surrogate NAs: (4'-n-butylphenyl)-4-butanoic acid (n-BPBA) and (4'-tert-butylphenyl)-4-butanoic acid (tert-BPBA), caused complete inhibition of FV/FM in E. huxleyi (≥10 mg L(-1)n-BPBA; ≥50 mg L(-1)tert-BPBA) but not in C. vulgaris. Growth rates and cell abundances in E. huxleyi were also reduced when exposed to ≥10 mg L(-1)n- and tert-BPBA; however, higher concentrations of n- and tert-BPBA (100 mg L(-1)) were required to reduce cell growth in C. vulgaris. AEO at ≥10 mg L(-1) stimulated E. huxleyi growth rate (p ≤ 0.002), yet had no apparent effect on C. vulgaris. In conclusion, E. huxleyi was generally more sensitive to NAs than C. vulgaris. This report provides a better understanding of the physiological responses of phytoplankton to NAs which will enable improved monitoring of NA pollution in aquatic ecosystems in the future. PMID:26692519

  17. Antiproliferative Activity of β-Hydroxy-β-Arylalkanoic Acids

    PubMed Central

    Dilber, Sanda P.; Žižak, Željko S.; Stanojković, Tatjana P.; Juranić, Zorica D.; Drakulić, Branko J.; Juranić, Ivan O.

    2007-01-01

    Article describes the synthesis of fifteen β-hydroxy-β-arylalkanoic acids by Reformatsky reaction using the 1-ethoxyethyl-2-bromoalkanoates, aromatic or cycloalkyl ketones or aromatic aldehydes. The short survey of previously reported synthetic procedures for title compounds, is given. The majority of obtained compounds exert antiproliferative activity in vitro toward human: HeLa, Fem-X cells, K562, and LS174 cells, having IC50 values from 62.20 to 205 μM. The most active compound is 3-OH-2,2-di-Me-3-(4- biphenylyl)-butanoic acid, having the IC50 value 62.20 μM toward HeLa cells. Seven examined compounds did not affect proliferation of healthy human blood peripheral mononuclear cells (PBMC and PBMC+ PHA), IC50 > 300 μM. The preliminary QSAR results show that estimated lipophilicity of compounds influences their antiproliferative activity in the first place. The ability of dehydration, and the spatial arrangement of hydrophobic portion, HBD and HBA in molecules are has almost equal importance as lipophilicity.

  18. Nest liquid resources of several cavity nesting bees in the genus Centris and the identification of a preservative, levulinic acid.

    PubMed

    Vinson, S Bradleigh; Frankie, Gordon W; Williams, H J

    2006-09-01

    Twig-nesting species of bees in the genus Centris including C. bicornuta, C. analis, C. vittata, and C. nitida, found in the dry forest of Guanacaste Province of Costa Rica, provision their nests with pollen and nectar, rather than pollen and oil as reported for other Centris species. The liquid contents of the nests of these four species were found to contain sugars including 66-75% fructose, 25-33% glucose, and a trace of sucrose. The sugar concentration averaged 47.2%, slightly higher than most flower nectars. No tri-, di-, or monoglycerides, the main components of the flower oil of Byrsonima crassifolia, were detected in the nest provisions. Although these four Centris species are also known to collect oil from B. crassifolia, the oil appears to be used for activities other than nest provisioning. The liquid nest contents did have a slight goat-like odor, suggesting the presence of short-chain fatty acids, and were found to contain a small amount (less than 1%) of three fatty acids. Two of these, butanoic and octanoic acid, were found in trace amounts and are responsible for the goat-like odor. A third was identified as levulinic acid, which made up about 99% of the nest fatty acid contents. This fatty acid had little odor, but may be important as a fungicidal agent. Attempts to determine the source of the fatty acids, were not successful. PMID:16902822

  19. The role of poly-hydroxy-alkanoate form in determining the response of enhanced biological phosphorus removal biomass to volatile fatty acids.

    PubMed

    Liu, Yan-Hua; Geiger, Cherie; Randall, Andrew Amis

    2002-01-01

    Anaerobic-aerobic batch experiments indicated that poly-hydroxy-alkanoate (PHA) form was important in determining the net phosphorus removal resulting from different volatile fatty acids (VFAs). Poly-3-hydroxy-butyrate (3HB) content was found to correlate fairly well with higher observed aerobic phosphorus uptake per unit PHA carbon degraded. Poly-3-hydroxy-valerate (3HV) correlated with lower aerobic phosphorus uptakes per unit PHA carbon degraded. These experiments, conducted with synthetic wastewater, imply that VFA speciation might have a significant effect on aerobic phosphorus uptakes and net phosphorus removal. In addition, the model parameter fP.UPT (Barker and Dold, 1997) could vary with the proportion of acetic to propionic acid received (i.e., the acetic/propionic acid ratio may be an important parameter for these systems). Carbohydrate data implied that the lower aerobic phosphorus uptake resulting from 3HV might have been caused by a greater fraction of PHA carbon shunting to carbohydrate biosynthesis during aerobiosis. PMID:11995868

  20. Preparation of betulinic acid derivatives by chemical and biotransformation methods and determination of cytotoxicity against selected cancer cell lines.

    PubMed

    Baratto, Leopoldo C; Porsani, Mariana V; Pimentel, Ida C; Pereira Netto, Adaucto B; Paschke, Reinhard; Oliveira, Brás H

    2013-10-01

    Several novel 2,4-dinitrophenylhydrazone betulinic acid derivatives have been prepared by chemical and biotransformation methods using fungi and carrot cells. Some compounds showed significant cytotoxicity and selectivity against some tumor cell lines. The most active, 3-[(2,4-dinitrophenyl)hydrazono]lup-(20R)-29-oxolupan-28-oic acid, showed IC50 values between 1.76 and 2.51 μM against five human cancer cell lines. The most selective, 3-hydroxy-20-[(2,4-dinitrophenyl)hydrazono]-29-norlupan-28-oic acid, was five to seven times more selective for cancer cells when compared to fibroblasts. Cell cycle analysis and apoptosis induction were studied for the most active derivatives. PMID:23973824

  1. The effect of several organic acids on phytate phosphorus hydrolysis in broiler chicks.

    PubMed

    Liem, A; Pesti, G M; Edwards, H M

    2008-04-01

    Supplementation of some organic acids to a P-deficient diet has been shown to improve phytate P utilization. Two experiments were conducted from 0 to 16 d in battery brooders to determine the effect of various organic acids supplementation on phytate P utilization. In both experiments, birds were fed P-deficient corn and soybean meal-based diets. In experiment 1, citric acid, malic acid, fumaric acid, and EDTA were supplemented. Experiment 2 had a 2 x 2 factorial design with 2 sources of Met, 2-hydroxy-4-(methylthio) butanoic acid (HMB) and dl-Met, with or without 500 U/kg of phytase. In experiment 1, the addition of citric, malic, and fumaric acids increased percentage of bone ash, but only the effect of citric acid was significant. The addition of citric and malic acids also significantly increased the retention of P and phytate P (P<0.05). In experiment 2, the addition of phytase to the diet significantly increased 16-d BW gain, feed intake, percentage of bone ash, milligrams of bone ash, phytate P disappearance, and decreased the incidence of P-deficiency rickets. Methionine source did not affect 16-d BW gain, feed intake, feed efficiency, milligrams of bone ash, or P rickets incidence. However, the birds fed HMB had a higher percentage of bone ash and phytate P disappearance compared with the groups fed dl-Met only when phytase was added to the diets. The additions of citric acid and HMB improved phytate P utilization. However, the reason why some organic acids are effective whereas others are not is not apparent. PMID:18339989

  2. Structure and polymer form of poly-3-hydroxyalkanoates produced by Pseudomonas oleovorans grown with mixture of sodium octanoate/undecylenic acid and sodium octanoate/5-phenylvaleric acid.

    PubMed

    Ho, I-Ching; Yang, Sheng-Pin; Chiu, Wen-Yen; Huang, Shih-Yow

    2007-01-30

    PHAs (poly-3-hydroxyalkanoates) obtained by Pseudomonas oleovorans grown with mixed carbon sources were investigated. Mixed carbon sources were sodium octanoate/undecylenic acid and sodium octanoate/5-phenylvaleric acid. Effect of carbon source in pre-culture on PHAs structure was investigated. Main fermentation was conducted with mixture of sodium octanoate/undecylenic acid, and PHA contained both saturated and unsaturated units. When more undecylenic acid was used in the medium, the ratio of unsaturated unit increased and the T(g) of the products also changed. The PHA grown with mixture of sodium octanoate and undecylenic acid was a random copolymer, which was determined by DSC analysis. Using mixed carbon sources of sodium octanoate and 5-phenylvaleric acid, highest dry cell weight and PHA concentration were obtained when 0.02g or 0.04g of 5-phenylvaleric acid were added in 50mL medium. Cultured with sodium octanoate and 5-phenylvaleric acid, PHA containing HO (3-hydroxyoctanoate) unit and HPV (3-hydroxy-5-phenylvalerate) unit was produced. T(g) of the products fell between those of pure PHO and pure PHPV. By means of DSC analysis and fractionation method, the PHA obtained was regarded as a random copolymer. PMID:16919325

  3. Characterization of some amino acid derivatives of benzoyl isothiocyanate: Crystal structures and theoretical prediction of their reactivity

    NASA Astrophysics Data System (ADS)

    Odame, Felix; Hosten, Eric C.; Betz, Richard; Lobb, Kevin; Tshentu, Zenixole R.

    2015-11-01

    The reaction of benzoyl isothiocyanate with L-serine, L-proline, D-methionine and L-alanine gave 2-[(benzoylcarbamothioyl)amino]-3-hydroxypropanoic acid (I), 1-(benzoylcarbamothioyl)pyrrolidine-2-carboxylic acid (II), 2-[(benzoylcarbamothioyl)amino]-4-(methylsulfanyl)butanoic acid (III) and 2-[(benzoylcarbamothioyl)amino]propanoic acid (IV), respectively. The compounds have been characterized by IR, NMR, microanalyses and mass spectrometry. The crystal structures of all the compounds have also been discussed. Compound II showed rotamers in solution. DFT calculations of the frontier orbitals of the compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity of these compounds. The calculations indicated that the carboxylic acid group in these compounds is unreactive hence making the conversion to benzimidazoles via cyclization on the carboxylic acids impractical. This has been further confirmed by the reaction of compounds I-IV, respectively, with o-phenylene diamine which was unsuccessful but gave compound V.

  4. Metabolism of the 18O-methoxy substituent of 3-methoxybenzoic acid and other unlabeled methoxybenzoic acids by anaerobic bacteria.

    PubMed

    DeWeerd, K A; Saxena, A; Nagle, D P; Suflita, J M

    1988-05-01

    O-methyl substituents of aromatic compounds can provide C1 growth substrates for facultative and strict anaerobic bacteria isolated from diverse environments. The mechanism of the bioconversion of methoxylated benzoic acids to the hydroxylated derivatives was investigated with a model substrate and cultures of one anaerobic consortium, eight strict anaerobic bacteria, and one facultative anaerobic microorganism. Using high-pressure liquid chromatography and gas chromatography-mass spectral analysis, we found that a haloaromatic dehalogenating consortium, a dehalogenating isolate from that consortium, Eubacterium limosum, and a strain of Acetobacterium woodii metabolized 3-[methoxy-18O]methoxybenzoic acid (3-anisic acid) to 3-[hydroxy-18O]hydroxybenzoic acid stoichiometrically at rates of 1.5, 3.2, 52.4, and 36.7 nmol/min per mg of protein, respectively. A different strain of Acetobacterium and strains of Syntrophococcus, Clostridium, Desulfotomaculum, Enterobacter, and an anaerobic bacterium, strain TH-001, were unable to transform this compound. The O-demethylating ability of E. limosum was induced only with appropriate methoxylated benzoates but not with D-glucose, lactate, isoleucine, or methanol. Cross-acclimation and growth experiments with E. limosum showed a rate of metabolism that was an order of magnitude slower and showed no growth with either 4-methoxysalicylic acid (2-hydroxy-4-methoxybenzoic acid) or 4-anisic acid (4-methoxybenzoic acid) when adapted to 3-anisic acid. However, A. woodii NZva-16 showed slower rates and no growth with 3- or 4-methoxysalicylic acid when adapted to 3-anisic acid in similar experiments. The results clearly indicate a methyl rather than methoxy group removal mechanism for such reactions. PMID:3389815

  5. Metabolism of the 18O-methoxy substituent of 3-methoxybenzoic acid and other unlabeled methoxybenzoic acids by anaerobic bacteria.

    PubMed Central

    DeWeerd, K A; Saxena, A; Nagle, D P; Suflita, J M

    1988-01-01

    O-methyl substituents of aromatic compounds can provide C1 growth substrates for facultative and strict anaerobic bacteria isolated from diverse environments. The mechanism of the bioconversion of methoxylated benzoic acids to the hydroxylated derivatives was investigated with a model substrate and cultures of one anaerobic consortium, eight strict anaerobic bacteria, and one facultative anaerobic microorganism. Using high-pressure liquid chromatography and gas chromatography-mass spectral analysis, we found that a haloaromatic dehalogenating consortium, a dehalogenating isolate from that consortium, Eubacterium limosum, and a strain of Acetobacterium woodii metabolized 3-[methoxy-18O]methoxybenzoic acid (3-anisic acid) to 3-[hydroxy-18O]hydroxybenzoic acid stoichiometrically at rates of 1.5, 3.2, 52.4, and 36.7 nmol/min per mg of protein, respectively. A different strain of Acetobacterium and strains of Syntrophococcus, Clostridium, Desulfotomaculum, Enterobacter, and an anaerobic bacterium, strain TH-001, were unable to transform this compound. The O-demethylating ability of E. limosum was induced only with appropriate methoxylated benzoates but not with D-glucose, lactate, isoleucine, or methanol. Cross-acclimation and growth experiments with E. limosum showed a rate of metabolism that was an order of magnitude slower and showed no growth with either 4-methoxysalicylic acid (2-hydroxy-4-methoxybenzoic acid) or 4-anisic acid (4-methoxybenzoic acid) when adapted to 3-anisic acid. However, A. woodii NZva-16 showed slower rates and no growth with 3- or 4-methoxysalicylic acid when adapted to 3-anisic acid in similar experiments. The results clearly indicate a methyl rather than methoxy group removal mechanism for such reactions. PMID:3389815

  6. [Progress in engineering Escherichia coli for production of high-value added organic acids and alcohols].

    PubMed

    Wang, Jiming; Liu, Wei; Xu, Xin; Zhang, Haibo; Xian, Mo

    2013-10-01

    Confronted with the gradual exhaustion of the earth's fossil energy resources and the grimmer environmental deterioration, the bio-based process to produce high-value added platform chemicals from renewable biomass is attracting growing interest. Escherichia coli has been chosen as a workhouse for the production of many valuable chemicals due to various advantages, such as clear genetic background, convenient to be genetically modified and good growth properties with low nutrient requirements. Rational strain development of E. coli achieved by metabolic engineering strategies has provided new processes for efficiently biotechnological production of various high-value chemical building blocks. This review focuses on recent progresses in metabolic engineering of E. coli that lead to efficient recombinant biocatalysts for production of high-value organic acids such as succinic acid, 3-hydroxypropanoic acid and glucaric acid as well as alcohols like glycerol and xylitol. Besides, this review also discusses several other platform chemicals, including 2,5-furan dicarboxylic acid, aspartic acid, glutamic acid, itaconic acid, levulinic acid, 3-hydroxy-gamma-butyrolactone and sorbitol, which have not been produced by E. coli until now. PMID:24432652

  7. 21 CFR 582.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...). Geranyl acetate (geraniol acetate). Glycerol (glyceryl) tributyrate (tributyrin, butyrin). Limonene (d-, l... (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone (carvol). Cinnamaldehyde...

  8. 21 CFR 582.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...). Geranyl acetate (geraniol acetate). Glycerol (glyceryl) tributyrate (tributyrin, butyrin). Limonene (d-, l... (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone (carvol). Cinnamaldehyde...

  9. 21 CFR 582.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...). Geranyl acetate (geraniol acetate). Glycerol (glyceryl) tributyrate (tributyrin, butyrin). Limonene (d-, l... (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone (carvol). Cinnamaldehyde...

  10. 21 CFR 582.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...). Geranyl acetate (geraniol acetate). Glycerol (glyceryl) tributyrate (tributyrin, butyrin). Limonene (d-, l... (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone (carvol). Cinnamaldehyde...

  11. 21 CFR 582.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...). Geranyl acetate (geraniol acetate). Glycerol (glyceryl) tributyrate (tributyrin, butyrin). Limonene (d-, l... (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone (carvol). Cinnamaldehyde...

  12. Metabolism of the /sup 18/O-methoxy substituent of 3-methoxybenzoic acid and other unlabeled methoxybenzoic acids by anaerobic bacteria. [Eubacterium limosum; Acetobacterium woodil; Syntrophococcus; Clostridium; Desulfotomaculum; Enterobacter

    SciTech Connect

    DeWeerd, J.A.; Saxena, A.; Nagle, D.P. Jr.; Sulflita, J.M.

    1988-05-01

    The mechanism of the bioconversion of methoxylated benzoic acids to the hydroxylated derivatives was investigated with a model substrate and cultures of one anaerobic consortium, eight strict anaerobic bacteria, and one facultative anaerobic microorganism. We found that a haloaromatic dehalogenating consortium, a dehalogenating isolate from that consortium, Eubacterium, limosum, and a strain of Acetobacterium woodii metabolized 3-(methoxy-/sup 18/O)methoxybenzoic acid (3-anisic acid) to 3-(hydroxy-/sup 18/O)hydroxybenzoic acid stoichiometrically at rates of 1.5, 3.2, 52.4, and 36.7 nmol/min per mg of protein, respectively. A different strain of Acetobacterium and strains of Syntrophococcus, Clostridium Desulfotomaculum, Enterobacter, and an anaerobic bacterium, strain TH-001, were unable to transform this compound. The O-demethylating ability of E. limosum was induced only with appropriate methoxylated benzoates but not with D-glucose, lactate, isoleucine, or methanol. Cross-acclimation and growth experiments with E. limosum showed a rate of metabolism that was an order of magnitude slower and showed no growth with either 4-methoxysalicylic acid (2-hydroxy-4-methoxybenzoic acid) or 4-anisic acid (4-methoxybenzoic acid) when adapted to 3-anisic acid. However, A. woodii NZva-16 showed slower rates and no growth with 3- or 4-methoxysalicylic acid when adapted to 3-anisic acid in similar experiments.

  13. Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood–brain phenylalanine transport in Pahenu2 mice: Preliminary findings✩

    PubMed Central

    Vogel, Kara R.; Arning, Erland; Wasek, Brandi L.; Bottiglieri, Teodoro; Gibson, K. Michael

    2014-01-01

    Background Our laboratory seeks a pharmacotherapeutic intervention for PKU that utilizes non-physiological amino acids (NPAAs) to block the accumulation of phenylalanine (Phe) in the brain. In previous studies (Vogel et al. 2013), methylation of the amino group of 2-aminoisobutyrate (AIB) provided an enhanced degree of selectivity for Phe restriction into the brain of Pahenu2 mice in comparison to unmethylated AIB, leading to the hypothesis that 2-(methylamino)alkanoic acid analogs of AIB might represent targeted inhibitors of Phe accretion into the brain. Methods Pahenu2 and control mice were intraperitoneally administered (500–750 mg/kg body weight, once daily; standard 19% protein diet) AIB, methyl AIB (MAIB), isovaline, and two MAIB analogs, 2-methyl-2-(methylamino)butanoic (MeVal) and 3-methyl-2-(methylamino)pentanoic (MePent) acids for one week, followed by brain and blood isolation for amino acid analyses using UPLC. Results In the brain, AIB significantly reduced Phe accretion in Pahenu2 mice, while MeVal significantly improved glutamine and aspartic acids. Four of five test compounds improved brain threonine and arginine levels. AIB, MAIB and IsoVal significantly reduced blood Phe, with no effect of any drug intervention on other sera amino acids. Conclusions Further evaluation of AIB and the 2-(methylamino)alkanoic acids as inhibitors of brain Phe accumulation in Pahenu2 mice is warranted, with more detailed evaluations of route of administration, combinatorial intervention, and detailed toxicity studies. PMID:23999161

  14. Kolaviron and L-Ascorbic Acid Attenuate Chlorambucil-Induced Testicular Oxidative Stress in Rats

    PubMed Central

    2014-01-01

    Chlorambucil (4-[4-[bis(2-chloroethyl)amino]phenyl]butanoic acid) is an alkylating agent, indicated in chronic lymphocytic leukaemia. Kolaviron (KV), a biflavonoid complex from Garcinia kola, and L-ascorbic acid (AA) are known to protect against oxidative damage in vivo. This study evaluates the protective capacity of KV and AA on chlorambucil-induced oxidative stress in the testes of rat. Twenty male Wistar rats (180–200 g) were randomized into four groups: I: control, II: chlorambucil (0.2 mg/kg b.w.), III: 0.2 mg/kg chlorambucil and 100 mg/kg KV, and IV: 0.2 mg/kg chlorambucil and 100 mg/kg AA. After 14 days of treatments, results indicated that chlorambucil caused significant reduction (P < 0.05) in testicular vitamin C and glutathione by 32% and 39%, respectively, relative to control. Similarly, activities of testicular GST, SOD, and CAT reduced significantly by 48%, 47%, and 49%, respectively, in chlorambucil-treated rats relative to control. Testicular MDA and activities of ALP, LDH, and ACP were increased significantly by 53%, 51%, 64%, and 70%, respectively, in the chlorambucil-treated rat. However, cotreatment with KV and AA offered protection and restored the levels of vitamin C, GSH, and MDA as well as SOD, CAT, GST, ACP, ALP, and LDH activities. Overall, kolaviron and L-ascorbic acid protected against chlorambucil-induced damage in the testes of the rat. PMID:25309592

  15. Analysis of four pentacyclic triterpenoid acids in several bioactive botanicals with gas and liquid chromatography and mass spectrometry detection.

    PubMed

    Moldoveanu, Serban C; Scott, Wayne A

    2016-01-01

    Several pentacyclic triterpenoid acids including betulinic, oleanolic, and ursolic acids were reported to have health beneficial properties such as antiviral and anti-inflammatory properties, as well as the capability to inhibit "in vitro" the development of various cancer cell types. For this reason betulinic, oleanolic, and ursolic acids are used as neutraceuticals. For the analysis of the pentacyclic triterpenoid acids in complex plant materials, an improved scheme was developed, involving a qualitative screening using silylation and gas chromatography with mass spectrometry analysis, followed by quantitation using a novel liquid chromatography with tandem mass spectrometry procedure. The use of the two methods provides more reliable information regarding the plant materials with unknown composition. Besides betulinic, oleanolic, and ursolic acids that were analyzed, by this procedure a fourth pentacyclic triterpenoid acid was identified and quantitated that was not previously reported to be present in plants. This acid has been identified as 3β-3-hydroxy-lupa-18,20(29)-dien-28-oic acid. The newly identified acid has a structure as a derivative of lupane, although lupane with a double bond in the 18-position was not previously reported as present in plants. The new liquid chromatography with tandem mass spectrometry procedure developed for this study offers a very low limit of quantitation, excellent precision, and robustness. Rosemary was found to contain the largest levels of pentacyclic triterpenoid acids among all the analyzed botanicals. PMID:26549610

  16. Synthesis and accumulation of poly(3-hydroxybutyric acid) by Rhizobium sp.

    PubMed

    Manna, A; Pal, S; Paul, A K

    2000-01-01

    Forty-two Rhizobium strains obtained from different culture collections were evaluated quantitatively for poly(3-hydroxy-butyric acid) [PHB] production in shake flask culture. The majority of the strains produced the maximum amount of PHB during the late exponential or stationary phase of growth. Synthesis and accumulation of PHB in different species of Rhizobium were found to vary between 1-38% of their dry biomass. Growth and PHB production by the Rhizobium strain TAL-640 were greatly influenced by the C-source and D-mannitol was fundamental to both processes. The identity and purity of PHB isolated from TAL-640 have also been confirmed by UV-, IR- and 1H-NMR spectroscopic analyses. PMID:10866363

  17. A simple colorimetric chemosensor bearing a carboxylic acid group with high selectivity for CN-

    NASA Astrophysics Data System (ADS)

    Park, Gyeong Jin; Choi, Ye Won; Lee, Dongkuk; Kim, Cheal

    2014-11-01

    A new simple ‘naked eye' chemosensor 1 (sodium (E)-2-((2-(3-hydroxy-2-naphthoyl)hydrazono)methyl)benzoate) has been synthesized for detection of CN- in a mixture of DMF/H2O (9:1). The sensor 1 comprises of a naphthoic hydrazide as efficient hydrogen bonding donor group and a benzoic acid as the moiety with the water solubility. The receptor 1 showed high selectivity toward cyanide ions in a 1:1 stoichiometric manner, which induces a fast color change from colorless to yellow for CN- over other anions. Therefore, receptor 1 could be useful for cyanide detection in aqueous environment, displaying a high distinguishable selectivity from hydrogen bonded anions and being clearly visible to the naked eye.

  18. Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents.

    PubMed

    Mäder, Patrick; Blohm, Ariane S; Quack, Thomas; Lange-Grünweller, Kerstin; Grünweller, Arnold; Hartmann, Roland K; Grevelding, Christoph G; Schlitzer, Martin

    2016-07-01

    Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure-activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis. PMID:27159334

  19. A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury

    PubMed Central

    Novitskaya, Tatiana; McDermott, Lee; Zhang, Ke Xin; Chiba, Takuto; Paueksakon, Paisit; Hukriede, Neil A.

    2013-01-01

    Phenylthiobutanoic acids (PTBAs) are a new class of histone deacetylase (HDAC) inhibitors that accelerate recovery and reduce postinjury fibrosis after ischemia-reperfusion-induced acute kidney injury. However, unlike the more common scenario in which patients present with protracted and less clearly defined onset of renal injury, this model of acute kidney injury gives rise to a clearly defined injury that begins to resolve over a short period of time. In these studies, we show for the first time that treatment with the PTBA analog methyl-4-(phenylthio)butanoate (M4PTB) accelerates recovery and reduces postinjury fibrosis in a progressive model of acute kidney injury and renal fibrosis that occurs after aristolochic acid injection in mice. These effects are apparent when M4PTB treatment is delayed 4 days after the initiating injury and are associated with increased proliferation and decreased G2/M arrest of regenerating renal tubular epithelial cells. In addition, there is reduced peritubular macrophage infiltration and decreased expression of the macrophage chemokines CX3Cl1 and CCL2. Since macrophage infiltration plays a role in promoting kidney injury, and since renal tubular epithelial cells show defective repair and a marked increase in maladaptive G2/M arrest after aristolochic acid injury, these findings suggest M4PTB may be particularly beneficial in reducing injury and enhancing intrinsic cellular repair even when administered days after aristolochic acid ingestion. PMID:24370591

  20. Combination of the dipeptidyl peptidase IV inhibitor LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the angiotensin II type 1 receptor antagonist valsartan [N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-L-valine] enhances pancreatic islet morphology and function in a mouse model of type 2 diabetes.

    PubMed

    Cheng, Qianni; Law, Pui Ki; de Gasparo, Marc; Leung, Po Sing

    2008-12-01

    LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] is an inhibitor of dipeptidyl peptidase IV that delays the degradation of glucagon-like peptide-1 (GLP-1). Valsartan [N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-l-valine] is an antagonist of the angiotensin II type 1 receptor (AT1R) that reduces the incidence of type 2 diabetes mellitus. LAF237 and valsartan act on a common target through separate pathways to improve pancreatic islet cell function. We hypothesize that the combination of these two drugs acts in a synergistic or additive manner on islet function and structure. To test this hypothesis, we performed in vitro and in vivo studies. To measure the acute effect of the treatment, pancreatic islets of db/db mice were isolated and stimulated in vitro with glucose in the presence of valsartan (1 microM) and exendin-4 (100 nM), a GLP-1 receptor agonist. Combination treatment with valsartan and exendin-4 significantly enhanced glucose-stimulated insulin secretion from isolated islets. For studies of chronic effect, db/db mice received LAF237 (1 mg/kg/day) and/or valsartan (10 mg/kg/day). Islet cell reactive oxygen species (ROS), proliferation, apoptosis, fibrosis, beta-cell area, and glucose homeostasis were evaluated after 8 weeks of treatment, which showed that combination treatment resulted in a significant increase in pancreatic islet beta-cell area compared with monotherapy. This beneficial effect correlated with an increase in beta-cell proliferation and a decrease in ROS-induced islet apoptosis and fibrosis. These in vitro and in vivo data indicate that combination treatment with LAF237 and valsartan has significant beneficial additive effects on pancreatic beta-cell structure and function compared with their respective monotherapeutic effects. PMID:18787107

  1. Simvastatin Hydroxy Acid Fails to Attain Sufficient Central Nervous System Tumor Exposure to Achieve a Cytotoxic Effect: Results of a Preclinical Cerebral Microdialysis Study.

    PubMed

    Patel, Yogesh T; Jacus, Megan O; Davis, Abigail D; Boulos, Nidal; Turner, David C; Vuppala, Pradeep K; Freeman, Burgess B; Gilbertson, Richard J; Stewart, Clinton F

    2016-04-01

    3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors were potent hits against a mouse ependymoma cell line, but their effectiveness against central nervous system tumors will depend on their ability to cross the blood-brain barrier and attain a sufficient exposure at the tumor. Among 3-hydroxy-3-methylglutaryl coenzyme A inhibitors that had activity in vitro, we prioritized simvastatin (SV) as the lead compound for preclinical pharmacokinetic studies based on its potential for central nervous system penetration as determined from in silico models. Furthermore, we performed systemic plasma disposition and cerebral microdialysis studies of SV (100 mg/kg, p.o.) in a murine model of ependymoma to characterize plasma and tumor extracellular fluid (tECF) pharmacokinetic properties. The murine dosage of SV (100 mg/kg, p.o.) was equivalent to the maximum tolerated dose in patients (7.5 mg/kg, p.o.) based on equivalent plasma exposure of simvastatin acid (SVA) between the two species. SV is rapidly metabolized in murine plasma with 15 times lower exposure compared with human plasma. SVA exposure in tECF was <33.8 ± 11.9 µg/l per hour, whereas the tumor to plasma partition coefficient of SVA was <0.084 ± 0.008. Compared with in vitro washout IC50 values, we did not achieve sufficient exposure of SVA in tECF to suggest tumor growth inhibition; therefore, SV was not carried forward in subsequent preclinical efficacy studies. PMID:26802130

  2. Vapor pressures of substituted polycarboxylic acids are much lower than previously reported

    NASA Astrophysics Data System (ADS)

    Huisman, A. J.; Krieger, U. K.; Zuend, A.; Marcolli, C.; Peter, T.

    2013-07-01

    The partitioning of compounds between the aerosol and gas phase is a primary focus in the study of the formation and fate of secondary organic aerosol. We present measurements of the vapor pressure of 2-methylmalonic (isosuccinic) acid, 2-hydroxymalonic (tartronic) acid, 2-methylglutaric acid, 3-hydroxy-3-carboxy-glutaric (citric) acid and DL-2,3-dihydroxysuccinic (DL-tartaric) acid, which were obtained from the evaporation rate of supersaturated liquid particles levitated in an electrodynamic balance. Our measurements indicate that the pure component liquid vapor pressures at 298.15 K for tartronic, citric and tartaric acids are much lower than the same quantity that was derived from solid state measurements in the only other room temperature measurement of these materials (made by Booth et al., 2010). This strongly suggests that empirical correction terms in a recent vapor pressure estimation model to account for the inexplicably high vapor pressures of these and similar compounds should be revisited, and that due caution should be used when the estimated vapor pressures of these and similar compounds are used as inputs for other studies.

  3. Vapor pressures of substituted polycarboxylic acids are much lower than previously reported

    NASA Astrophysics Data System (ADS)

    Huisman, A. J.; Krieger, U. K.; Zuend, A.; Marcolli, C.; Peter, T.

    2013-01-01

    The partitioning of compounds between the aerosol and gas phase is a primary focus in the study of the formation and fate of secondary organic aerosol. We present measurements of the vapor pressure of 2-Methylmalonic (isosuccinic) acid, 2-Hydroxymalonic (tartronic) acid, 2-Methylglutaric acid, 3-Hydroxy-3-carboxy-glutaric (citric) acid and 2,3-Dihydroxysuccinic (tartaric) acid which were obtained from the evaporation rate of supersaturated liquid particles levitated in an electrodynamic balance. Our measurements indicate that the pure component liquid vapor pressures at 298.15 K for tartronic, citric and tartaric acids are much lower than the same quantity which was derived from solid state measurements in the only other room temperature measurement of these materials (made by Booth et al., 2010). This strongly suggests that empirical correction terms in vapor pressure estimation models to account for the inexplicably high vapor pressures of these and similar compounds should be revisited, and that due caution should be used when the estimated vapor pressures of these and similar compounds are used as inputs for other studies.

  4. Effects of dietary tannic acid on the growth, hepatic gene expression, and antioxidant enzyme activity in Brandt's voles (Microtus brandti).

    PubMed

    Ye, Man-Hong; Nan, Yan-Lei; Ding, Meng-Meng; Hu, Jun-Bang; Liu, Qian; Wei, Wan-Hong; Yang, Sheng-Mei

    2016-01-01

    This study was designed to investigate the physiological and biochemical responses of Brandt's voles to the persistent presence of dietary tannic acid. The diet for animals in the experimental group was supplemented with 3% dietary tannic acid for 5weeks. The control group received a commercial lab chow. No significant differences were detected in body weight, organ (heart, kidney, and liver) weights, and organ parameters between animals from two groups. However, voles in the experimental group had significantly higher daily food intake, increased contents of proline and histidine in saliva and feces after protein hydrolysis, and elevated hepatic expression of transferrin than the control. Our results suggested the existence of adaptive strategies developed in Brandt's voles to overcome the adverse effects of dietary tannic acid. (1) Food consumption was increased to satisfy their nutritional demands. (2) The secretion of tannic-acid-binding salivary proteins was promoted. (3) The absorption of iron was enhanced. These alterations contributed to neutralize the negative effects of tannic acid and maintain body mass in animals supplemented with tannic acid. As the result of the consumption of tannic acid, hepatic expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase was significantly decreased, while the overall potential of the antioxidant system, characterized by increased hepatic enzymatic activities of catalase and glutathione peroxidase, was enhanced. Our results also implied the involvement of tannic acid in the regulation of lipid metabolism and oxidative stress in voles. PMID:26850644

  5. Molecular analysis of microbial community structure in the chicken ileum following organic acid supplementation.

    PubMed

    Nava, Gerardo M; Attene-Ramos, Matias S; Gaskins, H Rex; Richards, James D

    2009-06-12

    To compensate for possible decreases in animal production due to restrictions on the use of antibiotics as growth promoters, several non-antibiotic alternatives have been investigated. Organic acid supplementation (OAS) of feed or water has shown some promising results for affecting intestinal microbiota and reducing pathogenic bacteria in the gastrointestinal (GI) tract. However, few studies have explored the effects of OAS on microbial communities using objective molecular-based techniques. The aim of the present study was to characterize via 16S rRNA gene-based approaches responses of the intestinal microbiota after OAS in chicks. Newborn chicks were randomly divided in four treatments: (a) control (no antibiotic, no OAS); (b) antibiotic administration (bacitracin MD); (c) organic acid blend dl-2-hydroxy-4(methylthio) butanoic acid [HMTBA]; lactic, and phosphoric acid (HLP); and (d) organic acid blend HMTBA, formic, and propionic acid (HFP). Ileal contents and mucosal scrapings from 7 chicks/treatment/day were taken at 15, 22, and 29 days of age, and genomic DNA was isolated for the molecular analysis of the intestinal microbiota. The data demonstrate that HFP blend treatment for 29 consecutive days affected ileal microbial populations as indicated by community fingerprinting analysis (16S rRNA PCR-DGGE). In parallel, total bacterial and lactobacilli populations were increased by the HFP blend treatment as demonstrated by targeted qPCR analysis of 16S rRNA. In summary, the present data demonstrate that OAS, HFP blend treatment in particular, shifts intestinal microbiota, generates more homogenous and distinct populations, and increases Lactobacillus spp. colonization of the chick ileum. PMID:19269115

  6. Anthranilic Acid: A Potential Biomarker and Treatment Target for Schizophrenia

    PubMed Central

    Oxenkrug, Gregory; van der Hart, Marieke; Roeser, Julien; Summergrad, Paul

    2016-01-01

    Dysregulation of Trp-Kyn pathway is the most recent hypothesis of mechanisms of schizophrenia. In particular, over-production of kynurenic acid (KYNA), one of the three immediate downstream metabolites of kynurenine (Kyn) along tryptophan (Trp): Kyn pathway, has been considered as a new target for therapeutic intervention in schizophrenia. Up-regulation of KYNA formation was suggested to occur at the expense of down-regulated production of 3-hydroxyKyn (3-HK), the second immediate downstream metabolite of Kyn. We were interested to assess the third immediate downstream Kyn metabolite, anthranilic acid (AA). Serum AA concentrations were evaluated in schizophrenia patients and control subjects by HPLC-mass spectrometry method. We found 2-fold increase of AA and 3-fold decrease of 3-HK concentrations in serum of schizophrenia patients. Up regulated formation of AA might contribute to mechanisms of schizophrenia considering experimental evidences of AA augmentation of autoimmune processes in rat and mice; clinical findings of AA elevation in rheumatoid arthritis and type 1 diabetes, autoimmune diseases diametrical to schizophrenia; and involvement of autoimmunity in development of schizophrenia. Present data warrant further studies of AA as biological marker in, at least, a subgroup (associated with autoimmune mechanisms) of schizophrenia patients and as a new target for therapeutic intervention. PMID:27042691

  7. Fatty acid composition of lipids present in selected lichenized fungi: a chemotyping study.

    PubMed

    Sassaki, G L; Cruz, L M; Gorin, P A; Lacomini, M

    2001-02-01

    The total-lipid composition of 21 lichens of the ascomycetous genera Cladonia (11) and Cladina (1) of the family Cladoniacea, Cladia (1), Parmotrema (3), Ramalina (2), Leptogium (1), Cetraria (1), and the basidiomycetous genus Dictyonema (1) was determined. Analyses of those of Dictyonema glabratum were carried out with a total extract and those obtained after successive extractions with various solvents. Each extract was partitioned between n-heptane/isopropanol and 1 M sulfuric acid, giving triglycerides (TG) in the upper phase. Extracts were methanolyzed and the resulting methyl esters were analyzed by gas chromatography-mass spectrometry. Methanolyzates of TG unexpectedly contained esters of 9-oxodecanoic, 9-methyl-tetradecanoic, 6-methyl-tetradecanoic, 3-hydroxy-decanoic, nonanedioic, and decanedioic acids, as well as common fatty acids. Fatty acid methyl ester profiles from the lichens were submitted to cluster analysis, and the resulting dendogram showed a cluster consistent with Cladonia spp., suggesting an efficient aid to lichen taxonomy. The total carbohydrate content of each lipid extract was determined by a modified phenol-sulfuric acid method, which compensated for the presence of pigments. PMID:11269697

  8. Medium-chain fatty acids undergo elongation before {beta}-oxidation in fibroblasts

    SciTech Connect

    Jones, Patricia M. . E-mail: Patti.Jones@childrens.com; Butt, Yasmeen; Messmer, Bette; Boriak, Richard; Bennett, Michael J.

    2006-07-21

    Although mitochondrial fatty acid {beta}-oxidation (FAO) is considered to be well understood, further elucidation of the pathway continues through evaluation of patients with FAO defects. The FAO pathway can be examined by measuring the 3-hydroxy-fatty acid (3-OHFA) intermediates. We present a unique finding in the study of this pathway: the addition of medium-chain fatty acids to the culture media of fibroblasts results in generation of 3-OHFAs which are two carbons longer than the precursor substrate. Cultured skin fibroblasts from normal and LCHAD-deficient individuals were grown in media supplemented with various chain-length fatty acids. The cell-free medium was analyzed for 3-OHFAs by stable-isotope dilution gas-chromatography/mass-spectrometry. Our finding suggests that a novel carbon chain-length elongation process precedes the oxidation of medium-chain fatty acids. This previously undescribed metabolic step may have important implications for the metabolism of medium-chain triglycerides, components in the dietary treatment of a number of disorders.

  9. Accumulation of Polyhydroxyalkanoic Acid Containing Large Amounts of Unsaturated Monomers in Pseudomonas fluorescens BM07 Utilizing Saccharides and Its Inhibition by 2-Bromooctanoic Acid

    PubMed Central

    Lee, Ho-Joo; Choi, Mun Hwan; Kim, Tae-Un; Yoon, Sung Chul

    2001-01-01

    A psychrotrophic bacterium, Pseudomonas fluorescens BM07, which is able to accumulate polyhydroxyalkanoic acid (PHA) containing large amounts of 3-hydroxy-cis-5-dodecenoate unit up to 35 mol% in the cell from unrelated substrates such as fructose, succinate, etc., was isolated from an activated sludge in a municipal wastewater treatment plant. When it was grown on heptanoic acid (C7) to hexadecanoic acid (C16) as the sole carbon source, the monomer compositional characteristics of the synthesized PHA were similar to those observed in other fluorescent pseudomonads belonging to rRNA homology group I. However, growth on stearic acid (C18) led to no PHA accumulation, but instead free stearic acid was stored in the cell. The existence of the linkage between fatty acid de novo synthesis and PHA synthesis was confirmed by using inhibitors such as acrylic acid and two other compounds, 2-bromooctanoic acid and 4-pentenoic acid, which are known to inhibit β-oxidation enzymes in animal cells. Acrylic acid completely inhibited PHA synthesis at a concentration of 4 mM in 40 mM octanoate-grown cells, but no inhibition of PHA synthesis occurred in 70 mM fructose-grown cells in the presence of 1 to 5 mM acrylic acid. 2-Bromooctanoic acid and 4-pentenoic acid were found to much inhibit PHA synthesis much more strongly in fructose-grown cells than in octanoate-grown cells over concentrations ranging from 1 to 5 mM. However, 2-bromooctanoic acid and 4-pentenoic acid did not inhibit cell growth at all in the fructose media. Especially, with the cells grown on fructose, 2-bromooctanoic acid exhibited a steep rise in the percent PHA synthesis inhibition over a small range of concentrations below 100 μM, a finding indicative of a very specific inhibition, whereas 4-pentenoic acid showed a broad, featureless concentration dependence, suggesting a rather nonspecific inhibition. The apparent inhibition constant Ki (the concentration for 50% inhibition of PHA synthesis) for 2

  10. Amino acids

    MedlinePlus

    Amino acids are organic compounds that combine to form proteins . Amino acids and proteins are the building blocks of life. When proteins are digested or broken down, amino acids are left. The human body uses amino acids ...

  11. Substrate Specificity of Thiamine Pyrophosphate-Dependent 2-Oxo-Acid Decarboxylases in Saccharomyces cerevisiae

    PubMed Central

    Romagnoli, Gabriele; Luttik, Marijke A. H.; Kötter, Peter; Pronk, Jack T.

    2012-01-01

    Fusel alcohols are precursors and contributors to flavor and aroma compounds in fermented beverages, and some are under investigation as biofuels. The decarboxylation of 2-oxo acids is a key step in the Ehrlich pathway for fusel alcohol production. In Saccharomyces cerevisiae, five genes share sequence similarity with genes encoding thiamine pyrophosphate-dependent 2-oxo-acid decarboxylases (2ODCs). PDC1, PDC5, and PDC6 encode differentially regulated pyruvate decarboxylase isoenzymes; ARO10 encodes a 2-oxo-acid decarboxylase with broad substrate specificity, and THI3 has not yet been shown to encode an active decarboxylase. Despite the importance of fusel alcohol production in S. cerevisiae, the substrate specificities of these five 2ODCs have not been systematically compared. When the five 2ODCs were individually overexpressed in a pdc1Δ pdc5Δ pdc6Δ aro10Δ thi3Δ strain, only Pdc1, Pdc5, and Pdc6 catalyzed the decarboxylation of the linear-chain 2-oxo acids pyruvate, 2-oxo-butanoate, and 2-oxo-pentanoate in cell extracts. The presence of a Pdc isoenzyme was also required for the production of n-propanol and n-butanol in cultures grown on threonine and norvaline, respectively, as nitrogen sources. These results demonstrate the importance of pyruvate decarboxylases in the natural production of n-propanol and n-butanol by S. cerevisiae. No decarboxylation activity was found for Thi3 with any of the substrates tested. Only Aro10 and Pdc5 catalyzed the decarboxylation of the aromatic substrate phenylpyruvate, with Aro10 showing superior kinetic properties. Aro10, Pdc1, Pdc5, and Pdc6 exhibited activity with all branched-chain and sulfur-containing 2-oxo acids tested but with markedly different decarboxylation kinetics. The high affinity of Aro10 identified it as a key contributor to the production of branched-chain and sulfur-containing fusel alcohols. PMID:22904058

  12. Substrate specificity of thiamine pyrophosphate-dependent 2-oxo-acid decarboxylases in Saccharomyces cerevisiae.

    PubMed

    Romagnoli, Gabriele; Luttik, Marijke A H; Kötter, Peter; Pronk, Jack T; Daran, Jean-Marc

    2012-11-01

    Fusel alcohols are precursors and contributors to flavor and aroma compounds in fermented beverages, and some are under investigation as biofuels. The decarboxylation of 2-oxo acids is a key step in the Ehrlich pathway for fusel alcohol production. In Saccharomyces cerevisiae, five genes share sequence similarity with genes encoding thiamine pyrophosphate-dependent 2-oxo-acid decarboxylases (2ODCs). PDC1, PDC5, and PDC6 encode differentially regulated pyruvate decarboxylase isoenzymes; ARO10 encodes a 2-oxo-acid decarboxylase with broad substrate specificity, and THI3 has not yet been shown to encode an active decarboxylase. Despite the importance of fusel alcohol production in S. cerevisiae, the substrate specificities of these five 2ODCs have not been systematically compared. When the five 2ODCs were individually overexpressed in a pdc1Δ pdc5Δ pdc6Δ aro10Δ thi3Δ strain, only Pdc1, Pdc5, and Pdc6 catalyzed the decarboxylation of the linear-chain 2-oxo acids pyruvate, 2-oxo-butanoate, and 2-oxo-pentanoate in cell extracts. The presence of a Pdc isoenzyme was also required for the production of n-propanol and n-butanol in cultures grown on threonine and norvaline, respectively, as nitrogen sources. These results demonstrate the importance of pyruvate decarboxylases in the natural production of n-propanol and n-butanol by S. cerevisiae. No decarboxylation activity was found for Thi3 with any of the substrates tested. Only Aro10 and Pdc5 catalyzed the decarboxylation of the aromatic substrate phenylpyruvate, with Aro10 showing superior kinetic properties. Aro10, Pdc1, Pdc5, and Pdc6 exhibited activity with all branched-chain and sulfur-containing 2-oxo acids tested but with markedly different decarboxylation kinetics. The high affinity of Aro10 identified it as a key contributor to the production of branched-chain and sulfur-containing fusel alcohols. PMID:22904058

  13. Oxidative degradation of different chlorinated phenoxyalkanoic acid herbicides by a hybrid ZrO2 gel-derived catalyst without light irradiation.

    PubMed

    Sannino, Filomena; Pernice, Pasquale; Minieri, Luciana; Camandona, Gaia Aurora; Aronne, Antonio; Pirozzi, Domenico

    2015-01-14

    The oxidative degradation of 2-methyl-4-chlorophenoxyacetic acid (MCPA), 4-(4-chloro-2-methylphenoxy)butanoic acid (MCPB), 4-chlorophenoxyacetic acid (4-CPA) and 2,4-dichlorophenoxyacetic acid (2,4 D) by ZrO2-acetylacetonate hybrid catalyst (HSGZ) without light irradiation was assessed. The thermal stability of the catalyst was investigated by thermogravimetry, differential thermal analysis, and Fourier transform infrared spectroscopy. For each herbicide, a virtually complete removal in about 3 days without light irradiation at room temperature was achieved. The removal kinetics of the herbicides has been satisfactorily characterized by a double-stage physico-mathematical model, in the hypothesis that a first-order adsorption on HSGZ surface is followed by the herbicide degradation, catalytically driven by HSGZ surface groups. The long-term use of the HSGZ catalyst was assessed by repeated-batch tests. The specific cost for unit-volume removal of herbicide was evaluated by a detailed cost analysis showing that it is comparable with those pertaining to alternative methods. PMID:25479367

  14. Free amino acids in atmospheric particulate matter of Venice, Italy

    NASA Astrophysics Data System (ADS)

    Barbaro, Elena; Zangrando, Roberta; Moret, Ivo; Barbante, Carlo; Cescon, Paolo; Gambaro, Andrea

    2011-09-01

    The concentrations of free amino acids were determined in atmospheric particulate matter from the city of Venice (Italy) in order to better understand their origin. The analysis of aerosol samples was carried out via high-performance liquid chromatography coupled to a triple quadrupole tandem mass spectrometric detector (HPLC/ESI-MS/MS). The internal standard method was used and the analytical procedure was validated by evaluating the trueness, the precision, the recovery, the detection and the quantification limits. The particulate matter was collected using quartz fiber filters and extracted in methanol; after filtration the extract was directly analyzed. Forty samples were collected from April to October 2007 and the average concentrations of free amino acids in the aerosol were: alanine 35.6 pmol m -3, aspartic acid 31.1 pmol m -3, glycine 30.1 pmol m -3, glutamic acid 32.5 pmol m -3, isoleucine 2.4 pmol m -3, leucine 2.7 pmol m -3, methionine, cystine and 3-hydroxy-proline below the limit of detection, phenylalanine 2.8 pmol m -3, proline 43.3 pmol m -3, serine 8.6 pmol m -3, threonine 2.8 pmol m -3, tyrosine 1.7 pmolm -3, valine 3.8 pmol m -3, asparagine 70.2 pmol m -3, glutamine 38.0 pmol m -3, 4-hydroxy-proline 2.5 pmol m -3, methionine sulfoxide 1.1 pmol m -3, and methionine sulfone 0.1 pmol m -3. The total average concentration of these free amino acids in aerosol samples of Venice Lagoon was 334 pmol m -3. The temporal evolution and multivariate analysis indicated the photochemical origin of 4-hydroxy-proline and methionine sulfoxide and for other compounds an origin further away from the site of sampling, presumably reflecting transport from terrestrial sources.

  15. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity

    PubMed Central

    Mueller, Michaela; Thorell, Anders; Claudel, Thierry; Jha, Pooja; Koefeler, Harald; Lackner, Carolin; Hoesel, Bastian; Fauler, Guenter; Stojakovic, Tatjana; Einarsson, Curt; Marschall, Hanns-Ulrich; Trauner, Michael

    2015-01-01

    Background & Aims Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients. Methods In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery. Results Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7α-hydroxylase induction mirrored by elevated C4 and 7α-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid. Conclusion These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT. PMID:25617503

  16. Sugar and volatile fatty acids dynamic during anaerobic treatment of olive mill wastewater.

    PubMed

    Fernandes, L R; Gomes, A C; Lopes, A; Albuquerque, A; Simões, R M

    2016-01-01

    Biogas production has been the main route used to exploit olive mill wastewater (OMW), after pretreatment and/or in combination with other effluents, but more recently the production of chemicals and biopolymers by biotechnological routes has deserved increasing attention by the scientific community. The present paper aims to explore the potential of fresh OMW as a source of volatile fatty acids (VFAs) and biogas. The time profile of VFAs production and the corresponding sugar consumption was followed by high-performance liquid chromatography, in batch anaerobic assays. The experimental results have revealed the very high potential of the OMW for the production of VFAs, mainly due to the high sugar concentration in the effluent (37.8 g/L) and its complete conversion into VFAs, in a time period of 2-3 days. The most abundant VFAs were acetic (48-50%), n-butanoic (12-27%), iso-pentanoic (12-14%) and propanoic (5-13%). The ratio of VFA containing even and odd carbon chains increased with the reduction in the initial chemical oxygen demand concentration of the samples used in the experiments. The conversion of the VFAs to biogas was inhibited at concentrations of 3.5 g/L of VFAs. PMID:26496487

  17. Volatile flavor components of stored nonfat dry milk.

    PubMed

    Karagül-Yüceer, Yonca; Cadwallader, Keith R; Drake, MaryAnne

    2002-01-16

    Nonfat dry milk (NDM) is widely used both as an ingredient in other preparations and for direct consumption. Flavor quality of NDM is a critical parameter because it can directly impact final product quality. Flavors can be formed in NDM during subsequent storage. Identification of compounds responsible for storage-induced flavors is necessary to correlate sensory quality with potential sources of the flavors. Six NDM samples were selected for volatile flavor analysis based on sensory analysis and storage time. Volatile components were extracted by direct solvent extraction/high vacuum distillation. Volatile extracts were separated into neutral/basic and acidic fractions and analyzed by gas chromatography-olfactometry (GCO) and aroma extract dilution analysis (AEDA). A variety of aldehydes, ketones, and free fatty acids were responsible for generation of flavors in stored NDM. The following compounds exhibited high aroma impact by AEDA: 3-(methylthio)propanal (boiled potato); o-aminoacetophenone (corn tortilla); 2,5-dimethyl-4-hydroxy-3(2H)-furanone and 2-methyl-3-hydroxy-4H-pyran-4-one (burnt sugar); butanoic acid (cheesy); pentanoic acid (sweaty); acetic and hexanoic acids (sour/vinegar); octanoic, decanoic, and dodecanoic acids (waxy); p-cresol (cowy/barny); 3-methylindole (fecal); dimethyl trisulfide (cabbage); (E,E)-2,4-decadienal (fried/fatty); furfuryl alcohol (rubber/vitamin); phenylacetic acid (rose-like); and 1-octen-3-one (mushroom). PMID:11782199

  18. An analysis of [3H]gamma-aminobutyric acid (GABA) binding in the human brain.

    PubMed

    Lloyd, K G; Dreksler, S

    1979-03-01

    The binding of [3H]GABA to membranes prepared from human brains obtained post morten was examined. This binding was independent of patient sex, age (16--80 years), postmortem interval (4--33 h) or storage time when frozen (0-64 months). In preparations from cerebellar cortex various compounds displaced [3H]GABA binding with the following order of potency: muscimol greater than 3-aminopropanesulfonic acid greater than GABA greater than imidazoleacet acid greater than delta-amino-n-valeric acid greater than 3-hydroxyGABA greater than bicuculline. Other compounds active 'in vitro' included strychnine, homocarnosine and some (e.g. clozapine, thioridazine, pimozide) but not all (chlorpromazine, haloperiodol) neuroleptics. Compounds inactive 'in vitro' included aminooxyacetic acid, baclofen, picrotoxin, anticholinergics, metrazole, anticonvulsants and naloxone. Triton X-100 augmented the [3H]GABA binding (25 nM) by about 10--20-fold in most brain regions. [3H]GABA binding (IC50) was altered in Huntington's chorea and Reye's syndrome, but not in schizophrenics (4-neuroleptic-treated patients) or sudden infant death syndrome. The data presented strongly support the proposal that the measurement of [3H]GABA binding in postmortem human brain offers a reflection of the state of the physiologically relevant GABA receptor. PMID:218679

  19. Design, Synthesis, and Biological Evaluation of Beauveriolide Analogues Bearing Photoreactive Amino Acids.

    PubMed

    Masuda, Yuichi; Aoyama, Kazumasa; Yoshida, Masahito; Kobayashi, Keisuke; Ohshiro, Taichi; Tomoda, Hiroshi; Doi, Takayuki

    2016-07-01

    Beauveriolides I and III, which are naturally occurring cyclodepsipeptides, have been reported to bind to sterol O-acyltransferase (SOAT), inhibiting its ability to synthesize cholesteryl esters. To facilitate an analysis of the binding site(s) of these compounds, we designed beauveriolide analogues 1a-d wherein the Leu or D-allo-Ile residue was replaced by photoreactive amino acids possessing methyldiazirine or trifluoromethyldiazirine in the side chains. The methyldiazirine moiety was installed by reaction of methyl ketones with liquid ammonia to provide imine intermediates, followed by treatment with hydroxylamine-O-sulfonic acid to provide the diaziridines. Subsequent oxidation gave methyldiazirines. In contrast, trifluoromethyldiazirine derivatives were prepared from trifluoromethyl ketones via the oxime intermediates, which were transformed into diaziridines. Subsequent oxidation afforded trifluoromethyldiazirines. The synthesized photoreactive amino acids 3a-d were coupled with 3-hydroxy-4-methyloctanoic acid 4 and dipeptide 5, followed by macrolactamization to provide beauveriolide analogues 1a-d. The SOAT inhibitory activities of 1a-d were found to be as potent as those of beauveriolides I and III. Moreover, 1a-d inhibited SOAT1 selectively rather than SOAT2, which was also consistent with the behavior of beauveriolides I and III. PMID:27020600

  20. Characterization of Bacillus thuringiensis L-isoleucine dioxygenase for production of useful amino acids.

    PubMed

    Hibi, Makoto; Kawashima, Takashi; Kodera, Tomohiro; Smirnov, Sergey V; Sokolov, Pavel M; Sugiyama, Masakazu; Shimizu, Sakayu; Yokozeki, Kenzo; Ogawa, Jun

    2011-10-01

    We determined the enzymatic characteristics of an industrially important biocatalyst, α-ketoglutarate-dependent l-isoleucine dioxygenase (IDO), which was found to be the enzyme responsible for the generation of (2S,3R,4S)-4-hydroxyisoleucine in Bacillus thuringiensis 2e2. Depending on the amino acid used as the substrate, IDO catalyzed three different types of oxidation reactions: hydroxylation, dehydrogenation, and sulfoxidation. IDO stereoselectively hydroxylated several hydrophobic aliphatic l-amino acids, as well as l-isoleucine, and produced (S)-3-hydroxy-l-allo-isoleucine, 4-hydroxy-l-leucine, (S)-4-hydroxy-l-norvaline, 4-hydroxy-l-norleucine, and 5-hydroxy-l-norleucine. The IDO reaction product of l-isoleucine, (2S,3R,4S)-4-hydroxyisoleucine, was again reacted with IDO and dehydrogenated into (2S,3R)-2-amino-3-methyl-4-ketopentanoate, which is also a metabolite found in B. thuringiensis 2e2. Interestingly, IDO catalyzed the sulfoxidation of some sulfur-containing l-amino acids and generated l-methionine sulfoxide and l-ethionine sulfoxide. Consequently, the effective production of various modified amino acids would be possible using IDO as the biocatalyst. PMID:21821743

  1. Studies on the Biotransformation of Veratric Acid, a Human Metabolite of Mebeverine, by Using the Incubated Hen's Egg.

    PubMed

    Kiep, L; Göhl, M; Schmidt, J; Seifert, K

    2015-09-01

    Metabolism studies with selected test substances have shown that a model on the basis of the incubated hen's egg is suitable as a supplement to animal experimentation. Because of its 3,4-dimethoxyphenyl structure veratric acid (3,4-dimethoxybenzoic acid), a known human metabolite of mebeverine, was chosen as model substance for the present investigations and the parent compound as well as 4-hydroxy-3-methoxybenzoic acid were identified as main metabolites. The absence of 3-hydroxy-4-methoxybenzoic acid lets conclude that the O-demethylation takes place exclusively at the p-methoxyl function. In addition, 3,3',4,4'-tetramethoxy-l-ornithuric acid (2,5-bis-(3,4-dimethoxybenzoylamino)pentanoic acid) and its O-desmethyl derivative could be characterized as further metabolites. So far an amino acid conjugate has not been described after veratric acid administration in a vertebrate. There were no indications for the appearance of 3,4-dihydroxybenzoic acid in the veratric acid metabolism. This was confirmed by corresponding studies having the isomeric guaiacol acids as precursor. Furthermore, it could be proved that in ovo the O-methylation of 3,4-dihydroxybenzoic acid occurs regioselective at the m-hydroxyl group. The results which broaden the knowledge on the metabolic fate of veratric acid are discussed in comparison with those in mammals. The metabolites were identified by GC-MS, ESI-HRMS and LC/ESI-MS/MS. The structure of the synthesized reference substance was confirmed by MS, (1)H and (13)C NMR spectral data. PMID:25310250

  2. 40 CFR 180.473 - Glufosinate ammonium; tolerances for residues.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., pulp 0.20 Beet, sugar, molasses 5.0 Beet, sugar, roots 0.9 Beet, sugar, tops (leaves) 1.5 Bushberry... residues of the herbicide glufosinate-ammonium (butanoic acid, 2-amino-4-(hydroxymethylphosphinyl...-propionic acid, expressed as 2-amino-4-(hydroxymethylphosphinyl)butanoic acid equivalents, in or on...

  3. Folic Acid

    MedlinePlus

    Folic acid is a B vitamin. It helps the body make healthy new cells. Everyone needs folic acid. For women who may get pregnant, it is really important. Getting enough folic acid before and during pregnancy can prevent major birth ...

  4. Folic Acid

    MedlinePlus

    Folic acid is used to treat or prevent folic acid deficiency. It is a B-complex vitamin needed by ... Folic acid comes in tablets. It usually is taken once a day. Follow the directions on your prescription label ...

  5. Aspartic acid

    MedlinePlus

    ... also called asparaginic acid. Aspartic acid helps every cell in the body work. It plays a role in: Hormone production and release Normal nervous system function Plant sources of aspartic acid include: Legumes such as ...

  6. Preparation of 7-hydroxy-2-oxoindolin-3-ylacetic acid and its [13C2], [5-n-3H], and [5-n-3H]-7-O-glucosyl analogues for use in the study of indol-3-ylacetic acid catabolism

    NASA Technical Reports Server (NTRS)

    Lewer, P.; Bandurski, R. S. (Principal Investigator)

    1987-01-01

    An improved synthesis of 7-hydroxy-2-oxoindolin-3-ylacetic acid via the base-induced condensation reaction between oxalate esters and 7-benzyloxyindolin-2-one is described. 7-Benzyloxyindolin-2-one was prepared in four steps and 50% overall yield from 3-hydroxy-2-nitrotoluene. The yield of the title compound from 7-benzyloxyindolin-2-one was 56%. This route was used to prepare 7-hydroxy-2-oxoindolin-3-yl[13C2]acetic acid in 30% yield from [13C2]oxalic acid dihydrate. The method could not be extended to the preparation of the corresponding [14C2]-compound. However, an enzyme preparation from Zea mays roots catalysed the conversion of carrier-free [5-n-3H]indol-3-ylacetic acid with a specific activity of 16.7 Ci mmol-1 to a mixture of 7-hydroxy-2-oxo[5-n-3H]indolin-3-ylacetic acid and its [5-n-3H]-7-O-glucoside in ca. 3 and 40% radiochemical yield respectively. The glucoside was converted into the 7-hydroxy compound in 80% yield by means of beta-glucosidase.

  7. Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia.

    PubMed

    Hoogerbrugge-vd Linden, N; de Rooy, F W; Jansen, H; van Blankenstein, M

    1990-03-01

    Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p less than 0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p less than 0.01) from 1.06 to 0.75 during treatment with pravastatin. A reduction of 24% (p less than 0.01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gall stones. PMID:2108908

  8. Effect of eicosapentaenoic acid on cholesterol gallstone formation in C57BL/6J mice.

    PubMed

    Cho, Soo-Min; Park, Jin-A; Kim, Na-Hyun; Kim, Dong-Soon; Zhang, Dan; Yi, Hee; Cho, Hee-Jung; Kim, Ja Kyung; Lee, Dong Ki; Kim, Jin-Suk; Shin, Ho-Chul

    2015-01-01

    The present study investigated the preventive effect of ω-3 fatty acids against cholesterol gallstone (CG) formation. CG formation was induced in C57BL/6J mice using a lithogenic diet (LD). The mice were divided into four treatment groups: i) LD, ii) LD plus eicosapentaenoic acid (EPA), iii) LD plus docosahexaenoic acid (DHA) and iv) LD plus EPA plus DHA. Subsequent to feeding the mice the LD for four weeks, EPA and/or DHA (70 mg/kg/day) were orally administered for eight weeks. The mice in the EPA treatment groups exhibited significantly less gallstone formation than those in the LD group. By contrast, DHA treatment only slightly suppressed gallstone formation. The expression of mucin 2, 5AC, 5B and 6 was significantly decreased in the gallbladders of mice in the EPA groups (70-90%) and the LD plus DHA group (30-50%), compared with that in the mice in the LD group. In addition, the mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase was significantly decreased in the livers of mice in the EPA treatment group compared with that in the livers of mice in the LD group. In conclusion, EPA was found to have a dominant anti-lithogenic effect in C57BL/6J mice. PMID:25333303

  9. Chiral analysis of amino acid neurotransmitters and neuromodulators in mouse brain by CE-LIF.

    PubMed

    Jakó, Tamás; Szabó, Eszter; Tábi, Tamás; Zachar, Gergely; Csillag, András; Szökő, Eva

    2014-10-01

    Chiral CE method has been developed for quantitative determination of d-amino acid modulators of NMDA glutamate receptor; d-serine and d-aspartate along with l-glutamate and l-aspartate in biological samples. These ligands are suggested to be involved in regulation of NMDA receptor related brain functions, such as neurogenesis, neuronal plasticity, and memory formation. For sensitive determination of the amino acids LIF detection was chosen, and a fluorogenic reagent, 7-fluoro-4-nitro-2,1,3-benzoxadiazole was used for derivatization. An amino-modified β-CD, 6-monodeoxy-6-mono(3-hydroxy)propylamino-β-CD (HPA-β-CD) was applied as chiral selector. Determinations were accomplished in a polyacrylamide coated capillary and reverse polarity was used for the analysis of the negatively charged analytes. The method was optimized and validated; 6 mM HPA-β-CD in 50 mM HEPES buffer, pH 7 was appropriate to achieve baseline separation of the analytes. The limit of quantification with acceptable accuracy is 0.05 μM for both d-amino acids. The method was used for the determination of d-aspartate and d-serine content in various brain regions of adult mice. PMID:24931272

  10. Acid Rain.

    ERIC Educational Resources Information Center

    Openshaw, Peter

    1987-01-01

    Provides some background information on acid deposition. Includes a historical perspective, describes some effects of acid precipitation, and discusses acid rain in the United Kingdom. Contains several experiments that deal with the effects of acid rain on water quality and soil. (TW)

  11. Effect of feeding different sources of rumen-protected methionine on milk production and N-utilization in lactating dairy cows

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives of this study were to quantify production responses of lactating dairy cows to supplying absorbable Met as isopropyl-2-hydroxy-4-(methylthio)-butanoic acid (HMBi), or rumen-protected Met (RPM, Smartamine® M) fed with or without 2-hydroxy-4-(methylthio)-butanoic acid (HMB), and to determin...

  12. Antifungal activity of compounds extracted from Cortex Pseudolaricis against Colletotrichum gloeosporioides.

    PubMed

    Zhang, Jing; Yan, Li-Ting; Yuan, En-Lin; Ding, Hai-Xin; Ye, Huo-Chun; Zhang, Zheng-Ke; Yan, Chao; Liu, Ying-Qian; Feng, Gang

    2014-05-28

    Cortex Pseudolaricis is the root bark of Pseudolarix amabilis Rehder, found only in China, and has been widely used in folk antifungal remedies in traditional Chinese medicine. In order to find the natural antifungal agents against mango anthracnose, eight compounds, namely pseudolaric acid A (1), ethyl pseudolaric acid B (2), pseudolaric acid B (3), pseudolaric acid B-O-β-d-glucoside (4), piperonylic acid (5), propionic acid (6), 3-hydroxy-4-methoxybenzoic acid (7), and 4-(3-formyl-5-methoxyphenyl) butanoic acid (8) were isolated from the ethanol extracts of Cortex Pseudolaricis by bioassay-guided fractionation and evaluated for in vitro antifungal activity against Colletotrichum gloeosporioides Penz. Results demonstrated that all of the eight compounds inhibited the mycelial growth of C. gloeosporioides at 5 μg/mL. Among them, pseudolaric acid B and pseudolaric acid A showed the strongest inhibition with the EC50 values of 1.07 and 1.62 μg/mL, respectively. Accordingly, both Pseudolaric acid B and Pseudolaric acid A highly inhibited spore germination and germ tube elongation of C. gloeosporioides. Dipping 100 μg/mL pseudolaric acid B treatment exhibited more effective suppression on postharvest anthracnose in mango fruit when compared to the same concentration of carbendazim. Scanning electron microscopy observations revealed that pseudolaric acid B caused alterations in the hyphal morphology of C. gloeosporioides, including distortion, swelling, and collapse. Pseudolaric acid B caused the mycelial apexes to show an abnormal growth in dimensions with multiple ramifications in subapical expanded areas with irregular shape. These findings warrant further investigation into optimization of pseudolaric acid B to explore a potential antifungal agent for crop protection. PMID:24820992

  13. Aquatic photolysis: photolytic redox reactions between goethite and adsorbed organic acids in aqueous solutions

    USGS Publications Warehouse

    Goldberg, M.C.; Cunningham, K.M.; Weiner, Eugene R.

    1993-01-01

    Photolysis of mono and di-carboxylic acids that are adsorbed onto the surface of the iron oxyhydroxide (goethite) results in an oxidation of the organic material and a reduction from Fe(III) to Fe(II) in the iron complex. There is a subsequent release of Fe2+ ions into solution. At constant light flux and constant solution light absorption, the factors responsible for the degree of photolytic reaction include: the number of lattice sites that are bonded by the organic acid; the rate of acid readsorption to the surface during photolysis; the conformation and structure of the organic acid; the degree of oxidation of the organic acid; the presence or absence of an ??-hydroxy group on the acid, the number of carbons in the di-acid chain and the conformation of the di-acid. The ability to liberate Fe(III) at pH 6.5 from the geothite lattice is described by the lyotropic series: tartrate>citrate> oxalate > glycolate > maleate > succinate > formate > fumarate > malonate > glutarate > benzoate = butanoate = control. Although a larger amount of iron is liberated, the series is almost the same at pH 5.5 except that oxalate > citrate and succinate > maleate. A set of rate equations are given that describe the release of iron from the goethite lattice. It was observed that the pH of the solution increases during photolysis if the solutions are not buffered. There is evidence to suggest the primary mechanism for all these reactions is an electron transfer from the organic ligand to the Fe(III) in the complex. Of all the iron-oxyhydroxide materials, crystalline goethite is the least soluble in water; yet, this study indicates that in an aqueous suspension, iron can be liberated from the goethite lattice. Further, it has been shown that photolysis can occur in a multiphase system at the sediment- water interface which results in an oxidation of the organic species and release of Fe2+ to solution where it becomes available for further reaction. ?? 1993.

  14. Amino acids

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002222.htm Amino acids To use the sharing features on this page, please enable JavaScript. Amino acids are organic compounds that combine to form proteins . ...

  15. Mefenamic Acid

    MedlinePlus

    Mefenamic acid is used to relieve mild to moderate pain, including menstrual pain (pain that happens before or during a menstrual period). Mefenamic acid is in a class of medications called NSAIDs. ...

  16. Aminocaproic Acid

    MedlinePlus

    Aminocaproic acid is used to control bleeding that occurs when blood clots are broken down too quickly. This type ... the baby is ready to be born). Aminocaproic acid is also used to control bleeding in the ...

  17. Ascorbic Acid

    MedlinePlus

    Ascorbic acid is used to prevent and treat scurvy, a disease caused by a lack of vitamin C in ... Ascorbic acid comes in extended-release (long-acting) capsules and tablets, lozenges, syrup, chewable tablets, and liquid drops to ...

  18. Acid mucopolysaccharides

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003368.htm Acid mucopolysaccharides To use the sharing features on this page, please enable JavaScript. Acid mucopolysaccharides is a test that measures the amount ...

  19. Ethacrynic Acid

    MedlinePlus

    Ethacrynic acid, a 'water pill,' is used to treat swelling and fluid retention caused by various medical problems. It ... Ethacrynic acid comes as a tablet to take by mouth. It is usually taken once or twice a day ...

  20. Valproic Acid

    MedlinePlus

    Valproic acid is used alone or with other medications to treat certain types of seizures. Valproic acid is also used to treat mania (episodes of ... to relieve headaches that have already begun. Valproic acid is in a class of medications called anticonvulsants. ...

  1. Effect of mevalonic acid on cholesterol synthesis in bovine intramuscular and subcutaneous adipocytes.

    PubMed

    Liu, Xiaomu; You, Wei; Cheng, Haijian; Zhang, Qingfeng; Song, Enliang; Wan, Fachun; Han, Hong; Liu, Guifen

    2016-02-01

    Mevalonic acid (MVA) is a key material in the synthesis of cholesterol; indeed, intracellular cholesterol synthesis is also called the mevalonic acid pathway. 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGR) is an essential enzyme in cholesterol biosynthesis. This study suggests that MVA may play an important role in the differentiation of bovine adipose tissue in vivo. We investigated differential mRNA expression in bovine intramuscular preadipocytes (BIPs) and bovine subcutaneous preadipocytes (BSPs) by culturing cells from the longissimus dorsi muscle and subcutaneous fat tissues of Luxi yellow cattle. The morphology of lipid accumulation of bovine preadipocytes was detected by Oil Red O staining, and total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and high-density lipoprotein cholesterol (HDLC) levels were measured. Temporospatial expression of HMGR was investigated by real-time quantitative polymerase chain reaction (PCR). The TC, LDLC, and HDLC content did not significantly differ over time but increased slowly with increasing MVA concentration. HMGR expression increased over time and with increasing concentrations of MVA. MVA increased adipose cell proliferation in a dose-dependent and time-dependent manner. MVA stimulated HMGR expression in two cell types and its influence on adipocyte differentiation. PMID:26122311

  2. Fatty acids of lipid fractions in extracellular polymeric substances of activated sludge flocs.

    PubMed

    Conrad, Arnaud; Suutari, Merja Kontro; Keinänen, Minna M; Cadoret, Aurore; Faure, Pierre; Mansuy-Huault, Laurence; Block, Jean-Claude

    2003-10-01

    Phospholipid (PL), glycolipid (GL), and neutral lipid (NL) FA, and the lipopolysaccharide 2- and 3-hydroxy (LPS 2-OH and 3-OH) FA of activated sludges and extracted extracellular polymeric substances (EPS) were determined on samples collected from two wastewater treatment plants. EPS extracted from sludges by means of sonication and cation exchange contained proteins (43.4%), humic-like substances (11.5%), nucleic acids (10.9%), carbohydrates (9.9%), and lipid-bound FA (1.8%). The lipids associated with EPS were composed of GL, PL, NL, and LPS acids in proportions of 61, 21, 16, and 2%, respectively. The profiles of lipid-bound FA in activated sludges and EPS were similar (around 85 separate FA were identified). The FA signatures observed can be attributed to the likely presence of yeasts, fungi, sulfate-reducing bacteria, gram-positive and gram-negative bacteria, and, in lesser quantities, mycobacteria. Comparison of data from the dates of sampling (January and September) showed that there were more unsaturated PLFA in the EPS extracted from the activated sludges sampled in January. This observation could be partly related to microorganism adaptation to temperature variations. The comparison between two wastewater treatment plants showed that the FA profiles were similar, although differences in microbial community structure were also seen. Most of the FA in sludges had an even number of carbons. PMID:14669975

  3. Engineering a Polyketide Synthase for In Vitro Production of Adipic Acid.

    PubMed

    Hagen, Andrew; Poust, Sean; Rond, Tristan de; Fortman, Jeffrey L; Katz, Leonard; Petzold, Christopher J; Keasling, Jay D

    2016-01-15

    Polyketides have enormous structural diversity, yet polyketide synthases (PKSs) have thus far been engineered to produce only drug candidates or derivatives thereof. Thousands of other molecules, including commodity and specialty chemicals, could be synthesized using PKSs if composing hybrid PKSs from well-characterized parts derived from natural PKSs was more efficient. Here, using modern mass spectrometry techniques as an essential part of the design-build-test cycle, we engineered a chimeric PKS to enable production one of the most widely used commodity chemicals, adipic acid. To accomplish this, we introduced heterologous reductive domains from various PKS clusters into the borrelidin PKS' first extension module, which we previously showed produces a 3-hydroxy-adipoyl intermediate when coincubated with the loading module and a succinyl-CoA starter unit. Acyl-ACP intermediate analysis revealed an unexpected bottleneck at the dehydration step, which was overcome by introduction of a carboxyacyl-processing dehydratase domain. Appending a thioesterase to the hybrid PKS enabled the production of free adipic acid. Using acyl-intermediate based techniques to "debug" PKSs as described here, it should one day be possible to engineer chimeric PKSs to produce a variety of existing commodity and specialty chemicals, as well as thousands of chemicals that are difficult to produce from petroleum feedstocks using traditional synthetic chemistry. PMID:26501439

  4. Characterization of Five Fungal Endophytes Producing Cajaninstilbene Acid Isolated from Pigeon Pea [Cajanus cajan (L.) Millsp.

    PubMed Central

    Zu, Yuan Gang; Fu, Yu Jie; Wang, Wei; Luo, Meng; Efferth, Thomas

    2011-01-01

    Five fungal endophytes (K4, K5, K6, K9, K14) producing Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid) were isolated from the roots of pigeon pea [Cajanus cajan (L.) Millsp.]. CSA is responsible for the prominent pharmacological activities in pigeon pea. The amount of CSA in culture solution varied among the five fungal endophytes. K4 produced the highest levels of CSA (1037.13 µg/L) among the endophytes tested after incubation for five days. Both morphological characteristics and molecular methods were used for species identification of fungal endophytes. The five endophytic isolates were characterized by analyzing the internal transcribed spacer (ITS) rRNA and β-tubulin genes. The K4, K5, K9 and K14 strains isolated from pigeon pea roots were found to be closely related to the species Fusarium oxysporum. K6 was identified as Neonectria macrodidym. The present study is the first report on the isolation and identification of fungal endophytes producing CSA in pigeon pea. The study also provides a scientific base for large scale production of CSA. PMID:22102911

  5. Cholesterol 7{alpha}-hydroxylase is phosphorylated at multiple amino acids

    SciTech Connect

    Stroup, D. . E-mail: dstroup1@kent.edu; Ramsaran, J.R.

    2005-04-15

    The activity of cholesterol 7{alpha}-hydroxylase (gpCYP7A1), the rate limiting enzyme in bile acid synthesis, has been postulated to be regulated by phosphorylation/dephosphorylation. This study has found that several kinase activators rapidly reduce the amount of bile acid produced by the human hepatoma cell line, HepG2, and that gpCYP7A1 from HepG2 cell extracts eluted in the phosphoprotein fraction of FeIII columns. After incubating the HepG2 cells with radioactive orthophosphate, the band identified as gpCYP7Al on immunoblots was strongly labeled. Recombinant gpCYP7A was expressed as 6x HIS fusion polypeptides and subjected to kinase assays. The locations of phosphorylation were mapped further by screening synthetic peptides against AMP-activated protein kinase (AMPK), c-Jun N-terminal kinase, protein kinase A, and a panel of nine protein kinase C isoforms. AMPK, also known as 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase, phosphorylated cholesterol 7{alpha}-hydroxylase, suggesting a potential mechanism of coordination of cholesterol synthesis and degradation.

  6. Analysis of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase using different technologies.

    PubMed

    Musset, Lucile; Miyara, Makoto; Benveniste, Olivier; Charuel, Jean-Luc; Shikhman, Alexander; Boyer, Olivier; Fowler, Richard; Mammen, Andrew; Phillips, Joe; Mahler, Michael

    2014-01-01

    Diagnostic tests are needed to aid in the diagnosis of necrotizing myopathies associated with statin use. This study aimed to compare different technologies for the detection of anti-HMGCR antibodies and analyze the clinical phenotype and autoantibody profile of the patients. Twenty samples from myositis patients positive for anti-HMGCR antibodies using a research addressable laser bead assay and 20 negative controls were tested for autoantibodies to HMGCR: QUANTA Lite HMGCR ELISA and QUANTA Flash HMGCR CIA. All patients were also tested for antibodies to extractable nuclear antigens and myositis related antibodies. To verify the specificity of the ELISA, 824 controls were tested. All three assays showed qualitative agreements of 100% and levels of anti-HMGCR antibodies showed significant correlation: Spearman's rho > 0.8. The mean age of the anti-HMGCR antibody positive patients was 54.4 years, 16/20 were females, and 18/20 had necrotizing myopathy (two patients were not diagnosed). Nine out of 20 anti-HMGCR positive patients were on statin. All patients with anti-HMGCR antibodies were negative for all other autoantibodies tested. Testing various controls showed high specificity (99.3%). Anti-HMGCR antibodies are not always associated with the use of statin and appear to be the exclusive autoantibody specificity in patients with statin associated myopathies. PMID:24741598

  7. Analysis of Autoantibodies to 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Using Different Technologies

    PubMed Central

    Musset, Lucile; Miyara, Makoto; Benveniste, Olivier; Charuel, Jean-Luc; Boyer, Olivier; Fowler, Richard; Phillips, Joe

    2014-01-01

    Diagnostic tests are needed to aid in the diagnosis of necrotizing myopathies associated with statin use. This study aimed to compare different technologies for the detection of anti-HMGCR antibodies and analyze the clinical phenotype and autoantibody profile of the patients. Twenty samples from myositis patients positive for anti-HMGCR antibodies using a research addressable laser bead assay and 20 negative controls were tested for autoantibodies to HMGCR: QUANTA Lite HMGCR ELISA and QUANTA Flash HMGCR CIA. All patients were also tested for antibodies to extractable nuclear antigens and myositis related antibodies. To verify the specificity of the ELISA, 824 controls were tested. All three assays showed qualitative agreements of 100% and levels of anti-HMGCR antibodies showed significant correlation: Spearman's rho > 0.8. The mean age of the anti-HMGCR antibody positive patients was 54.4 years, 16/20 were females, and 18/20 had necrotizing myopathy (two patients were not diagnosed). Nine out of 20 anti-HMGCR positive patients were on statin. All patients with anti-HMGCR antibodies were negative for all other autoantibodies tested. Testing various controls showed high specificity (99.3%). Anti-HMGCR antibodies are not always associated with the use of statin and appear to be the exclusive autoantibody specificity in patients with statin associated myopathies. PMID:24741598

  8. Proteomic Analysis of α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate Receptor Complexes*

    PubMed Central

    Kang, Myoung-Goo; Nuriya, Mutsuo; Guo, Yurong; Martindale, Kevin D.; Lee, Daniel Z.; Huganir, Richard L.

    2012-01-01

    The AMPA receptor (AMPA-R) is a major excitatory neurotransmitter receptor in the brain. Identifying and characterizing the neuronal proteins interacting with AMPA-Rs have provided important information about the molecular mechanisms underlying synaptic transmission and plasticity. In this study, to identify more AMPA-R interactors in vivo, we performed proteomic analyses of AMPA-R complexes from the brain. AMPA-R complexes were isolated from the brain through various combinations of biochemical techniques for solubilization, enrichment, and immunoprecipitation. Mass spectrometry analyses of these isolated complexes identified several novel components of the AMPA-R complexes as well as some previously identified components. The identification of these novel components helps to further define the complex mechanisms involved in the regulation of AMPA receptor function and synaptic plasticity. PMID:22753414

  9. The 3-hydroxy-2-butanone pathway is required for Pectobacterium carotovorum pathogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pectobacterium species are necrotrophic bacterial pathogens that cause soft rot diseases in potatoes and several other crops worldwide. A tiled microarray based on the genome sequence of Pectobacterium carotovorum subsp. carotovorum WPP14 was used to identify Pectobacterium genes that are differenti...

  10. Strategic 3-hydroxy-2-butanone release in the dominant male lobster cockroach, Nauphoeta cinerea

    NASA Astrophysics Data System (ADS)

    Chen, Shu-Chun; Yang, Rou-Ling; Ho, Hsiao-Yung; Chou, Szu-Ying; Kou, Rong

    2007-11-01

    In the lobster cockroach Nauphoete cinerea, the dominant subordinate hierarchy formed via the agonistic interactions is unstable, and changes in rank order are common. Our previous results showed that in the first encounter fight during initial rank formation, microgram levels of 3H-2B are released by the aggressive posture (AP)-adopting dominant male. In the present study, the pattern of daily pheromone (3H-2B) release during the domination period and on the day of rank switch, rank duration, and rank switch frequency were investigated in three-male groups and six-male groups to examine the effect of higher frequency of agonistic encounters. The results showed that, in the three-male groups (50-day observation period), daily 3H-2B release rate was not constant, but fluctuated, the average duration of dominant rank was 16.6 ± 2.0 days, rank switch occurred in 58.8% of groups, and the frequency of rank switching (average number of rank switches/group/50 days) was 1.4 ± 0.2. For the six-male groups (30-day observation period), the daily 3H-2B release rate also fluctuated, but the duration of dominant rank was significantly shorter at 4.2 ± 0.6 days, rank switch occurred in 100% of groups, and the frequency of rank switching (average number of rank switches/group/30 days) was significantly higher at 6.9 ± 0.6. The results for both sets of male groups showed that as a new rank formed (either on the first encounter day or on the day of rank switching), the dominant status was significantly associated with a higher 3H-2B release rate. In the animal kingdom, fighting usually involves communication or the exchange of signals, and the results of this study indicated that the fluctuating daily 3H-2B release rate adopted by the dominants is a kind of strategic release and the 3H-2B release rate is a signal used to determine dominance.

  11. Joy and flustration with organofluorine compounds - a fluorous autobiography.

    PubMed

    Seebach, Dieter

    2014-01-01

    An overview is given about our work on fluoro-organic compounds, published or described in PhD theses between 1977 and 2013. After a discussion of structural F-effects and F-tagging applications the material is ordered by the various areas of our research, in which we have used and/or prepared F-derivatives: Li- and Ti-organic compounds and reagents, polylithiated hydroxy-esters and nitroalkanes, the enantiopure trifluoro-lactic, -Roche, and -3-hydroxy-butanoic acids as toolbox for the preparation of numerous F₃C-substituted compounds, including natural products and dendrimers, and fluoro-α-, -β-, and -δ-amino acids, as well as peptides with back-bond-bound fluorine. The strong influence on β-peptide folding by fluoro-substituents in the α-position of β-amino-acid residues is discussed in terms of the α-fluoro-amide conformational effect. Finally, some cases of totally unexpected effects on reactivity and structure exerted by fluoro-substitution are presented and taken as examples for our use of the terms flustrate and flustration in connection with organo-fluorine chemistry. PMID:25198744

  12. Fatty acids - trans fatty acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The data supporting a negative effect of dietary trans fatty acids on cardiovascular disease risk is consistent. The primary dietary sources of trans fatty acids include partially hydrogenated fat and rudiment fat. The adverse effect of trans fatty acids on plasma lipoprotein profiles is consisten...

  13. Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor α.

    PubMed

    Takao, Koichi; Noguchi, Kaori; Hashimoto, Yosuke; Shirahata, Akira; Sugita, Yoshiaki

    2015-01-01

    A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists. PMID:25832022

  14. Rapid Stimulation of 5-Lipoxygenase Activity in Potato by the Fungal Elicitor Arachidonic Acid 1

    PubMed Central

    Bostock, Richard M.; Yamamoto, Hiroyuki; Choi, Doil; Ricker, Karin E.; Ward, Bernard L.

    1992-01-01

    The activity of lipoxygenase (LOX) in aged potato tuber discs increased by almost 2-fold following treatment of the discs with the fungal elicitor arachidonic acid (AA). Enzyme activity increased above that in untreated discs within 30 min after AA treatment, peaked at 1 to 3 h, and returned to near control levels by 6 h. The majority of the activity was detected in a soluble fraction (105,000g supernatant), but a minor portion was also associated with a particulate fraction enriched in microsomal membranes (105,000g pellet); both activities were similarly induced. 5-Hydroperoxyeicosatetraenoic acid was the principal product following incubation of these extracts with AA. Antibodies to soybean LOX strongly reacted with a protein with a molecular mass of approximately 95-kD present in both soluble and particulate fractions whose abundance generally corresponded with LOX activity in extracts. LOX activity was not enhanced by treatment of the discs with nonelicitor fatty acids or by branched β-glucans from the mycelium of Phytophthora infestans. Prior treatment of the discs with abscisic acid, salicylhydroxamic acid, or n-propyl gallate, all of which have been shown to suppress AA induction of the hypersensitive response, inhibited the AA-induced increment in LOX activity. Cycloheximide pretreatment, which abolishes AA elicitor activity for other responses such as phytoalexin induction, did not inhibit LOX activity in water- or elicitor-treated discs but enhanced activity similar to that observed by AA treatment. The elicitor-induced increase in 5-LOX activity preceded or temporally paralleled the induction of other studied responses to AA, including the accumulation of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A reductase and phenylalanine ammonia lyase reported here. The results are discussed in relation to the proposed role of the 5-LOX in signal-response coupling of arachidonate elicitation of the hypersensitive response. Images Figure 4 Figure 7 PMID

  15. Microbial synthesis of polyhydroxyalkanoate using seaweed-derived crude levulinic acid as co-nutrient.

    PubMed

    Bera, Anupam; Dubey, Sonam; Bhayani, Khushbu; Mondal, Dibyendu; Mishra, Sandhya; Ghosh, Pushpito K

    2015-01-01

    Production of polyhydroxyalkanoates (PHAs) from Jatropha biodiesel residues, namely crude glycerol and oil cake hydrolysate, has been reported previously. Halomonas hydrothermalis (MTCC accession no. 5445; NCBI Genbank accession no. GU938192), a wild marine strain, was used in the bio-synthesis. The present study was initiated to vary the properties of the polymer. Seaweed-derived crude levulinic acid (SDCLA), containing formic acid, residual sugars and dissolved minerals additionally, was proposed as co-feed along with the biodiesel residues. Experiments were conducted at 100mL scale in batch process. Whereas the PHA yield was only 0.40 ± 0.01 g when only biodiesel residues were employed, it rose to 1.07 ± 0.02 g in presence of 0.35% (w/v) of SDCLA. The corresponding carbon utilisation efficiencies were 29.3% and 57.5%, respectively. 3-Hydroxy valerate incorporation in the PHA was pronounced in presence of SDCLA, with associated changes in polymer properties. The microbial synthesis fared poorly when SDCLA was substituted with pure levulinic acid. Thus, Halomonas hydrothermalis had a poor response to levulinic acid, as such, and other constituents present in SDCLA appear to have played a vital role in bacterial cell division and accumulation of PHA. Biodegradability tests in moist soil were also conducted as part of the study. Marine microalgal cultivation for biodiesel and seaweed cultivation for fuels may help generate biodiesel residues and crude levulinic acid in proximity, which would open up the possibility of large scale PHA manufacture in efficient and practical manner in the future through the methodology of the present study. PMID:25193103

  16. Acid Deposition

    EPA Science Inventory

    This indicator presents acid deposition trends in the contiguous U.S. from 1989 to 2007. Data are broken down by wet and dry deposition and deposition of nitrogen and sulfur compounds. Acid deposition is particularly damaging to lakes, streams, and forests and the plants and a...

  17. Acid rain

    SciTech Connect

    White, J.C. )

    1988-01-01

    This book presents the proceedings of the third annual conference sponsored by the Acid Rain Information Clearinghouse (ARIC). Topics covered include: Legal aspects of the source-receptor relationship: an energy perspective; Scientific uncertainty, agency inaction, and the courts; and Acid rain: the emerging legal framework.

  18. Acid rain

    SciTech Connect

    Elsworth, S.

    1985-01-01

    This book was written in a concise and readable style for the lay public. It's purpose was to make the public aware of the damage caused by acid rain and to mobilize public opinion to favor the elimination of the causes of acid rain.

  19. Acid rain

    SciTech Connect

    Sweet, W.

    1980-06-20

    Acid precipitation includes not only rain but also acidified snow, hail and frost, as well as sulfur and nitrogen dust. The principal source of acid precipitation is pollution emitted by power plants and smelters. Sulfur and nitrogen compounds contained in the emissions combine with moisture to form droplets with a high acid content - sometimes as acidic as vinegar. When sufficiently concentrated, these acids can kill fish and damage material structures. Under certain circumstances they may reduce crop and forest yields and cause or aggravate respiratory diseases in humans. During the summer, especially, pollutants tend to collect over the Great Lakes in high pressure systems. Since winds typically are westerly and rotate clockwise around high pressure systems, the pollutants gradually are dispersed throughout the eastern part of the continent.

  20. Asparagusic acid.

    PubMed

    Mitchell, Stephen C; Waring, Rosemary H

    2014-01-01

    Asparagusic acid (1,2-dithiolane-4-carboxylic acid) is a simple sulphur-containing 5-membered heterocyclic compound that appears unique to asparagus, though other dithiolane derivatives have been identified in non-food species. This molecule, apparently innocuous toxicologically to man, is the most probable culprit responsible for the curious excretion of odorous urine following asparagus ingestion. The presence of the two adjacent sulphur atoms leads to an enhanced chemical reactivity, endowing it with biological properties including the ability to substitute potentially for α-lipoic acid in α-keto-acid oxidation systems. This brief review collects the scattered data available in the literature concerning asparagusic acid and highlights its properties, intermediary metabolism and exploratory applications. PMID:24099657

  1. [Gastric Acid].

    PubMed

    Ruíz Chávez, R

    1996-01-01

    Gastric acid, a product of parietal cells secretion, full fills multiple biological roles which are absolutely necessary to keep corporal homeostasis. The production of the acid depends upon an effector cellular process represented in the first step by histamine, acetilcholine and gastrin, first messengers of the process. These interact with specific receptors than in sequence activate second messengers -cAMP and the calcium-calmodulin system- which afterwards activate a kinase. An specific protein is then phosphorilated by this enzyme, being the crucial factor that starts the production of acid. Finally, a proton bomb, extrudes the acid towards the gastric lumen. The secretion process mentioned above, is progressive lyactivated in three steps, two of which are stimulators -cephalic and gastric phases- and the other one inhibitor or intestinal phase. These stages are started by mental and neurological phenomena -thought, sight, smell or memory-; by food, drugs or other ingested substances; and by products of digestion. Changes in regulation of acid secretion, in the structure of gastro-duodenal mucosal barrier by a wide spectrum of factors and agents including food, drugs and H. pylori, are the basis of acid-peptic disease, entity in which gastric acid plays a fundamental role. From the therapeutic point of view, so at the theoretical as at the practical levels, t is possible to interfere with the secretion of acid by neutralization of some of the steps of the effector cellular process. An adequate knowledge of the basics related to gastric acid, allows to create strategies for the clinical handling of associated pathology, specifically in relation to peptic acid disease in all of the known clinical forms. PMID:12165790

  2. The influence of temperature and aerosol acidity on biogenic secondary organic aerosol tracers: Observations at a rural site in the central Pearl River Delta region, South China

    NASA Astrophysics Data System (ADS)

    Ding, Xiang; Wang, Xin-Ming; Zheng, Mei

    2011-02-01

    At a rural site in the central Pearl River Delta (PRD) region in south China, fine particle (PM 2.5) samples were collected during fall-winter 2007 to measure biogenic secondary organic aerosol (SOA) tracers, including isoprene SOA tracers (3-methyl-2,3,4-trihydroxy-1-butene, 2-methylglyceric acid, 2-methylthreitol and 2-methylerythritol), α-pinene SOA tracers ( cis-pinonic acid, pinic acid, 3-methyl-1,2,3-butanetricarboxylic acid, 3-hydroxyglutaric acid and 3-hydroxy-4,4-dimethylglutaric acid) and a sesquiterpene SOA tracer (β-caryophyllinic acid). The isoprene-, α-pinene- and sesquiterpene-SOA tracers averaged 30.8 ± 15.9, 6.61 ± 4.39, and 0.54 ± 0.56 ng m -3, respectively; and 2-methyltetrols (sum of 2-methylthreitol and 2-methylerythritol, 27.6 ± 15.1 ng m -3) and cis-pinonic acid (3.60 ± 3.76 ng m -3) were the dominant isoprene- and α-pinene-SOA tracers, respectively. 2-Methyltetrols exhibited significantly positive correlations ( p < 0.05) with ambient temperature, probably resulting from the enhanced isoprene emission strength and tracer formation rate under higher temperature. The significantly positive correlation ( p < 0.05) between 2-methyltetrols and the estimated aerosol acidity with a slope of 59.4 ± 13.4 ng m -3 per μmol [H +] m -3 reflected the enhancement of isoprene SOA formation by aerosol acidity, and acid-catalyzed heterogeneous reaction was probably the major formation pathway for 2-methyltetrols in the PRD region. 2-Methylglyceric acid showed poor correlations with both temperature and aerosol acidity. The α-pinene SOA tracers showed poor correlations with temperature, probably due to the counteraction between temperature effects on the precursor emission/tracer formation and gas/particle partitioning. Among the α-pinene SOA tracers, only cis-pinonic acid and pinic acid exhibited significant correlations with aerosol acidity with slopes of -11.7 ± 3.7 and -2.2 ± 0.8 ng m -3 per μmol [H +] m -3, respectively. The negative

  3. The synthesis of short- and medium-chain-length poly(hydroxyalkanoate) mixtures from glucose- or alkanoic acid-grown Pseudomonas oleovorans.

    PubMed

    Ashby, R D; Solaiman, D K Y; Foglia, T A

    2002-03-01

    Pseudomonas oleovorans NRRL B-778 accumulated mixtures of poly-3-hydroxybutyrate (PHB) and medium-chain-length poly(hydroxyalkanoates) (mcl-PHAs) when grown on glucose, octanoic acid or oleic acid, whereas growth on nonanoic acid or undecanoic acid resulted in copolymers of poly-3-hydroxybutyrate-co-3-hydroxyvalerate (PHB-co-HV). Acetone fractionation verified the presence of PHB/mcl-PHA mixtures. The acetone-insoluble (AIS) fractions of the polymers derived from glucose (PHA-glucose), octanoic acid (PHA-octanoic) and oleic acid (PHA-oleic) were exclusively PHB while the acetone-soluble (AS) fractions contained mcl-PHA composed of differing ratios of 3-hydroxy-acid monomer units, which ranged in chain length from 6 to 14 carbon atoms. In contrast, both the AIS and AS fractions from the polymers derived from nonanoic acid (PHA-nonanoic) and undecanoic acid (PHA-undecanoic) were composed of comparable ratios of 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV). The unfractionated PHA-glucose, PHA-octanoic and PHA-oleic polymers had melting temperatures (Tm) between 177 and 179 degrees C, enthalpies of fusion (AHf) of 20 cal/g and glasstransition temperatures (Tg) of 3-4 degrees C. This was due to the large PHB content in the polymer mixtures. On the other hand, the PHA-nonanoic and PHA-undecanoic polymers had thermal properties that supported their copolymer nature. In both cases, the Tm values were 161 degrees C, deltaHf values were 7 cal/g and Tg values were - 3 degrees C. PMID:12074088

  4. Enhancement of ganoderic acid production by constitutively expressing Vitreoscilla hemoglobin gene in Ganoderma lucidum.

    PubMed

    Li, Huan-Jun; He, Yi-Long; Zhang, De-Huai; Yue, Tong-Hui; Jiang, Lu-Xi; Li, Na; Xu, Jun-Wei

    2016-06-10

    The Vitreoscilla hemoglobin (VHb) gene was expressed in Ganoderma lucidum to enhance antitumor ganoderic acid (GA) production. The effects of VHb expression on the accumulation of GAs and lanosterol (intermediate) and the transcription of GA biosynthesis genes were also investigated. In VHb-expressing G. lucidum, the maximum concentrations of four individual GAs (GA-S, GA-T, GA-Mk and GA-Me) were 19.1±1.8, 34.6±2.1, 191.5±13.1 and 45.2±2.8μg/100mg dry weight, respectively, which were 1.4-, 2.2, 1.9- and 2.0-fold higher than those obtained in the wild-type strain. Moreover, the maximum lanosterol concentration in the strain expressing VHb was 1.28-fold lower than that in the wild-type strain. The transcription levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, squalene synthase, and lanosterol synthase genes were up-regulated by 1.6-, 1.5-, and 1.6-fold, respectively, in the strain expressing VHb. This work is beneficial in developing an efficient fermentation process for the hyperproduction of GAs. PMID:27080449

  5. Acid fog

    SciTech Connect

    Hileman, B.

    1983-03-01

    Fog in areas of southern California previously thought to be pollution-free has been shown to have a pH as low as 1.69. It has been found to be most acidic after smoggy days, suggesting that it forms on the aerosol associated with the previously exiting smog. Studies on Whiteface Mountain in the Adirondacks show that fog water is often 10 times as acidic as rainwater. As a result of their studies, California plans to spend $4 million on acid deposition research in the coming year. (JMT)

  6. Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Extension Study for Subjects Previously Enrolled in Triheptanoin Studies.

    ClinicalTrials.gov

    2016-02-26

    Carnitine Palmitoyltransferase (CPT I or CPT II) Deficiency; Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency; Long-chain 3-hydroxy-acyl-CoA Dehydrogenase (LCHAD) Deficiency; Trifunctional Protein (TFP) Deficiency; Carnitine-acylcarnitine Translocase (CACT) Deficiency

  7. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood–brain barrier permeability

    PubMed Central

    Oláh, Gáspár; Herédi, Judit; Menyhárt, Ákos; Czinege, Zsolt; Nagy, Dávid; Fuzik, János; Kocsis, Kitti; Knapp, Levente; Krucsó, Erika; Gellért, Levente; Kis, Zsolt; Farkas, Tamás; Fülöp, Ferenc; Párdutz, Árpád; Tajti, János; Vécsei, László; Toldi, József

    2013-01-01

    Cortical spreading depression (CSD) involves a slowly-propagating depolarization wave in the cortex, which can appear in numerous pathophysiological conditions, such as migraine with aura, stroke, and traumatic brain injury. Neurons and glial cells are also depolarized transiently during the phenomena. CSD is followed by a massive increase in glutamate release and by changes in the brain microcirculation. The aim of this study was to investigate the effects of two N-methyl-D-aspartate receptor antagonists, endogenous kynurenic acid (KYNA) and dizocilpine, on CSD and the related blood–brain barrier (BBB) permeability in rats. In intact animals, KYNA hardly crosses the BBB but has some positive features as compared with its precursor L-Kynurenine, which is frequently used in animal studies (KYNA cannot be metabolized to excitotoxic agents such as 3-hydroxy-L-kynurenine and quinolinic acid). We therefore investigated the possible effects of peripherally administered KYNA. Repetitive CSD waves were elicited by the application of 1 M KCl solution to the cortex. Direct current-electrocorticograms were measured for 1 hour. Four parameters of the waves were compared. Evans blue dye and fluorescent microscopy were used to study the possible changes in the permeability of the BBB. The results demonstrated that N-methyl-D-aspartate receptor antagonists can reduce the number of CSD waves and decrease the permeability of the BBB during CSD. These results suggest that KYNA itself or its derivatives may offer a new approach in the therapy of migraines. PMID:24068867

  8. Synthesis and structure--activity relationships of substituted cinnamic acids and amide analogues: a new class of herbicides.

    PubMed

    Vishnoi, Shipra; Agrawal, Vikash; Kasana, Virendra K

    2009-04-22

    In the present investigation, substituted cinnamic acids (3-hydroxy, 4-hydroxy, 2-nitro, 3-nitro, 4-nitro, 3-chloro, and 4-methoxy) and their amide analogues with four different types of substituted anilines have been synthesized. The synthesized compounds have been screened for their germination inhibition activity on radish (Raphanus sativus L. var. Japanese White) seeds at 50, 100, and 200 ppm concentrations, and the activity was compared with standard herbicide, metribuzin formulation (sencor). Significant activity was exhibited by all of the compounds. It was observed that with the increase in concentration of the test solution, the activity also increased. All of the compounds showed more than 70% inhibition at 100 ppm concentration except 4-hydroxy cinnamanilide. The compound, 2-chloro (4'-hydroxy) cinnamanilide was the best among the tested compounds, and it was found to be at par with the standard, metribuzin at all concentrations. Thus, it can be concluded that substituted cinnamic acids and their amide analogues may be developed as potential herbicides. PMID:19368353

  9. High Throughput Liquid Chromatography-Tandem Mass Spectrometry Assay for Mercapturic Acids of Acrolein and Crotonaldehyde in Cigarette Smokers’ Urine

    PubMed Central

    Carmella, Steven G.; Chen, Menglan; Zarth, Adam; Hecht, Stephen S.

    2014-01-01

    3-Hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) are urinary metabolites of the toxicants acrolein and crotonaldehyde, respectively. Virtually all human urine samples contain these metabolites, resulting from the action of glutathione-S-transferases on acrolein and crotonaldehyde, which are lipid peroxidation products, environmental and dietary contaminants, and constituents of cigarette smoke. We have developed a high throughput liquid chromatography-tandem mass spectrometry method for quantitative analysis of 3-HPMA and HMPMA in large numbers of small urine samples, as would be required in molecular epidemiology and clinical studies relating levels of these metabolites to cancer risk. Solid-phase extraction on mixed mode reverse phase-anion exchange 96-well plates provided sufficient purification for LC-MS/MS analysis, which was performed by auto-injection using a 96-well format, and resulted in clean, readily interpretable chromatograms, with detection limits of 4.5 pmol/mL urine for 3-HPMA and 3.5 pmol/mL urine for HMPMA. Accuracy was 92% for 3-HPMA and 97% for HMPMA while inter-day precision was 9.1% (coefficient of variation) for 3-HPMA and 11.0% for HMPMA. The method was applied to more than 2600 urine samples from smokers; mean levels of 3-HPMA and HMPMA were 4800 ± 5358 (S.D.) pmol/ml and 3302 ± 3341 pmol/ml, respectively. PMID:23934173

  10. Folic acid

    MedlinePlus

    ... in the blood vessel to keep it open. Bipolar disorder. Taking folic acid does not appear to improve the antidepressant effects of lithium in people with bipolar disorder. However, taking folate with the medication valproate improves ...

  11. Mefenamic Acid

    MedlinePlus

    ... as mefenamic acid may cause ulcers, bleeding, or holes in the stomach or intestine. These problems may ... like coffee grounds, blood in the stool, or black and tarry stools.Keep all appointments with your ...

  12. ACID RAIN

    EPA Science Inventory

    Acid precipitation has become one of the major environmental problems of this decade. It is a challenge to scientists throughout the world. Researchers from such diverse disciplines as plant pathology, soil science, bacteriology, meteorology and engineering are investigating diff...

  13. Acid Precipitation

    ERIC Educational Resources Information Center

    Likens, Gene E.

    1976-01-01

    Discusses the fact that the acidity of rain and snow falling on parts of the U.S. and Europe has been rising. The reasons are still not entirely clear and the consequences have yet to be well evaluated. (MLH)

  14. Carnosic acid.

    PubMed

    Birtić, Simona; Dussort, Pierre; Pierre, François-Xavier; Bily, Antoine C; Roller, Marc

    2015-07-01

    Carnosic acid (salvin), which possesses antioxidative and antimicrobial properties, is increasingly exploited within the food, nutritional health and cosmetics industries. Since its first extraction from a Salvia species (∼70 years ago) and its identification (∼50 years ago), numerous articles and patents (∼400) have been published on specific food and medicinal applications of Rosmarinus and Salvia plant extracts abundant in carnosic acid. In contrast, relevant biochemical, physiological or molecular studies in planta have remained rare. In this overview, recent advances in understanding of carnosic acid distribution, biosynthesis, accumulation and role in planta, and its applications are summarised. We also discuss the deficiencies in our understanding of the relevant biochemical processes, and suggest the molecular targets of carnosic acid. Finally, future perspectives and studies related to its potential roles are highlighted. PMID:25639596

  15. Aminocaproic Acid

    MedlinePlus

    Amicar® Oral Solution ... Aminocaproic acid comes as a tablet and a solution (liquid) to take by mouth. It is usually ... it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away ...

  16. Tranexamic Acid

    MedlinePlus

    ... is used to treat heavy bleeding during the menstrual cycle (monthly periods) in women. Tranexamic acid is in ... tablets for more than 5 days in a menstrual cycle or take more than 6 tablets in a ...

  17. Acidic precipitation

    SciTech Connect

    Martin, H.C.

    1987-01-01

    At the International Symposium on Acidic Precipitation, over 400 papers were presented, and nearly 200 of them are included here. They provide an overview of the present state of the art of acid rain research. The Conference focused on atmospheric science (monitoring, source-receptor relationships), aquatic effects (marine eutrophication, lake acidification, impacts on plant and fish populations), and terrestrial effects (forest decline, soil acidification, etc.).

  18. 21 CFR 182.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (geraniol acetate). Limonene (d-, l-, and dl-). Linalool (linalol, 3,7-dimethyl-1,6-octadien-3-ol). Linalyl... (parapropenyl anisole). Benzaldehyde (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone...

  19. 21 CFR 182.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (geraniol acetate). Limonene (d-, l-, and dl-). Linalool (linalol, 3,7-dimethyl-1,6-octadien-3-ol). Linalyl... (parapropenyl anisole). Benzaldehyde (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone...

  20. 21 CFR 182.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... (geraniol acetate). Limonene (d-, l-, and dl-). Linalool (linalol, 3,7-dimethyl-1,6-octadien-3-ol). Linalyl... (parapropenyl anisole). Benzaldehyde (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone...

  1. 21 CFR 182.60 - Synthetic flavoring substances and adjuvants.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... (geraniol acetate). Limonene (d-, l-, and dl-). Linalool (linalol, 3,7-dimethyl-1,6-octadien-3-ol). Linalyl... (parapropenyl anisole). Benzaldehyde (benzoic aldehyde). N-Butyric acid (butanoic acid). d- or l-Carvone...

  2. Fermented Rhus verniciflua Stokes Extract Exerts an Antihepatic Lipogenic Effect in Oleic-Acid-Induced HepG2 Cells via Upregulation of AMP-Activated Protein Kinase.

    PubMed

    Lee, Myoung-Sun; Kim, Joo-Seok; Cho, Sun-Mi; Lee, Seon Ok; Kim, Sung-Hoon; Lee, Hyo-Jeong

    2015-08-19

    Rhus verniciflua Stokes has been used as a traditional medicine and food supplement in Korea. In the present study, fermented R. verniciflua Stokes extract (FRVE), an allergen-free extract of R. verniciflua Stokes fermented with the yeast Saccharomyces carlsbergensis, was assessed for its lipid-lowering potential in an in vitro non-alcoholic fatty liver disease model. FRVE markedly suppressed lipid accumulation and intracellular triglycerides (TGs) in the presence of oleic acid (OA). Additionally, FRVE decreased both mRNA and protein levels of lipid-synthesis- and cholesterol-metabolism-related factors, such as sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS), glycerol-3-phosphate acyltransferase (GPAT), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), in OA-induced HepG2 cells. Moreover, FRVE activated low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK), and fatty acid oxidation-related factors peroxisome proliferator activated receptor α (PPARα) and carnitine palmitoyltransferase 1 (CPT-1). Further, the AMPK inhibitor compound C suppressed the increased expression of AMPK phosphorylation induced by FRVE. Phenolics and cosanols in FRVE increased the phosphorylation of AMPK and decreased that of SREBP-1. Taken together, our findings suggest that FRVE has antilipogenic potential in non-alcoholic fatty livers via AMPK upregulation. PMID:26176317

  3. Unraveling the mechanism of β-N-oxalyl-α,β-diaminopropionic acid (β-ODAP) induced excitotoxicity and oxidative stress, relevance for neurolathyrism prevention.

    PubMed

    Van Moorhem, M; Lambein, F; Leybaert, L

    2011-03-01

    β-N-Oxalyl-α,β-diaminopropionic acid (β-ODAP) is a plant metabolite present in Lathyrus sativus (L. Sativus) seeds that is proposed to be responsible for the neurodegenerative disease neurolathyrism. This excitatory amino acid binds to α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors and several lines of evidence indicate that β-ODAP triggers motor neuron degeneration by inducing excitotoxic cell death and increasing oxidative stress. In addition, this toxin is known to disturb the mitochondrial respiration chain and recent data indicate that β-ODAP may inhibit the uptake of cystine thereby compromising the cells' abilities to cope with oxidative stress. Recent work from our group furthermore suggests that β-ODAP disturbs the cellular Ca(2+) homeostasis machinery with increased Ca(2+) loading in the endoplasmic reticulum (ER)-mitochondrial axis. In this review, we aim to integrate the various mechanistic levels of β-ODAP toxicity into a consistent pathophysiological picture. Interestingly, the proposed cascade contains several aspects that are common with other neurodegenerative diseases, for example amyotrophic lateral sclerosis (ALS). Based on these mechanistic insights, we conclude that dietary supplementation with methionine (Met) and cysteine (Cys) may significantly lower the risk for neurolathyrism and can thus be considered, in line with epidemiological data, as a preventive measure for neurolathyrism. PMID:20510327

  4. Synthesis and biological evaluation of a new set of pyrazolo[1,5-c]quinazolines as glycine/N-methyl-D-aspartic acid receptor antagonists.

    PubMed

    Varano, Flavia; Catarzi, Daniela; Colotta, Vittoria; Poli, Daniela; Filacchioni, Guido; Galli, Alessandro; Costagli, Chiara

    2009-08-01

    Previous studies have shown that 8-chloro-5,6-dihydro-5-oxo-pyrazolo[1,5-c]quinazoline-2-carboxylates (PQZ series) represent a family of glycine/N-methyl-D-aspartic acid (NMDA) and/or (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and/or kainic acid (KA) receptor antagonists. Moreover, some groups have been identified that introduced in suitable positions of the PQZ 2-carboxylate framework shift affinity and selectivity toward glycine/NMDA receptor. These substituents are a carboxylate function at position-1 and/or a chlorine atom at position-9. In this paper we report a study on some new 5,6-dihydro-5-oxo-pyrazolo[1,5-c]quinazoline-1-carboxylates bearing at position-2 a lipophilic amide group or lacking substituent at this same position. All the newly synthesised compounds were evaluated for their binding at glycine/NMDA, AMPA and KA receptors. These studies led to the identification of some new PQZ derivatives endowed with good glycine/NMDA receptor affinity and selectivity and to better definition of the structure-activity relationship (SAR) of this class of compounds. PMID:19652407

  5. Local inhibitory reflexes excited by mucosal application of nutrient amino acids in guinea pig jejunum.

    PubMed

    Gwynne, R M; Bornstein, J C

    2007-06-01

    The motility of the gut depends on the chemicals contained in the lumen, but the stimuli that modify motility and their relationship to enteric neural pathways are unclear. This study examined local inhibitory reflexes activated by various chemical stimulants applied to the mucosa to characterize effective physiological stimuli and the pathways they excite. Segments of the jejunum were dissected to allow access to the circular muscle on one-half of the preparation while leaving the mucosa intact on the circumferentially adjacent half. Chemicals were transiently applied to the mucosa, and responses were recorded intracellularly in nearby circular muscle cells. The amino acids l-phenylalanine, l-alanine, or l-tryptophan (all 1 mM) evoked inhibitory junction potentials (IJPs; latency 150-300 ms, amplitude 3-8 mV, each n > 6) that were blocked by TTX and partially blocked by antagonists of P2X receptors and/or a combination of antagonists at 5-HT(3) and 5-HT(4) receptors. The putative mediators 5-HT (10 microM), ATP (1 mM), and CCK-8 (1-10 microM) elicited IJPs mediated via 5-HT(3), P2X, and CCK-B receptors, respectively. Responses were only partially reduced by the effective antagonists. IJPs evoked by electrically stimulating the mucosa were unaffected by antagonists that reduced chemically evoked responses. Both chemically and electrically evoked IJPs were resistant to nicotinic, NK(1), NK(3), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, N-methyl-d-aspartate, or CGRP receptor blockade. We conclude that mucosal stimulation by amino acids activates local neural pathways whose pharmacology depends on the nature of the stimulus. Transmitters involved at some synapses in these pathways remain to be identified. PMID:17347449

  6. Dynamic changes of excitatory amino acid receptors in the rat hippocampus following transient cerebral ischemia

    SciTech Connect

    Westerberg, E.; Monaghan, D.T.; Kalimo, H.; Cotman, C.W.; Wieloch, T.W.

    1989-03-01

    The changes in excitatory amino acid receptor ligand binding induced by transient cerebral ischemia were studied in the rat hippocampal subfields. Ten minutes of ischemia was induced by common carotid artery occlusion combined with hypotension, and the animals were allowed variable periods of recovery ranging from 1 day to 4 weeks. The binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) to quisqualate receptors, 3H-kainic acid (KA) to kainate receptors, and 3H-glutamate to N-methyl-D-aspartate (NMDA) receptors as determined by quantitative autoradiography. One week following ischemia the CA1 region of the hippocampus displayed a severe (90%) dendrosomatic lesion with preservation of presynaptic terminals. This was associated with a 60% decrease in AMPA binding and a 25% decrease in glutamate binding to NMDA receptors. At 4 weeks postischemia, both AMPA and NMDA sites were greatly reduced. Although the dentate gyrus granule cells are resistant to an ischemic insult of this magnitude, this region showed marked changes in receptor binding. One week following ischemia, the AMPA and NMDA binding decreased by approximately 40 and 20%, respectively. Following 2 weeks of recovery, the NMDA binding was not significantly different from control level, while the AMPA binding remained depressed up to 4 weeks postischemia. The high density of KA binding sites in the inner molecular layer of the dentate gyrus was unaffected by the ischemic insult, despite an extensive degeneration of cells in the hilus of dentate gyrus which projects glutamatergic afferents to this area.

  7. Salicylic acids

    PubMed Central

    Hayat, Shamsul; Irfan, Mohd; Wani, Arif; Nasser, Alyemeni; Ahmad, Aqil

    2012-01-01

    Salicylic acid is well known phytohormone, emerging recently as a new paradigm of an array of manifestations of growth regulators. The area unleashed yet encompassed the applied agriculture sector to find the roles to strengthen the crops against plethora of abiotic and biotic stresses. The skipped part of integrated picture, however, was the evolutionary insight of salicylic acid to either allow or discard the microbial invasion depending upon various internal factors of two interactants under the prevailing external conditions. The metabolic status that allows the host invasion either as pathogenesis or symbiosis with possible intermediary stages in close systems has been tried to underpin here. PMID:22301975

  8. Folic acid

    MedlinePlus

    ... disease called vitiligo, and an inherited disease called Fragile-X syndrome. It is also used for reducing harmful side ... to blood clots (ischemic stroke). Inherited disease called Fragile-X syndrome.Taking folic acid by mouth does not improve ...

  9. Acid rain

    SciTech Connect

    Not Available

    1984-06-01

    An overview is presented of acid rain and the problems it causes to the environment worldwide. The acidification of lakes and streams is having a dramatic effect on aquatic life. Aluminum, present in virtually all forest soils, leaches out readily under acid conditions and interferes with the gills of all fish, some more seriously than others. There is evidence of major damage to forests in European countries. In the US, the most severe forest damage appears to be in New England, New York's Adirondacks, and the central Appalachians. This small region is part of a larger area of the Northeast and Canada that appears to have more acid rainfall than the rest of the country. It is downwind from major coal burning states, which produce about one quarter of US SO/sub 2/ emissions and one sixth of nitrogen oxide emissions. Uncertainties exist over the causes of forest damage and more research is needed before advocating expensive programs to reduce rain acidity. The President's current budget seeks an expansion of research funds from the current $30 million per year to $120 million.

  10. Formic acid

    Integrated Risk Information System (IRIS)

    Formic acid ; CASRN 64 - 18 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effect

  11. Selenious acid

    Integrated Risk Information System (IRIS)

    Selenious acid ; CASRN 7783 - 00 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic E

  12. Benzoic acid

    Integrated Risk Information System (IRIS)

    Benzoic acid ; CASRN 65 - 85 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effec

  13. Trichloroacetic acid

    Integrated Risk Information System (IRIS)

    Trichloroacetic acid ( TCA ) ; CASRN 76 - 03 - 9 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Nonca

  14. Dichloroacetic acid

    Integrated Risk Information System (IRIS)

    Dichloroacetic acid ; CASRN 79 - 43 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogeni

  15. Acrylic acid

    Integrated Risk Information System (IRIS)

    Acrylic acid ( CASRN 79 - 10 - 7 ) Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Eff

  16. Cacodylic acid

    Integrated Risk Information System (IRIS)

    Cacodylic acid ; CASRN 75 - 60 - 5 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Eff

  17. Phosphoric acid

    Integrated Risk Information System (IRIS)

    Phosphoric acid ; CASRN 7664 - 38 - 2 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic

  18. Stearic Acid

    ERIC Educational Resources Information Center

    Young, Jay A.

    2004-01-01

    A chemical laboratory information profile (CLIP) is presented for the chemical, stearic acid. The profile lists the chemical's physical and harmful characteristics, exposure limits, and symptoms of major exposure, for the benefit of teachers and students, who use the chemical in the laboratory.

  19. Investigation of gene expressions related to cholesterol metabolism in rats fed diets enriched in n-6 or n-3 fatty acid with a cholesterol after long-term feeding using quantitative-competitive RT-PCR analysis.

    PubMed

    Fukushima, M; Shimada, K; Ohashi, E; Saitoh, H; Sonoyama, K; Sekikawa, M; Nakano, M

    2001-06-01

    We have developed a method to quantitate hepatic apolipoprotein (apo) B, LDL receptor, 3-hydroxy-3-methylglutary coenzyme A reductase (HMG-CoA reductase) and cholesterol 7alpha-hydroxylase mRNA expression in rats fed a cholesterol-enriched diet after long-term feeding using competitive RT-RCR. Rats (8 wk of age) fed a conventional diet were shifted to diets containing 10% perilla oil (PEO, oleic acid+linoleic acid+alpha-linolenic acid), borage oil (BRO, oleic acid+linoleic acid+gamma-linolenic acid), evening primrose oil (EPO, linoleic acid+gamma-linolenic acid), mixed oil (MIO, oleic acid+linoleic acid+gamma-linolenic acid+alpha-linolenic acid), or palm oil (PLO, palmitic acid+oleic acid+linoleic acid) with 0.5% cholesterol for 15 wk. There were no significant differences in the food intake and body weight gain among the groups. The liver weight in the PEO and PLO groups was significantly higher than other groups. The serum total cholesterol and very low density lipoprotein (VLDL)+intermediate density lipoprotein (IDL)+low density lipoprotein (LDL)-cholesterol concentrations were consistently higher in PLO group than in the other groups. The serum high density lipoprotein cholesterol concentration was significantly lower in the PEO group than in the other groups. The liver cholesterol concentration group was significantly higher in the PEO than in the other groups. There were no significant differences in the hepatic LDL receptor mRNA level among the groups. Hepatic apo B, HMG-CoA reductase and cholesterol 7alpha-hydroxylase mRNA levels were not affected by the experimental conditions. However, hepatic cholesterol 7alpha-hydroxylase mRNA level in the PEO and MIO groups tended to be higher than in the other groups. The fecal cholesterol extraction was significantly higher in the MIO and PLO groups than in the PEO and EPO groups and the total bile acid extraction was significantly higher in the PEO and MIO groups than in the PLO group. The results of this study

  20. Purification and amino acid sequence of a highly insecticidal toxin from the venom of the brazilian spider Phoneutria nigriventer which inhibits NMDA-evoked currents in rat hippocampal neurones.

    PubMed

    de Figueiredo, S G; de Lima, M E; Nascimento Cordeiro, M; Diniz, C R; Patten, D; Halliwell, R F; Gilroy, J; Richardson, M

    2001-01-01

    A new insecticidal toxin Tx4(5-5) was isolated from the fraction PhTx4 of the venom of the spider Phoneutria nigriventer by reverse phase high performance liquid chromatography (HPLC) and anion exchange HPLC. The complete amino acid sequence determined by automated Edman degradation showed that Tx4(5-5) is a single chain polypeptide composed of 47 amino acid residues, including 10 cysteines, with a calculated molecular mass of 5175 Da. Tx4(5-5) shows 64% of sequence identity with Tx4(6-1), another insecticidal toxin from the same venom. Tx4(5-5) was highly toxic to house fly (Musca domestica), cockroach (Periplaneta americana) and cricket (Acheta domesticus ), producing neurotoxic effects (knock-down, trembling with uncoordinated movements) at doses as low as 50 ng/g (house fly), 250 ng/g (cockroach) and 150 ng/g (cricket). In contrast, intracerebroventricular injections (30 microg) into mice induced no behavioural effects. Preliminary electrophysiological studies carried out on whole-cell voltage-clamped rat hippocampal neurones indicated that Tx4(5-5) (at 1 microM) reversibly inhibited the N-methyl-D-aspartate-subtype of ionotropic glutamate receptor, while having little or no effect on kainate-, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid- or gamma-aminobutyric acid-activated currents. PMID:10978749

  1. Extraction of medium chain fatty acids from organic municipal waste and subsequent production of bio-based fuels.

    PubMed

    Kannengiesser, Jan; Sakaguchi-Söder, Kaori; Mrukwia, Timo; Jager, Johannes; Schebek, Liselotte

    2016-01-01

    This paper provides an overview on investigations for a new technology to generate bio-based fuel additives from bio-waste. The investigations are taking place at the composting plant in Darmstadt-Kranichstein (Germany). The aim is to explore the potential of bio-waste as feedstock in producing different bio-based products (or bio-based fuels). For this investigation, a facultative anaerobic process is to be integrated into the normal aerobic waste treatment process for composting. The bio-waste is to be treated in four steps to produce biofuels. The first step is the facultative anaerobic treatment of the waste in a rotting box namely percolate to generate a fatty-acid rich liquid fraction. The Hydrolysis takes place in the rotting box during the waste treatment. The organic compounds are then dissolved and transferred into the waste liquid phase. Browne et al. (2013) describes the hydrolysis as an enzymatically degradation of high solid substrates to soluble products which are further degraded to volatile fatty acids (VFA). This is confirmed by analytical tests done on the liquid fraction. After the percolation, volatile and medium chain fatty acids are found in the liquid phase. Concentrations of fatty acids between 8.0 and 31.5 were detected depending on the nature of the input material. In the second step, a fermentation process will be initiated to produce additional fatty acids. Existing microorganism mass is activated to degrade the organic components that are still remaining in the percolate. After fermentation the quantity of fatty acids in four investigated reactors increased 3-5 times. While fermentation mainly non-polar fatty acids (pentanoic to octanoic acid) are build. Next to the fermentation process, a chain-elongation step is arranged by adding ethanol to the fatty acid rich percolate. While these investigations a chain-elongation of mainly fatty acids with pair numbers of carbon atoms (acetate, butanoic and hexanoic acid) are demonstrated. After

  2. A comparison of skin delivery of ferulic acid and its derivatives: evaluation of their efficacy and safety.

    PubMed

    Zhang, Li-Wen; Al-Suwayeh, Saleh A; Hsieh, Pei-Wen; Fang, Jia-You

    2010-10-31

    Ferulic acid (FA) can be used as an antioxidant to prevent damage from ultraviolet (UV) radiation and skin carcinogenesis. To this end, the feasibility of the skin absorption of FA and its derivatives was evaluated in the present study. The percutaneous absorption of five compounds into/across porcine skin was measured and compared using Franz diffusion cells. The skin delivery from pH 6 and 9.9 buffers was the highest for ferulic acid ethyl ether (FAEE), followed by coniferyl aldehyde (CD), coniferyl alcohol (CA), FA, and 3-hydroxy-4-methoxycinnamic acid (HMA). The skin deposition and flux of FAEE with a pH 6 buffer were 136 nmol/g and 26 nmol/cm(2)/h, respectively. No significant difference in permeation profiles was observed between the two pH buffers. According to permeation via the skin with different treatments (delipidization, ethanol, and oleic acid treatments), it was determined that the lipid bilayers in the stratum corneum (SC) comprised the predominant barrier for FA permeation. On the other hand, FAEE could easily partition into and penetrate across the skin through intercellular pathways. Nude mouse was used as an in vivo animal model to examine the amount of permeants remaining in the skin. The in vivo skin deposition was generally correlated with the in vitro results. The in vivo skin deposition of FAEE (145 nmol/g) was comparable to that of CD (150 nmol/g). The safety study which examined transepidermal water loss (TEWL), erythema, and the skin pH value demonstrated that the topical application of FA and related compounds for up to 24h did not cause skin irritation. It can be concluded that topical delivery may serve as an efficient and safe route for FA and its derivatives against photodamage. PMID:20692328

  3. Regulation of mevalonate synthesis in rat mammary glands by dietary n-3 and n-6 polyunsaturated fatty acids.

    PubMed

    El-Sohemy, A; Archer, M C

    1997-09-01

    It is well established that dietary n-6 polyunsaturated fatty acids (PU-FAs) enhance rat mammary tumor development whereas n-3 PUFAs inhibit it, yet the mechanisms are unclear. The objective of this study was to investigate a mechanism by which n-3 and n-6 PUFAs could modulate mammary carcinogenesis. Female Sprague Dawley rats were fed diets containing either menhaden (n-3) or safflower oil (n-6) in a 7% fat diet for 1 week. In comparison to the n-6 diet, the n-3 diet significantly reduced the activity and levels of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in mammary glands, thereby suppressing the formation of mevalonate. In addition to being essential for cholesterol biosynthesis, mevalonate is also required for DNA synthesis and may be involved in malignant transformation. Serum cholesterol was lower in the n-3 group than in the n-6 group (1.91 +/- 0.18 versus 2.61 +/- 0.37 mM; P < 0.01). Extrahepatic tissues meet most of their cholesterol requirements from circulating cholesterol, and the internalized cholesterol down-regulates HMG-CoA reductase. Thus, the concomitant decrease in serum cholesterol and mammary gland HMG-CoA reductase levels suggests that changes in circulating cholesterol levels do not solely determine the activity of extrahepatic reductase. We conclude that the mevalonate pathway may be a mechanism through which different types of dietary fat modulate breast cancer development. PMID:9288773

  4. Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

    PubMed Central

    Liepinsh, E; Makrecka-Kuka, M; Kuka, J; Vilskersts, R; Makarova, E; Cirule, H; Loza, E; Lola, D; Grinberga, S; Pugovics, O; Kalvins, I; Dambrova, M

    2015-01-01

    Background and Purpose The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia–reperfusion injury. Key Results In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg−1) decreased the infarct size by 45–48%. In vivo pretreatment with Methyl-GBB (20 mg·kg−1) attenuated the infarct size by 45% and improved 24 h survival of rats by 20–30%. Conclusions and Implications Reduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia–reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism. PMID:25363063

  5. Hydroxycarboxylic acids and salts

    DOEpatents

    Kiely, Donald E; Hash, Kirk R; Kramer-Presta, Kylie; Smith, Tyler N

    2015-02-24

    Compositions which inhibit corrosion and alter the physical properties of concrete (admixtures) are prepared from salt mixtures of hydroxycarboxylic acids, carboxylic acids, and nitric acid. The salt mixtures are prepared by neutralizing acid product mixtures from the oxidation of polyols using nitric acid and oxygen as the oxidizing agents. Nitric acid is removed from the hydroxycarboxylic acids by evaporation and diffusion dialysis.

  6. Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over beta-oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states.

    PubMed Central

    Drynan, L; Quant, P A; Zammit, V A

    1996-01-01

    The Flux Control Coefficients of mitochondrial outer membrane carnitine palmitoyltransferase (CPT I) with respect to the overall rates of beta-oxidation, ketogenesis and tricarboxylic acid cycle activity were measured in hepatocytes isolated from rats in different metabolic states (fed, 24 h-starved, starved-refed and starved/insulin-treated). These conditions were chosen because there is controversy as to whether, when significant control ceases to be exerted by CPT I over the rate of fatty oxidation [Moir and Zammit (1994) Trends Biochem. Sci. 19, 313-317], this is transferred to one or more steps proximal to acylcarnitine synthesis (e.g. decreased delivery of fatty acids to the liver) or to the reaction catalysed by mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA synthase [Hegardt (1995) Biochem. Soc. Trans. 23, 486-490]. Therefore isolated hepatocytes were used in the present study to exclude the involvement of changes in the rate of delivery of non-esterified fatty acids (NEFA) to the liver, such as occur in vivo, and to ascertain whether, under conditions of constant supply of NEFA, CPT I retains control over the relevant fluxes of fatty acid oxidation to ketones and carbon dioxide, or whether control is transferred to another (intrahepatocytic) site. The results clearly show that the Flux Control Coefficients of CPT I with respect to overall beta-oxidation and ketogenesis are very high under all conditions investigated, indicating that control is not lost to another intrahepatic site during the metabolic transitions studied. The control of CPT I over tricarboxylic acid cycle activity was always very low. The significance of these findings for the integration of fatty acid and carbohydrate metabolism in the liver is discussed. PMID:8760364

  7. Vanillic acid prevents the deregulation of lipid metabolism, endothelin 1 and up regulation of endothelial nitric oxide synthase in nitric oxide deficient hypertensive rats.

    PubMed

    Kumar, Subramanian; Prahalathan, Pichavaram; Saravanakumar, Murugesan; Raja, Boobalan

    2014-11-15

    Hypertension is one of the main factors causing cardiovascular diseases. The present study was designed to evaluate the protective effect of vanillic acid against nitric oxide deficient rats. Hypertension was induced in adult male albino rats of Wistar strain, weighing 180-220g, by oral administration of N(ω)-nitro-l arginine methyl ester (l-NAME) 40mg/kg in drinking water for 4 weeks. Vanillic acid was administered orally at a dose of 50mg/kg b.w. Nitric oxide deficient rats showed increased levels of mean arterial pressure (MAP), heart rate (HR) and decreased heart nitric oxide metabolites (NOx). A significant increase in the levels of plasma cholesterol, low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein-cholesterol (VLDL-C), triglycerides (TG), free fatty acids (FFA), phospholipids (PL), 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase in the plasma, liver and kidney and decreased level of high density lipoprotein-cholesterol (HDL-C) are observed, whereas there is a decrease in the activities of plasma lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) in nitric oxide deficient rats. l-NAME rats also showed an increase in TC, TG, FFA and PL levels in the liver and kidney tissues. Vanillic acid treatment brought the above parameters towards near normal level. Moreover the down regulated endothelial nitric oxide synthase (eNOS) and up regulated expression of endothelin 1 (ET1) components was also attenuated by vanillic acid treatment. All the above outcomes were confirmed by the histopathological examination. These results suggest that vanillic acid has enough potential to attenuate hypertension, dyslipidemia and hepatic and renal damage in nitric oxide deficient rats. PMID:25239071

  8. An experimental and theoretical investigation of the photophysics of 1-hydroxy-2-naphthoic acid.

    PubMed

    Mishra, H; Maheshwary, S; Tripathi, H B; Sathyamurthy, N

    2005-03-31

    Photophysical and photochemical properties of 1-hydroxy-2-naphthoic acid (1,2-HNA) have been investigated experimentally by steady state and time domain fluorescence measurements and theoretically by Hartree-Fock (HF), configuration interaction at the single excitation (CIS) level, density functional theoretic (DFT), and semiempirical (AM1) methods. 1,2-HNA exhibits normal fluorescence that depends on its concentration, nature of the solvent, pH, temperature, and wavelength of excitation. It seems to form different emitting species in different media, akin to 3-hydroxy-2-naphthoic acid (3,2-HNA). The large Stokes shifted emission observed at pH 13 is attributed to species undergoing excited-state intramolecular proton transfer. Nonradiative transition seems to increase on protonation and decrease on deprotonation. AM1(PECI=8) calculations predict the absorption maximum (lambda(max) = 335.9 nm) in reasonable agreement with experiment (lambda(max) = 352 nm) for the neutral 1,2-HNA. They also predict a red shift in absorption on protonation and a blue shift on deprotonation as observed experimentally. CIS calculations tend to overestimate the energy gap and hence underestimate the absorption maxima between the ground and the excited electronic states of 1,2-HNA and its protonated and deprotonated forms. However, they do predict correctly that the excited state intramolecular proton transfer is likely to occur in the deprotonated form of 1,2-HNA and not in the neutral and the protonated forms. A single minimum is found in the potential energy profile for the ground state as well as the first excited state of 1,2-HNA and its protonated species. In contrast, a double minimum with a nominal barrier in between is predicted for the ground state and also the first three excited states of the deprotonated species. The keto form of the deprotonated species is found to be slightly less stable than the enol form in all the states investigated. PMID:16833586

  9. Analysis of Mycosporine-Like Amino Acids in Selected Algae and Cyanobacteria by Hydrophilic Interaction Liquid Chromatography and a Novel MAA from the Red Alga Catenella repens

    PubMed Central

    Hartmann, Anja; Becker, Kathrin; Karsten, Ulf; Remias, Daniel; Ganzera, Markus

    2015-01-01

    Mycosporine-like amino acids (MAAs), a group of small secondary metabolites found in algae, cyanobacteria, lichens and fungi, have become ecologically and pharmacologically relevant because of their pronounced UV-absorbing and photo-protective potential. Their analytical characterization is generally achieved by reversed phase HPLC and the compounds are often quantified based on molar extinction coefficients. As an alternative approach, in our study a fully validated hydrophilic interaction liquid chromatography (HILIC) method is presented. It enables the precise quantification of several analytes with adequate retention times in a single run, and can be coupled directly to MS. Excellent linear correlation coefficients (R2 > 0.9991) were obtained, with limit of detection (LOD) values ranging from 0.16 to 0.43 µg/mL. Furthermore, the assay was found to be accurate (recovery rates from 89.8% to 104.1%) and precise (intra-day precision: 5.6%, inter-day precision ≤6.6%). Several algae were assayed for their content of known MAAs like porphyra-334, shinorine, and palythine. Liquid chromatography-mass spectrometry (LC-MS) data indicated a novel compound in some of them, which could be isolated from the marine species Catenella repens and structurally elucidated by nuclear magnetic resonance spectroscopy (NMR) as (E)-3-hydroxy-2-((5-hydroxy-5-(hydroxymethyl)-2-methoxy-3-((2-sulfoethyl)amino)cyclohex-2-en-1-ylidene)amino) propanoic acid, a novel MAA called catenelline. PMID:26473886

  10. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers

    PubMed Central

    Kwan, Hiu Yee; Niu, Xuyan; Dai, Wenlin; Tong, Tiejun; Chao, Xiaojuan; Su, Tao; Chan, Chi Leung; Lee, Kim Chung; Fu, Xiuqiong; Yi, Hua; Yu, Hua; Li, Ting; Tse, Anfernee Kai Wing; Fong, Wang Fun; Pan, Si-Yuan; Lu, Aiping; Yu, Zhi-Ling

    2015-01-01

    Schisandrin B (SchB) is one of the most abundant bioactive dibenzocyclooctadiene derivatives found in the fruit of Schisandra chinensis. Here, we investigated the potential therapeutic effects of SchB on non-alcoholic fatty-liver disease (NAFLD). In lipidomic study, ingenuity pathway analysis highlighted palmitate biosynthesis metabolic pathway in the liver samples of SchB-treated high-fat-diet-fed mice. Further experiments showed that the SchB treatment reduced expression and activity of fatty acid synthase, expressions of hepatic mature sterol regulatory element binding protein-1 and tumor necrosis factor-α, and hepatic level of palmitic acid which is known to promote progression of steatosis to steatohepatitis. Furthermore, the treatment also reduced hepatic fibrosis, activated nuclear factor-erythroid-2-related factor-2 which is known to attenuate the progression of NASH-related fibrosis. Interestingly, in fasting mice, a single high-dose SchB induced transient lipolysis and increased the expressions of adipose triglyceride lipase and phospho-hormone sensitive lipase. The treatment also increased plasma cholesterol levels and 3-hydroxy-3-methylglutaryl-CoA reductase activity, reduced the hepatic low-density-lipoprotein receptor expression in these mice. Our data not only suggest SchB is a potential therapeutic agent for NAFLD, but also provided important information for a safe consumption of SchB because SchB overdosed under fasting condition will have adverse effects on lipid metabolism. PMID:25766252

  11. Analysis of Mycosporine-Like Amino Acids in Selected Algae and Cyanobacteria by Hydrophilic Interaction Liquid Chromatography and a Novel MAA from the Red Alga Catenella repens.

    PubMed

    Hartmann, Anja; Becker, Kathrin; Karsten, Ulf; Remias, Daniel; Ganzera, Markus

    2015-10-01

    Mycosporine-like amino acids (MAAs), a group of small secondary metabolites found in algae, cyanobacteria, lichens and fungi, have become ecologically and pharmacologically relevant because of their pronounced UV-absorbing and photo-protective potential. Their analytical characterization is generally achieved by reversed phase HPLC and the compounds are often quantified based on molar extinction coefficients. As an alternative approach, in our study a fully validated hydrophilic interaction liquid chromatography (HILIC) method is presented. It enables the precise quantification of several analytes with adequate retention times in a single run, and can be coupled directly to MS. Excellent linear correlation coefficients (R² > 0.9991) were obtained, with limit of detection (LOD) values ranging from 0.16 to 0.43 µg/mL. Furthermore, the assay was found to be accurate (recovery rates from 89.8% to 104.1%) and precise (intra-day precision: 5.6%, inter-day precision ≤6.6%). Several algae were assayed for their content of known MAAs like porphyra-334, shinorine, and palythine. Liquid chromatography-mass spectrometry (LC-MS) data indicated a novel compound in some of them, which could be isolated from the marine species Catenella repens and structurally elucidated by nuclear magnetic resonance spectroscopy (NMR) as (E)-3-hydroxy-2-((5-hydroxy-5-(hydroxymethyl)-2-methoxy-3-((2-sulfoethyl)amino)cyclohex-2-en-1-ylidene)amino) propanoic acid, a novel MAA called catenelline. PMID:26473886

  12. 21 CFR 74.1334 - D&C Red No. 34.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... sulfates (calculated at sodium salts), not more than 15 percent. 2-Amino-1-naphthalenesulfonic acid, calcium salt, not more than 0.2 percent. 3-Hydroxy-2-naphthoic acid, not more than 0.4 percent. Subsidiary... Red No. 34 is principally the calcium salt of 3-hydroxy-4- -2-naphthalene-carboxylic acid. (2)...

  13. 21 CFR 74.1334 - D&C Red No. 34.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... sulfates (calculated at sodium salts), not more than 15 percent. 2-Amino-1-naphthalenesulfonic acid, calcium salt, not more than 0.2 percent. 3-Hydroxy-2-naphthoic acid, not more than 0.4 percent. Subsidiary... Red No. 34 is principally the calcium salt of 3-hydroxy-4- -2-naphthalene-carboxylic acid. (2)...

  14. 21 CFR 74.1334 - D&C Red No. 34.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... sulfates (calculated at sodium salts), not more than 15 percent. 2-Amino-1-naphthalenesulfonic acid, calcium salt, not more than 0.2 percent. 3-Hydroxy-2-naphthoic acid, not more than 0.4 percent. Subsidiary... Red No. 34 is principally the calcium salt of 3-hydroxy-4- -2-naphthalene-carboxylic acid. (2)...

  15. Methylmalonic acid blood test

    MedlinePlus

    ... acid is a substance produced when proteins, called amino acids, in the body break down. The health care ... Cederbaum S, Berry GT. Inborn errors of carbohydrate, ammonia, amino acid, and organic acid metabolism. In: Gleason CA, Devaskar ...

  16. Folic acid - test

    MedlinePlus

    Folic acid is a type of B vitamin. This article discusses the test to measure the amount of folic acid in the blood. ... that may interfere with test results, including folic acid supplements. Drugs that can decrease folic acid measurements ...

  17. Uric acid urine test

    MedlinePlus

    The uric acid urine test measures the level of uric acid in urine. Uric acid level can also be checked using a blood ... help determine the cause of a high uric acid level in the blood. It may also be ...

  18. Methylmalonic acid blood test

    MedlinePlus

    The methylmalonic acid blood test measures the amount of methylmalonic acid in the blood. ... Methylmalonic acid is a substance produced when proteins, called amino acids, in the body break down. The health care ...

  19. Folic Acid and Pregnancy

    MedlinePlus

    ... 5 Things to Know About Zika & Pregnancy Folic Acid and Pregnancy KidsHealth > For Parents > Folic Acid and ... before conception and during early pregnancy . About Folic Acid Folic acid, sometimes called folate, is a B ...

  20. Anti-inflammatory potential of ursolic acid in Mycobacterium tuberculosis-sensitized and concanavalin A-stimulated cells.

    PubMed

    Zerin, Tamanna; Lee, Minjung; Jang, Woong Sik; Nam, Kung-Woo; Song, Ho-Yeon

    2016-03-01

    Ursolic acid (3-β-3-hydroxy-urs-12-ene-28-oic-acid; UA) is a triterpenoid carboxylic acid with various pharmaceutical properties. It is commonly found in apples, basil, berries, rosemary, peppermint, lavender, oregano, thyme, hawthorn and prunes. In the present study, the activities of UA against the Mycobacterium tuberculosis H37Rv‑induced release of a panel of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 from RAW 264.7 murine macrophages, A549 alveolar epithelial cells and in concanavalin A (Con A)-stimulated rat splenocytes were investigated. In addition, the present study examined the ability of UA to reduce the expression levels of the inflammatory mediators, cyclooxygenase‑2 (COX‑2) and inducible nitric oxide synthase (iNOS) in the stimulated cells. The reduction of nitric oxide (NO) release by UA was also examined in the stimulated cells. UA significantly inhibited the mRNA expression levels of TNF‑α, IL‑1β and IL‑6 in the stimulated cells. The expression levels of COX‑2 and iNOS were also suppressed by UA, as was the release of NO at a significant level. The data indicated the potency of UA on different cell types, which may assist in the development of anti‑inflammatory drugs. In the case of adjunct host‑directed immune therapy for tuberculosis, UA may be used, in addition to established antibiotic therapies, to improve treatment efficacy and outcome due to their anti‑inflammatory potential. Further detailed investigations are required to establish its use as an anti-inflammatory. PMID:26847129

  1. The seeds from Plantago ovata lower plasma lipids by altering hepatic and bile acid metabolism in guinea pigs.

    PubMed

    Romero, Ana Lourdes; West, Kristy L; Zern, Tosca; Fernandez, Maria Luz

    2002-06-01

    Psyllium, the husks from Plantago ovata (PO), is recognized as a potent agent in lowering plasma cholesterol. In this study, we tested the potential hypolipidemic effects of the seeds from PO and the mechanisms associated with the lowering of plasma lipids. Male Hartley guinea pigs (n = 30; 10 per group) were fed either a control diet or diets containing 7.5 or 10 g/100 g PO for 4 wk. Diets were identical in composition except for the fiber source. The control diet contained 10 g/100 g cellulose and 2.5 g/100 g guar gum, whereas the PO diets were adjusted to a total of 12.5 g/100 g fiber with cellulose. Although a dose response was not observed, plasma triglycerides and LDL cholesterol were 34 and 23% lower in the PO groups compared with the control (P < 0.01). Lecithin cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activities were significantly affected by the PO diets. The control group had 100 and 36% higher LCAT and CETP (P < 0.01) activities, respectively, compared with the PO groups. Hepatic total and free cholesterol concentrations were not affected by PO, but cholesteryl ester concentrations were 50% (P < 0.01) lower in the PO groups compared with the control. The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis was up-regulated in the PO groups by 37%. Similarly, the activity of cholesterol 7alpha-hydroxylase, the regulatory enzyme of cholesterol catabolism to bile acids was 33% higher in the PO groups (P < 0.02). Fecal bile acids were 3 times higher in the PO groups than in the control group. These results suggest that PO exerts its hypolipidemic effect by affecting bile acid absorption and altering hepatic cholesterol metabolism. PMID:12042433

  2. Analysis of polyanionic macromolecular carrier poly-(N-vinylpyrrolidone-co-maleic acid) and its bioconjugats by capillary electrophoresis.

    PubMed

    Györffy, E; Pató, J; Horváth, A; Erchegyi, J; Teplán, I; Kéri, G; Idei, M

    1998-02-01

    Anionic carrier poly(N-vinylpyrrolidone-co-maleic acid) and its conjugates, prepared with coupling of 2-cyano-3-hydroxy-5-amino-2-pentenoyc(4-trifluoromethyl anilide) or (6', 7'-dimethyl-l'-quinoxalinyl)-4-(2' amino) acetanilide to the carrier, were analyzed by capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC) in the following buffers: 0.25 N triethylammonium phosphate (TEAP); sodium dodecyl sulfate (SDS; 25-150 mM) in TEAP (pH 2.25-6.30); 0.1 N Na-borate buffer (pH range 7-11) and SDS (25-150 mM) in Na-borate buffer (pH range 7-11). The presence of strong carboxyl groups (dissociated even at pH 2.25) on the polymer chain was proved by the CZE method. It was also proved by potentiometric titration that carboxyls with a wide range of acidity were on the polymer chain. CZE was able to differentiate among the analytes possessing carboxyl groups of different acidic strengths at pH 2.25. These components were not distinguished by CZE at high pH values (11.0). Interaction between the analyte and SDS affected the separation at this pH, and hence good resolution was obtained by MEKC. Informative separations were achieved both for the carrier and the conjugates in TEAP buffer at pH 2.25 by the CZE method. Optimal separation was achieved in borate buffer containing 75 mM SDS at pH 11.0 for the carrier and at pH 7.7 for the conjugates in MEKC. PMID:9548294

  3. Understanding Acid Rain

    ERIC Educational Resources Information Center

    Damonte, Kathleen

    2004-01-01

    The term acid rain describes rain, snow, or fog that is more acidic than normal precipitation. To understand what acid rain is, it is first necessary to know what an acid is. Acids can be defined as substances that produce hydrogen ions (H+), when dissolved in water. Scientists indicate how acidic a substance is by a set of numbers called the pH…

  4. New bioactive fatty acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many oxygenated fatty acids are bioactive compounds. Nocardia cholesterolicum and Flavobacterium DS5 convert oleic acid to 10 hydroxy stearic acid and linoleic acid to 10-hydroxy-12(Z)-octadecanoic acid. Pseudomonas aeruginosa PR3 converts oleic acid to the new compounds, 7,10-dihydroxy-8(E)-octad...

  5. New Bioactive Fatty Acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Many oxygenated fatty acids are bioactive compounds. Nocardia cholesterolicum and Flavobacterium DS5 convert oleic acid to 10 hydroxy stearic acid and linoleic acid to 10-hydroxy-12(Z)-octadecanoic acid. Pseudomonas aeruginosa PR3 converts oleic acid to new compounds, 7,10-dihydroxy-8(E)-octadecen...

  6. Metabolic biology of 3-methylglutaconic acid-uria: a new perspective

    PubMed Central

    Su, Betty; Ryan, Robert O.

    2014-01-01

    Summary Over the past twenty-five years a growing number of distinct syndromes / mutations associated with compromised mitochondrial function have been identified that share a common feature: urinary excretion of 3-methylglutaconic acid (3MGA). In the leucine degradation pathway, carboxylation of 3-methylcrotonyl CoA leads to formation of 3-methylglutaconyl CoA while 3-methylglutaconyl CoA hydratase converts this metabolite to 3-hydroxy-3-methylglutaryl CoA (HMG CoA). In “primary” 3MGA-uria, mutations in the hydratase are directly responsible for the accumulation of 3MGA. On the other hand, in all “secondary” 3MGA-urias, no defect in leucine catabolism exists and the metabolic origin of 3MGA is unknown. Herein, a path to 3MGA from mitochondrial acetyl CoA is proposed. The pathway is initiated when syndrome-associated mutations / DNA deletions result in decreased Krebs cycle flux. When this occurs, acetoacetyl CoA thiolase condenses two acetyl CoA into acetoacetyl CoA plus CoASH. Subsequently, HMG CoA synthase 2 converts acetoacetyl CoA and acetyl CoA to HMG CoA. Under syndrome-specific metabolic conditions, 3-methylglutaconyl CoA hydratase converts HMG CoA into 3-methylglutaconyl CoA in a reverse reaction of the leucine degradation pathway. This metabolite fails to proceed further up the leucine degradation pathway owing to the kinetic properties of 3-methylcrotonyl CoA carboxylase. Instead, hydrolysis of the CoA moiety of 3-methylglutaconyl CoA generates 3MGA, which appears in urine. If experimentally confirmed, this pathway provides an explanation for the occurrence of 3MGA in multiple disorders associated with compromised mitochondrial function. PMID:24407466

  7. Bioactive Fatty Acids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Oxygenated fatty acids are useful as specialty chemicals, plasticizers, and biomedicals. Microbial enzymes convert fatty acids to mono-, di-, and trihydroxy fatty acid products. Among them, Bacillus megaterium ALA2 converted n-6 and n-3 PUFAs to many new oxygenated fatty acids. Linoleic acid was ...

  8. Further improvement in ganoderic acid production in static liquid culture of Ganoderma lucidum by integrating nitrogen limitation and calcium ion addition.

    PubMed

    Li, Huan-Jun; Zhang, De-Huai; Han, Li-Liang; Yu, Xuya; Zhao, Peng; Li, Tao; Zhong, Jian-Jiang; Xu, Jun-Wei

    2016-01-01

    To further improve the ganoderic acid (GA) production, a novel integrated strategy by combining nitrogen limitation and calcium ion addition was developed. The effects of the integrated combination on the content of GA-T (one powerful anticancer compound), their intermediates (squalene and lanosterol) and on the transcription levels of GA biosynthetic genes in G. lucidum fermentation were investigated. The maximum GA-T content with the integrated strategy were 1.87 mg/ 100 mg dry cell weight, which was 2.1-4.2 fold higher than that obtained with either calcium ion addition or nitrogen limitation alone, and it is also the highest record as ever reported in submerged fermentation of G. lucidum. The squalene content was increased by 3.9- and 2.2-fold in this case compared with either individual strategy alone. Moreover, the transcription levels of the GA biosynthetic genes encoding 3-hydroxy-3-methyglutaryl coenzyme A reductase and lanosterol synthase were also up-regulated by 3.3-7.5 and 1.3-2.3 fold, respectively. PMID:26508324

  9. Activation of the central pattern generators for locomotion by serotonin and excitatory amino acids in neonatal rat.

    PubMed Central

    Cazalets, J R; Sqalli-Houssaini, Y; Clarac, F

    1992-01-01

    1. The role of serotonin (5-HT) and excitatory amino-acids (EAAs) in the activation of the neural networks (i.e. the central pattern generators) that organize locomotion in mammals was investigated in an isolated brainstem-spinal cord preparation from the newborn rat. 2. The neuroactive substances were bath applied and the activity of fictive locomotion was recorded in the ventral roots. 3. Serotonin initiated an alternating pattern of right and left action potential bursts. The period of this rhythm was dose dependent, i.e. it decreased from around 10 s at 2 x 10(-5) M to 5 s at 10(-4) M. The effects of serotonin were blocked by a 5-HT1 antagonist (propranolol) and by 5-HT2 antagonists (ketanserin, cyproheptadine, mianserin). 5-HT3 antagonists were ineffective. The effects of methoxytryptamine, a non-selective 5-HT agonist, mimicked the 5-HT effects. 4. The endogenous EAAs, glutamate and aspartate, also triggered an alternating rhythmic pattern. Their effects were blocked by 2-amino-5-phosphonovaleric acid (AP-5; a N-methyl-D-aspartate (NMDA) receptor blocker) and 6,7-dinitro-quinoxaline-2,3-dione (a non-NMDA receptor blocker). 5. Several EAA agonists (N-methyl-D,L-aspartate (NMA) and kainate) initiated rhythmic activity. The period of the induced rhythm (from 3 to 1 s) was similar with both of these substances but in a range of concentrations which was ten times lower in the case of kainate (10(-6) to 5 x 10(-6) M) than in that of NMA (10(-5) to 4 x 10(-5) M). alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionate and quisqualate occasionally triggered some episodes of fictive locomotion with a threshold at 6 x 10(-7) and 10(-5) M, respectively. PMID:1362441

  10. Crystal structure of (2S/2R,3S/3R)-3-hydroxy-2-phenyl-chroman-4-one.

    PubMed

    Belguedj, Roumaissa; Bouacida, Sofiane; Merazig, Hocine; Chibani, Aissa; Bouraiou, Abdelmalek

    2015-02-01

    In the title mol-ecule, C15H12O3, the C atoms bearing the hy-droxy group and the phenyl ring are disordered over two sets of sites with refined occupancies of 0.573 (7) and 0.427 (7). There is also disorder of the phenyl ring but the hy-droxy group was refined as ordered. The dihedral angles between the benzene ring of the chromane ring system and the phenyl ring are 89.7 (2)° for the major component of disorder and 72.1 (3)° for the minor component. Both disorder components of the the di-hydro-pyran ring are in a half-chair conformation. In the crystal, mol-ecules are linked by pairs of O-H⋯O hydrogen bonds, forming inversion dimers with an R 2 (2)(10) graph-set motif. Weak C-H⋯π inter-actions link these dimers into ladders along [001]. PMID:25878868

  11. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduces thrombolytic-induced intracerebral hemorrhage in embolized rabbits.

    PubMed

    Lapchak, Paul A; Han, Moon Ku

    2009-12-15

    Statins were designed as cholesterol-lowering drugs for the prevention of coronary artery disease. It is estimated that there are currently 33.5 million U.S. patients on chronic statin treatment regimens. Recently, statins have been shown to have pleiotropic including anti-inflammatory and neuroprotective effects. In this study, we assessed the pharmacological effects of simvastatin administered alone and in combination with tissue plasminogen activator (tPA) on measures of ischemia and hemorrhage in large clot embolized New Zealand white rabbits. For these studies, simvastatin (20 mg/kg, SC in DMSO) was administered 24 and 4 h prior to large clot embolization in order to achieve a "loading dose" pretreatment with the drug. In combination studies, tPA (3.3 mg/kg, IV) was administered 1 h following embolization. Intravenous tPA administration significantly increased hemorrhage volume by 175% (p=0.015) and hemorrhage incidence by 60% (p>0.05) compared to control, but did not affect infarct incidence or volume. Simvastatin treatment significantly decreased tPA-induced hemorrhage incidence (p=0.022) and volume (p=0.0001) following embolization. The study suggests that simvastatin treatment blocks or attenuates mechanisms involved in tPA-induced hemorrhage. Based upon our results, patients on simvastatin treatment may have significantly reduced tPA-induced side effects should they require tPA administration following an embolic stroke. PMID:19781532

  12. Sensitive spectrophotometric assay for 3-hydroxy-substituted flavonoids, based on their binding with molybdenum, antimony, or bismuth.

    PubMed

    Viswanathan, P; Sriram, V; Yogeeswaran, G

    2000-07-01

    A sensitive spectrophotometric assay has been developed for flavonoids based on their binding with molybdenum, antimony, or bismuth. Acetylation of the hydroxyl group of flavonoids abolished metal binding, thus suggesting a direct role of the hydroxyl groups. From a comparison of several related flavonoids differing in the position of hydroxyl substitutions, the hydroxyl group at position 3 was found to be an important requirement for the formation of a yellow complex. This flavonoid metal complex showed that a specific and significant bathochromic shift in the visible spectrum of the native flavonoid and the corresponding lambda(max) value was used for the colorimetric assays with different metal salts. The molybdenum complex was found to yield higher absorbance compared to antimony and bismuth complexes of various flavonoids. The present method offers a sensitive assay in the 5-25 nM range for these flavonoids and gave comparable results with HPLC quantitative determination. PMID:10898625

  13. Uric acid test (image)

    MedlinePlus

    Uric acid urine test is performed to check for the amount of uric acid in urine. Urine is collected over a 24 ... testing. The most common reason for measuring uric acid levels is in the diagnosis or treatment of ...

  14. Amino Acid Metabolism Disorders

    MedlinePlus

    ... defects & other health conditions > Amino acid metabolism disorders Amino acid metabolism disorders E-mail to a friend Please ... baby’s newborn screening may include testing for certain amino acid metabolism disorders. These are rare health conditions that ...

  15. Plasma amino acids

    MedlinePlus

    Amino acids blood test ... types of methods used to determine the individual amino acid levels in the blood. ... test is done to measure the level of amino acids in the blood. An increased level of a ...

  16. Stomach acid test

    MedlinePlus

    Gastric acid secretion test ... of the cells in the stomach to release acid. The stomach contents are then removed and analyzed. ... 3.5). These numbers are converted to actual acid production in units of milliequivalents per hour in ...

  17. Azelaic Acid Topical

    MedlinePlus

    Azelaic acid gel is used to clear the bumps, lesions, and swelling caused by rosacea (a skin disease that ... redness, flushing, and pimples on the face). Azelaic acid cream is used to treat acne. Azelaic acid ...

  18. Facts about Folic Acid

    MedlinePlus

    ... Information For... Media Policy Makers Facts About Folic Acid Language: English Español (Spanish) Recommend on Facebook Tweet ... of the baby's brain and spine. About folic acid Folic acid is a B vitamin. Our bodies ...

  19. Acid Lipase Disease

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Acid Lipase Disease Information Page Synonym(s): Cholesterol Ester Storage ... Trials Related NINDS Publications and Information What is Acid Lipase Disease ? Acid lipase disease or deficiency occurs ...

  20. Folic acid - test

    MedlinePlus

    ... folic acid measurements include: Alcohol Aminosalicylic acid Birth control pills Estrogens Tetracyclines Ampicillin Chloramphenicol Erythromycin Methotrexate Penicillin Aminopterin Phenobarbital Phenytoin Drugs to treat malaria

  1. Oxalic acid poisoning

    MedlinePlus

    Symptoms of oxalic acid poisoning include: Abdominal pain Burns and blisters where the acid contacted the skin Collapse Convulsions Mouth pain Shock Throat pain Tremors (unintentional trembling) Vomiting

  2. Acid distribution in phosphoric acid fuel cells

    SciTech Connect

    Okae, I.; Seya, A.; Umemoto, M.

    1996-12-31

    Electrolyte acid distribution among each component of a cell is determined by capillary force when the cell is not in operation, but the distribution under the current load conditions had not been clear so far. Since the loss of electrolyte acid during operation is inevitable, it is necessary to store enough amount of acid in every cell. But it must be under the level of which the acid disturbs the diffusion of reactive gases. Accordingly to know the actual acid distribution during operation in a cell is very important. In this report, we carried out experiments to clarify the distribution using small single cells.

  3. Acid tolerance in amphibians

    SciTech Connect

    Pierce, B.A.

    1985-04-01

    Studies of amphibian acid tolerance provide information about the potential effects of acid deposition on amphibian communities. Amphibians as a group appear to be relatively acid tolerant, with many species suffering increased mortality only below pH 4. However, amphibians exhibit much intraspecific variation in acid tolerance, and some species are sensitive to even low levels of acidity. Furthermore, nonlethal effects, including depression of growth rates and increases in developmental abnormalities, can occur at higher pH.

  4. Chemical characterization of Brickellia cavanillesii (Asteraceae) using gas chromatographic methods

    PubMed Central

    Eshiet, Etetor R; Zhu, Jinqiu; Anderson, Todd A; Smith, Ernest E

    2014-01-01

    A methanol extract of lyophilized Brickellia cavanillesii was quantitatively analyzed using gas chromatographic (GC) techniques. The chromatographic methods employed were (i) GC-flame ionization detector (GC-FID), (ii) GC-mass spectrometry (GC-MS), and (iii) purge and trap GC-MS (P&T GC-MS). Thirteen compounds were identified with a quality match of 90% and above using GC-MS. The compounds were (1) Cyclohexene, 6-ethenyl-6-methyl-1-(1-methylethyl)-3-(1-methylethylidene)-, (S)-; (2) Bicylo (2.2.1) heptan-2-one, 1, 7, 7-trimethyl-(1S, 4S)-; (3) Phenol, 2-methoxy-4-(1-propenyl)-; (4) Benzene, 1-(1, 5-dimethyl-4-hexenyl)-4-methyl-; (5) Naphthalene, 1, 2, 3, 5, 6, 8a-hexahydro4, 7-dimethyl-1-1-(1-methylethyl)-, (1S-cis)-; (6) Phenol, 2-methoxy-; (7) Benzaldehyde, 3-hydroxy-4-methoxy-; (8) 11, 13-Eicosadienoic acid, methyl ester; (9) 2-Furancarboxaldehyde, 5-methyl-; (10) Maltol; (11) Phenol; (12) Hydroquinone; (13) 1H-Indene, 1-ethylideneoctahydro-7a-methyl-, (1E, 3a.alpha, 7a.beta.). Other compounds (14) 3-methyl butanal; (15) (D)-Limonene; (16) 1-methyl-4-(1-methyl ethyl) benzene; (17) Butanoic acid methyl ester; (18) 2-methyl propanal; (19) 2-butanone; (20) 2-pentanone; and (21) 2-methyl butane were also identified when P&T GC-MS was performed. Of the 21 compounds identified, 12 were validated using chemical standards. The identified compounds were found to be terpenes, derivatives of terpenes, esters, ketones, aldehydes, and phenol-derived aromatic compounds; these are the primary constituents of the essential oils of many plants and flowers. PMID:24804069

  5. Toxicity of adipic acid.

    PubMed

    Kennedy, Gerald L

    2002-05-01

    Adipic acid has very low acute toxicity in rats with an LD50 > 5000 mg/kg. Adipic acid produced mild to no skin irritation on intact guinea pig skin as a 50% concentration in propylene glycol; it was not a skin sensitizer. Adipic acid caused mild conjunctival irritation in washed rabbit eyes; in unwashed rabbit eyes, there was mild conjunctival irritation, minimal iritis, but no corneal effects. Adipic acid dust may irritate the mucous membranes of the lungs and nose. In a 2-year feeding study, rats fed adipic acid at concentrations up to 5% in the diet exhibited only weight loss. Adipic acid is not genetically active in a wide variety of assay systems. Adipic acid caused no developmental toxicity in mice, rats, rabbits, or hamsters when administered orally. Adipic acid is partially metabolized in humans; the balance is eliminated unchanged in the urine. Adipic acid is slightly to moderately toxic to fish, daphnia, and algae in acute tests. PMID:12024802

  6. Acid Thunder: Acid Rain and Ancient Mesoamerica

    ERIC Educational Resources Information Center

    Kahl, Jonathan D. W.; Berg, Craig A.

    2006-01-01

    Much of Mesoamerica's rich cultural heritage is slowly eroding because of acid rain. Just as water dissolves an Alka-Seltzer tablet, acid rain erodes the limestone surfaces of Mexican archaeological sites at a rate of about one-half millimeter per century (Bravo et al. 2003). A half-millimeter may not seem like much, but at this pace, a few…

  7. Quantity of acid in acid fog

    SciTech Connect

    Deal, W.J.

    1983-07-01

    This communication notes the actual magnitude of the acidity in acidic fog particles and suggests a possible line of inquiry into the health effects of such fog so that it can be determined whether a typical fog is detrimental or beneficial relative to dry air.

  8. [Amino acids in saliva].

    PubMed

    Klinger, G; Gruhn, K

    1984-01-01

    Total amino acids in saliva and free and peptide-bound amino acids from 21 saliva samples were determined. The contents of amino acids was 25 mmol/1; total nitrogen content was 78-80 mmol/1. Amino acids consist of Prolin in 25%. Some patients were examined before and after application of the depot estrogen ethinyl estradiosulfonat, which stimulates the assimilation of protein. After application, amino acids increased and the authors found a shift between the single amino acids. Estrogen medication induced an increase in proteins with the character of collagens. Clinical effects are discussed. (author's modified) PMID:6240853

  9. Structural identification of Diindole agonists of the aryl hydrocarbon receptor derived from degradation of indole-3-pyruvic acid.

    PubMed

    Chowdhury, Goutam; Dostalek, Miroslav; Hsu, Erin L; Nguyen, Linh P; Stec, Donald F; Bradfield, Christopher A; Guengerich, F Peter

    2009-12-01

    Aerobic incubation of the tryptophan transamination/oxidation product indole-3-pyruvic acid (I3P) at pH 7.4 and 37 degrees C yielded products with activity as Ah receptor (AHR) agonists. The extracts were fractionated using HPLC and screened for AHR agonist activity. Two compounds were identified as agonists: 1,3-di(1H-indol-3-yl)propan-2-one (1) and 1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene) propan-2-one (2), with the potency of 2 being 100-fold > 1 [ Nguyen et al. ( 2009 ) Chem. Res. Toxicol. , DOI: 10.1021/tx900043s . ]. Both 1 and 2 showed UV spectra indicative of indole. The molecular formulas were established by high-resolution mass spectrometry (HRMS), and the structures were determined by a combination of NMR methods, including (1)H, natural abundance (13)C, and two-dimensional methods. An intermediate in the oxidation of I3P to 1 is 3-hydroxy-2,4-di(1H-indol-3-yl)butanal (HRMS established the presence of a compound with the formula C(20)H(19)N(2)O(2)). Compound 1 was converted to 2 in air or (faster) with mild oxidants, and 2 could be further oxidized to 1,3-di(3H-indol-3-ylidene)propan-2-one. Determination of the structures allowed estimation of the molar Ah receptor agonist activity of these natural products, similar in potency to known classical AHR inducers. PMID:19860413

  10. Hydrochloric acid poisoning

    MedlinePlus

    Hydrochloric acid is a clear, poisonous liquid. It is highly corrosive, which means it immediately causes severe damage, ... discusses poisoning due to swallowing or breathing in hydrochloric acid. This article is for information only. Do NOT ...

  11. Omega-3 Fatty Acids

    MedlinePlus

    Omega-3 fatty acids are used together with lifestyle changes (diet, weight-loss, exercise) to reduce the amount ... the blood in people with very high triglycerides. Omega-3 fatty acids are in a class of medications ...

  12. Omega-6 Fatty Acids

    MedlinePlus

    Omega-6 fatty acids are types of fats. Some types are found in vegetable oils, including corn, evening primrose seed, safflower, and soybean oils. Other types of omega-6 fatty acids are found in black currant seed, borage seed, ...

  13. Zoledronic Acid Injection

    MedlinePlus

    Zoledronic acid (Reclast) is used to prevent or treat osteoporosis (condition in which the bones become thin and weak ... of life,' end of regular menstrual periods). Zoledronic acid (Reclast) is also used to treat osteoporosis in ...

  14. Aminolevulinic Acid Topical

    MedlinePlus

    Aminolevulinic acid is used in combination with photodynamic therapy (PDT; special blue light) to treat actinic keratoses (small crusty ... skin cancer) of the face or scalp. Aminolevulinic acid is in a class of medications called photosensitizing ...

  15. Acid-fast stain

    MedlinePlus

    The acid-fast stain is a laboratory test that determines if a sample of tissue, blood, or other body ... dye. The slide is then washed with an acid solution and a different stain is applied. Bacteria ...

  16. Uric acid - blood

    MedlinePlus

    Uric acid is a chemical created when the body breaks down substances called purines. Purines are found in some ... dried beans and peas, and beer. Most uric acid dissolves in blood and travels to the kidneys. ...

  17. Hydrochloric acid poisoning

    MedlinePlus

    Hydrochloric acid is a clear, poisonous liquid. It is highly corrosive, which means it immediately causes severe damage, such ... poisoning due to swallowing or breathing in hydrochloric acid. This article is for information only. Do NOT ...

  18. Omega-6 Fatty Acids

    MedlinePlus

    ... types of fats. Some types are found in vegetable oils, including corn, evening primrose seed, safflower, and soybean ... from studying specific omega-6 fatty acids or plant oils containing omega-6 fatty acids. See the separate ...

  19. Uric Acid Test

    MedlinePlus

    ... limited. Home Visit Global Sites Search Help? Uric Acid Share this page: Was this page helpful? Also known as: Serum Urate; UA Formal name: Uric Acid Related tests: Synovial Fluid Analysis , Kidney Stone Analysis , ...

  20. Acid-fast stain

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003766.htm Acid-fast stain To use the sharing features on this page, please enable JavaScript. The acid-fast stain is a laboratory test that determines ...

  1. Aminocaproic Acid Injection

    MedlinePlus

    Aminocaproic acid injection is used to control bleeding that occurs when blood clots are broken down too quickly. This ... the baby is ready to be born). Aminocaproic acid injection is also used to control bleeding in ...

  2. Deoxycholic Acid Injection

    MedlinePlus

    Deoxycholic acid injection is used to improve the appearance and profile of moderate to severe submental fat ('double chin'; fatty tissue located under the chin). Deoxycholic acid injection is in a class of medications called ...

  3. Methylmalonic Acid Test

    MedlinePlus

    ... limited. Home Visit Global Sites Search Help? Methylmalonic Acid Share this page: Was this page helpful? Also known as: MMA Formal name: Methylmalonic Acid Related tests: Vitamin B12 and Folate , Homocysteine , Intrinsic ...

  4. Fatty acid analogs

    DOEpatents

    Elmaleh, David R.; Livni, Eli

    1985-01-01

    In one aspect, a radioactively labeled analog of a fatty acid which is capable of being taken up by mammalian tissue and which exhibits an in vivo beta-oxidation rate below that with a corresponding radioactively labeled fatty acid.

  5. Boric acid poisoning

    MedlinePlus

    ... boric acid poisoning usually occurs when someone swallows powdered roach-killing products that contain the chemical. Chronic ... vein (IV) Medicines to treat symptoms Note: Activated charcoal does not effectively treat (absorb) boric acid. For ...

  6. Lactic acid test

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003507.htm Lactic acid test To use the sharing features on this page, please enable JavaScript. Lactic acid is mainly produced in muscle cells and red ...

  7. Binding interaction of a gamma-aminobutyric acid derivative with serum albumin: an insight by fluorescence and molecular modeling analysis.

    PubMed

    Pal, Uttam; Pramanik, Sumit Kumar; Bhattacharya, Baisali; Banerji, Biswadip; C Maiti, Nakul

    2016-01-01

    gamma-Aminobutyric acid (GABA) is a naturally occurring inhibitory neurotransmitter and some of its derivatives showed potential to act as neuroprotective agents. With the aim of developing potential leads for anti-Alzheimer's drugs, in this study we synthesized a novel GABA derivative, methyl 4-(4-((2-(tert-butoxy)-2-oxoethyl)(4-methoxyphenyl)amino)benzamido)butanoate by a unique method of Buchwald-Hartwig cross coupling synthesis; with some modification the yield was significant (97 %) and spectroscopic analysis confirmed that the compound was highly pure (98.8 % by HPLC). The druglikeness properties such as logP, logS, and polar surface area were 3.87, -4.86 and 94.17 Å(2) respectively and it satisfied the Lipinski's rule of five. We examined the binding behavior of the molecule to human serum albumin (HSA) and bovine serum albumin (BSA) which are known as universal drug carrier proteins. The molecule binds to the proteins with low micromolar efficiency and the calculated binding constants were 3.85 and 2.75 micromolar for BSA and HSA, respectively. Temperature dependent study using van't Hoff equation established that the binding was thermodynamically favorable and the changes in the Gibb's free energy, ΔG for the binding process was negative. However, the binding of the molecule to HSA was enthalpy driven and the change of enthalpy (ΔH) was -10.63 kJ/mol, whereas, the binding to BSA was entropy driven and the change in entropy ΔS was 222 J/mol. The molecular docking analysis showed that the binding sites of the molecule lie in the groove between domain I and domain III of BSA, whereas it is within the domain I in case of HSA, which also supported the different thermodynamic nature of binding with HSA and BSA. Molecular dynamics analysis suggested that the binding was stable with time and provided further details of the binding interaction. Molecular dynamics study also highlighted the effect of this ligand binding on the serum albumin structure. PMID

  8. One-pot catalyst free synthesis of novel kojic acid tagged 2-aryl/alkyl substituted-4H-chromenes and evaluation of their antimicrobial and anti-biofilm activities.

    PubMed

    Bingi, Chiranjeevi; Emmadi, Narender Reddy; Chennapuram, Madhu; Poornachandra, Y; Kumar, C Ganesh; Nanubolu, Jagadeesh Babu; Atmakur, Krishnaiah

    2015-05-01

    A number of 3-hydroxy-6-(hydroxymethyl)-2-(2-phenyl-4H-chromen-4-yl)-4H-pyran-4-ones (3) have been synthesized in a one pot catalyst free reaction of 2-hydroxy chalcone (1) with kojic acid (2) in toluene at reflux temperature and evaluated for antimicrobial and anti-biofilm activities. Compounds 3a, 3e, 3f, 3l showed potent antimicrobial activity against Staphylococcus aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739, whereas 3b and 3k exhibited excellent activity against Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739, while 3g showed promising activity against Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739. On the other hand, compounds 3a, 3b and 3l showed very good anti-biofilm activity and 3g showed moderate activity against Bacillus subtilis MTCC 121. Whereas, compounds 3a and 3f showed moderate activity against Escherichia coli MTCC 739, while compounds 3a, 3b, 3k and 3l displayed similar activity against Staphylococcus aureus MLS-16 MTCC 2940. PMID:25838145

  9. PRODUCTION OF TRIFLUOROACETIC ACID

    DOEpatents

    Haworth, W.N.; Stacey, M.

    1949-07-19

    A method is given for the production of improved yields of trifluoroacetic acid. The compound is prepared by oxidizing m-aminobenzotrifluoride with an alkali metal or alkaline earth metal permanganate at a temperature in the range of 80 deg C to 100 deg C while dissolved ln a mixture of water with glacial acetic acid and/or trifluoroacetic acid. Preferably a mixture of water and trifluoroacetic acid ls used as the solvent.

  10. Plant fatty acid hydroxylases

    DOEpatents

    Somerville, Chris; Broun, Pierre; van de Loo, Frank

    2001-01-01

    This invention relates to plant fatty acyl hydroxylases. Methods to use conserved amino acid or nucleotide sequences to obtain plant fatty acyl hydroxylases are described. Also described is the use of cDNA clones encoding a plant hydroxylase to produce a family of hydroxylated fatty acids in transgenic plants. In addition, the use of genes encoding fatty acid hydroxylases or desaturases to alter the level of lipid fatty acid unsaturation in transgenic plants is described.

  11. Selectivity of substrate binding and ionization of 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase.

    PubMed

    Luanloet, Thikumporn; Sucharitakul, Jeerus; Chaiyen, Pimchai

    2015-08-01

    2-Methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase (EC 1.14.12.4) from Pseudomonas sp. MA-1 is a flavin-dependent monooxygenase that catalyzes a hydroxylation and aromatic ring cleavage reaction. The functional roles of two residues, Tyr223 and Tyr82, located ~ 5 Å away from MHPC, were characterized using site-directed mutagenesis, along with ligand binding, product analysis and transient kinetic experiments. Mutation of Tyr223 resulted in enzyme variants that were impaired in their hydroxylation activity and had Kd values for substrate binding 5-10-fold greater than the wild-type enzyme. Because this residue is adjacent to the water molecule that is located next to the 3-hydroxy group of MHPC, the results indicate that the interaction between Tyr223, H2 O and the 3-hydroxyl group of MHPC are important for substrate binding and hydroxylation. By contrast, the Kd for substrate binding of Tyr82His and Tyr82Phe variants were similar to that of the wild-type enzyme. However, only ~ 40-50% of the substrate was hydroxylated in the reactions of both variants, whereas most of the substrate was hydroxylated in the wild-type enzyme reaction. In free solution, MHPC or 5-hydroxynicotinic acid exists in a mixture of monoanionic and tripolar ionic forms, whereas only the tripolar ionic form binds to the wild-type enzyme. The binding of tripolar ionic MHPC would allow efficient hydroxylation through an electrophilic aromatic substitution mechanism. For the Tyr82His and Tyr82Phe variants, both forms of substrates can bind to the enzymes, indicating that the mutation at Tyr82 abolished the selectivity of the enzyme towards the tripolar ionic form. Transient kinetic studies indicated that the hydroxylation rate constants of both Tyr82 variants are approximately two- to 2.5-fold higher than that of the wild-type enzyme. Altogether, our findings suggest that Tyr82 is important for the binding selectivity of MHPC oxygenase towards the tripolar ionic species, whereas the

  12. Quantity of acid in acid fog

    SciTech Connect

    Deal, W.J.

    1983-07-01

    The chemical composition of fog particles has become of considerable interest, because of both the possibility of interpreting atmospheric- chemistry processes in fog particles in terms of the principles of aqueous chemistry and the potential health effects of species present in fog particles. The acidity of fog particles has received wide attention. This communication noted the actual magnitude of the excess acidity in acidic fog particles and suggested a possible line of inquiry into the health effects of such fog so that it can be determined whether a typical fog is detrimental or beneficial relative to dry air. (DP)

  13. Lipid Composition, Fatty Acids and Sterols in the Seaweeds Ulva armoricana, and Solieria chordalis from Brittany (France): An Analysis from Nutritional, Chemotaxonomic, and Antiproliferative Activity Perspectives

    PubMed Central

    Kendel, Melha; Wielgosz-Collin, Gaëtane; Bertrand, Samuel; Roussakis, Christos; Bourgougnon, Nathalie; Bedoux, Gilles

    2015-01-01

    Lipids from the proliferative macroalgae Ulva armoricana (Chlorophyta) and Solieria chordalis (Rhodophyta) from Brittany, France, were investigated. The total content of lipids was 2.6% and 3.0% dry weight for U. armoricana and S. chordalis, respectively. The main fractions of S. chordalis were neutral lipids (37%) and glycolipids (38%), whereas U. armoricana contained mostly neutral lipids (55%). Polyunsaturated fatty acids (PUFA) represented 29% and 15% of the total lipids in U. armoricana and S. chordalis, respectively. In both studied algae, the phospholipids were composed of PUFA for 18%. In addition, PUFA were shown to represent 9% and 4.5% of glycolipids in U. armoricana and S. chordalis, respectively. The essential PUFA were 16:4n-3, 18:4n-3, 18:2n-3, 18:2n-6, and 22:6n-3 in U. armoricana, and 20:4n-6 and 20:5n-3 in S. chordalis. It is important to notice that six 2-hydroxy-, three 3-hydroxy-, and two monounsaturated hydroxy fatty acids were also identified and may provide a chemotaxonomic basis for algae. These seaweeds contained interesting compounds such as squalene, α-tocopherol, cholest-4-en-3-one and phytosterols. The antiproliferative effect was evaluated in vitro on human non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) with an IC50 of 23 μg/mL for monogalactosyldiacylglycerols isolated from S. chordalis and 24 μg/mL for digalactosyldiacylglycerols from U. armoricana. These results confirm the potentialities of valorization of these two species in the fields of health, nutrition and chemotaxonomy. PMID:26404323

  14. Mercapturic Acids Derived from the Toxicants Acrolein and Crotonaldehyde in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer

    PubMed Central

    Park, Sungshim L.; Carmella, Steven G.; Chen, Menglan; Patel, Yesha; Stram, Daniel O.; Haiman, Christopher A.; Le Marchand, Loic; Hecht, Stephen S.

    2015-01-01

    The Multiethnic Cohort epidemiology study has clearly demonstrated that, compared to Whites and for the same number of cigarettes smoked, African Americans and Native Hawaiians have a higher risk for lung cancer whereas Latinos and Japanese Americans have a lower risk. Acrolein and crotonaldehyde are two important constituents of cigarette smoke which have well documented toxic effects and could play a role in lung cancer etiology. Their urinary metabolites 3-hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), respectively, are validated biomarkers of acrolein and crotonaldehyde exposure. We quantified levels of 3-HPMA and HMPMA in the urine of more than 2200 smokers from these five ethnic groups, and also carried out a genome wide association study using blood samples from these subjects. After adjusting for age, sex, creatinine, and total nicotine equivalents, geometric mean levels of 3-HPMA and HMPMA were significantly different in the five groups (P<0.0001). Native Hawaiians had the highest and Latinos the lowest geometric mean levels of both 3-HPMA and HMPMA. Levels of 3-HPMA and HMPMA were 3787 and 2759 pmol/ml urine, respectively, in Native Hawaiians and 1720 and 2210 pmol/ml urine in Latinos. These results suggest that acrolein and crotonaldehyde may be involved in lung cancer etiology, and that their divergent levels may partially explain the differing risks of Native Hawaiian and Latino smokers. No strong signals were associated with 3-HPMA in the genome wide association study, suggesting that formation of the glutathione conjugate of acrolein is mainly non-enzymatic, while the top significant association with HMPMA was located on chromosome 12 near the TBX3 gene, but its relationship to HMPMA excretion is not clear. PMID:26053186

  15. Fluorophosphonate-functionalised titanium via a pre-adsorbed alkane phosphonic acid: a novel dual action surface finish for bone regenerative applications.

    PubMed

    Ayre, Wayne Nishio; Scott, Tom; Hallam, Keith; Blom, Ashley W; Denyer, Stephen; Bone, Heather K; Mansell, Jason P

    2016-02-01

    Enhancing vitamin D-induced human osteoblast (hOB) maturation at bone biomaterial surfaces is likely to improve prosthesis integration with resultant reductions in the need for revision arthroplasty consequent to aseptic loosening. Biomaterials that are less appealing to microorganisms implicated in implant failures through infection are also highly desirable. However, finding surfaces that enhance hOB maturation to active vitamin D yet deter bacteria remain elusive. In addressing this, we have sought to bio-functionalise titanium (Ti) with lysophosphatidic acid (LPA) and related, phosphatase-resistant, LPA analogues. The impetus for this follows our discovery that LPA co-operates with active vitamin D3 metabolites to secure hOB maturation in vitro including cells grown upon Ti. LPA has also been found, by others, to inhibit virulence factor production and biofilm formation of the human opportunistic pathogen Pseudomonas aeruginosa. Collectively, selected LPA species might offer potential dual-action surface finishes for contemporary bone biomaterials. In attaching a phosphatase-resistant LPA analogue to Ti we took advantage of the affinity of alkane phosphonic acids for TiO2. Herein, we provide evidence for the facile development of a dual-action Ti surface for potential orthopaedic and dental applications. Successful conjugation of an LPA analogue (3S)1-fluoro-3-hydroxy-4-(oleoyloxy)butyl-1-phosphonate (FHBP) to the Ti surface was supported through physiochemical characterisation using x-ray photoelectron spectroscopy and secondary ion mass spectrometry. hOB maturation to active vitamin D3 was enhanced for cells grown on FHBP-Ti whilst these same surfaces exhibited clear antiadherent properties towards a clinical isolate of Staphylococcus aureus. PMID:26704553

  16. In vitro oxidative metabolism of cajaninstilbene Acid by human liver microsomes and hepatocytes: involvement of cytochrome p450 reaction phenotyping, inhibition, and induction studies.

    PubMed

    Hua, Xin; Peng, Xiao; Tan, Shengnan; Li, Chunying; Wang, Wei; Luo, Meng; Fu, Yujie; Zu, Yuangang; Smyth, Hugh

    2014-10-29

    Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid), an active constituent of pigeonpea leaves, an important tropical crop, is known for its clinical effects in the treatment of diabetes, hepatitis, and measles and its potential antitumor effect. In this study, the effect of the cytochrome P450 isozymes on the activity of CSA was investigated. Two hydroxylation metabolites were identified in the study. The reaction phenotype study showed that CYP3A4, CYP2C9, and CYP1A2 were the major cytochrome P450 isozymes in the metabolism of CSA. The metabolic food-drug interaction potential was also evaluated in vitro. The effect of CSA inhibition/induction of enzymatic activities of seven drug-metabolizing CYP450 isozymes in vitro was estimated by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques. CSA showed different inhibitory effects on different isozymes. CSA reversibly inhibited CYP3A4 and CYP2C9 activities in human liver microsomes with IC50 values of 28.3 and 31.3 μM, respectively, but exhibited no inhibition activities to CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP2E1. CSA showed a weak effect on CYP450 enzymes in a time-dependent manner. CSA did not substantially induce CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations up to 30 μM in primary human hepatocytes. The results of our experiments may be helpful to predict clinically significant food-drug interactions when other drugs are administered in combination with CSA. PMID:25272989

  17. Mercapturic Acids Derived from the Toxicants Acrolein and Crotonaldehyde in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer.

    PubMed

    Park, Sungshim L; Carmella, Steven G; Chen, Menglan; Patel, Yesha; Stram, Daniel O; Haiman, Christopher A; Le Marchand, Loic; Hecht, Stephen S

    2015-01-01

    The Multiethnic Cohort epidemiology study has clearly demonstrated that, compared to Whites and for the same number of cigarettes smoked, African Americans and Native Hawaiians have a higher risk for lung cancer whereas Latinos and Japanese Americans have a lower risk. Acrolein and crotonaldehyde are two important constituents of cigarette smoke which have well documented toxic effects and could play a role in lung cancer etiology. Their urinary metabolites 3-hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), respectively, are validated biomarkers of acrolein and crotonaldehyde exposure. We quantified levels of 3-HPMA and HMPMA in the urine of more than 2200 smokers from these five ethnic groups, and also carried out a genome wide association study using blood samples from these subjects. After adjusting for age, sex, creatinine, and total nicotine equivalents, geometric mean levels of 3-HPMA and HMPMA were significantly different in the five groups (P < 0.0001). Native Hawaiians had the highest and Latinos the lowest geometric mean levels of both 3-HPMA and HMPMA. Levels of 3-HPMA and HMPMA were 3787 and 2759 pmol/ml urine, respectively, in Native Hawaiians and 1720 and 2210 pmol/ml urine in Latinos. These results suggest that acrolein and crotonaldehyde may be involved in lung cancer etiology, and that their divergent levels may partially explain the differing risks of Native Hawaiian and Latino smokers. No strong signals were associated with 3-HPMA in the genome wide association study, suggesting that formation of the glutathione conjugate of acrolein is mainly non-enzymatic, while the top significant association with HMPMA was located on chromosome 12 near the TBX3 gene, but its relationship to HMPMA excretion is not clear. PMID:26053186

  18. Possible Role of Intestinal Fatty Acid Oxidation in the Eating-Inhibitory Effect of the PPAR-α Agonist Wy-14643 in High-Fat Diet Fed Rats

    PubMed Central

    Karimian Azari, Elnaz; Leitner, Claudia; Jaggi, Thomas; Langhans, Wolfgang; Mansouri, Abdelhak

    2013-01-01

    PPAR-α plays a key role in lipid metabolism; it enhances fatty acid oxidation (FAO) and ketogenesis. Pharmacological PPAR-α activation improves insulin sensitivity and reduces food intake, but its mechanisms of action remain unknown. We here report that intraperitoneal (IP) administration of the PPAR-α agonist Wy-14643 (40 mg/kg BW) reduced food intake in adult male rats fed a high-fat diet (HFD, 49% of the energy) mainly through an increase in the latency to eat after injection, and without inducing a conditioned taste avoidance. Also, IP administered Wy-14643 caused an acute (the first 60 min) decrease in the respiratory quotient (RQ) and an increase in hepatic portal vein β-hydroxybutyrate level (at 35 min) without affecting plasma non-esterified fatty acids. Given the known stimulatory effect of PPAR-α on FAO and ketogenesis, we measured the protein expression level of carnitine palmitoyltransferase-1 (CPT 1A) and mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMG-CoAS2), two key enzymes for FAO and ketogenesis, respectively, in liver, duodenum and jejunum. Wy-14643 induced a significant increase in the expression of CPT 1A in the jejunum and duodenum and of HMG-CoAS2 in the jejunum, but neither CPT 1A nor HMG-CoAS2 expression was increased in the liver. The induction of CPT 1A and HMG-CoAS2 expression was associated with a decrease in the lipid droplet content selectively in the jejunum. Our findings indicate that Wy-14643 stimulates FAO and ketogenesis in the intestine, in particular in the jejunum, rather than in the liver, thus supporting the hypothesis that PPAR-α activation inhibits eating by stimulating intestinal FAO. PMID:24069361

  19. Lipid Composition, Fatty Acids and Sterols in the Seaweeds Ulva armoricana, and Solieria chordalis from Brittany (France): An Analysis from Nutritional, Chemotaxonomic, and Antiproliferative Activity Perspectives.

    PubMed

    Kendel, Melha; Wielgosz-Collin, Gaëtane; Bertrand, Samuel; Roussakis, Christos; Bourgougnon, Nathalie; Bedoux, Gilles

    2015-09-01

    Lipids from the proliferative macroalgae Ulva armoricana (Chlorophyta) and Solieria chordalis (Rhodophyta) from Brittany, France, were investigated. The total content of lipids was 2.6% and 3.0% dry weight for U. armoricana and S. chordalis, respectively. The main fractions of S. chordalis were neutral lipids (37%) and glycolipids (38%), whereas U. armoricana contained mostly neutral lipids (55%). Polyunsaturated fatty acids (PUFA) represented 29% and 15% of the total lipids in U. armoricana and S. chordalis, respectively. In both studied algae, the phospholipids were composed of PUFA for 18%. In addition, PUFA were shown to represent 9% and 4.5% of glycolipids in U. armoricana and S. chordalis, respectively. The essential PUFA were 16:4n-3, 18:4n-3, 18:2n-3, 18:2n-6, and 22:6n-3 in U. armoricana, and 20:4n-6 and 20:5n-3 in S. chordalis. It is important to notice that six 2-hydroxy-, three 3-hydroxy-, and two monounsaturated hydroxy fatty acids were also identified and may provide a chemotaxonomic basis for algae. These seaweeds contained interesting compounds such as squalene, α-tocopherol, cholest-4-en-3-one and phytosterols. The antiproliferative effect was evaluated in vitro on human non-small-cell bronchopulmonary carcinoma line (NSCLC-N6) with an IC50 of 23 μg/mL for monogalactosyldiacylglycerols isolated from S. chordalis and 24 μg/mL for digalactosyldiacylglycerols from U. armoricana. These results confirm the potentialities of valorization of these two species in the fields of health, nutrition and chemotaxonomy. PMID:26404323

  20. The Acid Rain Reader.

    ERIC Educational Resources Information Center

    Stubbs, Harriett S.; And Others

    A topic which is often not sufficiently dealt with in elementary school textbooks is acid rain. This student text is designed to supplement classroom materials on the topic. Discussed are: (1) "Rain"; (2) "Water Cycle"; (3) "Fossil Fuels"; (4) "Air Pollution"; (5) "Superstacks"; (6) "Acid/Neutral/Bases"; (7) "pH Scale"; (8) "Acid Rain"; (9)…