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Sample records for acid transaminase inhibitor

  1. Genotoxic and mutagenic effects of vigabatrin, a γ-aminobutyric acid transaminase inhibitor, in Wistar rats submitted to rotarod task.

    Science.gov (United States)

    Coelho, V R; Sousa, K; Pires, T R; Papke, Dkm; Vieira, C G; de Souza, L P; Leal, M B; Schunck, Rva; Picada, J N; Pereira, P

    2016-09-01

    Vigabatrin (VGB) is an antiepileptic drug thatincreases brain γ-aminobutyric acid (GABA) levels through irreversible inhibition of GABA transaminase. The aim of this study was to evaluate neurotoxicological effects of VGB measuring motor activity and genotoxic and mutagenic effects after a single and repeated administration. Male Wistar rats received saline, VGB 50, 100, or 250 mg/kg by gavage for acute and subchronic (14 days) treatments and evaluated in the rotarod task. Genotoxicity was evaluated using the alkaline version of the comet assay in samples of blood, liver, hippocampus, and brain cortex after both treatments. Mutagenicity was evaluated using the micronucleus test in bone marrow of the same animals that received subchronic treatment. The groups treated with VGB showed similar performance in rotarod compared with the saline group. Regarding the acute treatment, it was observed that only higher VGB doses induced DNA damage in blood and hippocampus. After the subchronic treatment, VGB did not show genotoxic or mutagenic effects. In brief, VGB did not impair motor activities in rats after acute and subchronic treatments. It showed a repairable genotoxic potential in the central nervous system since genotoxicity was observed in the acute treatment group. PMID:26500220

  2. Effects of Vigabatrin, an Irreversible GABA Transaminase Inhibitor, on Ethanol Reinforcement and Ethanol Discriminative Stimuli in Mice

    OpenAIRE

    Griffin, William C.; Nguyen, Shaun A.; Deleon, Christopher P.; Middaugh, Lawrence D.

    2012-01-01

    We tested the hypothesis that the irreversible gamma-amino butyric acid (GABA) transaminase inhibitor, γ-vinyl GABA (Vigabatrin; VGB) would reduce ethanol reinforcement and enhance the discriminative stimulus effect of ethanol, effectively reducing ethanol intake. The present studies used adult C57BL/6J (B6) mice in well-established operant, two-bottle choice consumption, locomotor activity and ethanol discrimination procedures, to examine comprehensively the effects of VGB on ethanol-support...

  3. Effect of chronic treatment with the GABA transaminase inhibitors γ-vinyl GABA and ethanolamine O-sulphate on the in vitro GABA release from rat hippocampus

    OpenAIRE

    Qume, M; Fowler, L. J.

    1997-01-01

    The effects of 2, 8 and 21 day oral treatment with the specific γ-aminobutyric acid transaminase (GABA-T) inhibitors γ-vinyl GABA (GVG) and ethanolamine O-sulphate (EOS) on brain GABA levels, GABA-T activity, and basal and stimulated GABA release from rat cross-chopped brain hippocampal slices was investigated.Treatment with GABA-T inhibitors lead to a reduction in brain GABA-T activity by 65–80% compared with control values, with a concomitant increase in brain GABA content of 40–100%.Basal ...

  4. Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

    Directory of Open Access Journals (Sweden)

    Masoumeh Asgarshirazi

    2015-06-01

    Full Text Available The present study has been directed to investigate Ursodeoxycholic Acid (UDCA effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis. This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

  5. [Asymmetric synthesis of aromatic L-amino acids catalyzed by transaminase].

    Science.gov (United States)

    Xia, Wenna; Sun, Yu; Min, Cong; Han, Wei; Wu, Sheng

    2012-11-01

    Aromatic L-Amino acids are important chiral building blocks for the synthesis of many drugs, pesticides, fine chemicals and food additives. Due to the high activity and steroselectivity, enzymatic synthesis of chiral building blocks has become the main research direction in asymmetric synthesis field. Guided by the phylogenetic analysis of transaminases from different sources, two representative aromatic transaminases TyrB and Aro8 in type I subfamily, from the prokaryote Escherichia coli and eukaryote Saccharomyces cerevisia, respectively, were applied for the comparative study of asymmetric transamination reaction process and catalytic efficiency of reversely converting keto acids to the corresponding aromatic L-amino acid. Both TyrB and Aro8 could efficiently synthesize the natural aromatic amino acids phenylalanine and tyrosine as well as non-natural amino acid phenylglycine. The chiral HPLC analysis showed the produced amino acids were L-configuration and the e.e value was 100%. L-alanine was the optimal amino donor, and the transaminase TyrB and Aro8 could not use D-amino acids as amino donor. The optimal molar ratio of amino donor (L-alanine) and amino acceptor (aromatic alpha-keto acids) was 4:1. Both of the substituted group on the aromatic ring and the length of fatty acid carbon chain part in the molecular structure of aromatic substrate alpha-keto acid have the significant impact on the enzyme-catalyzed transamination efficiency. In the experiments of preparative-scale transamination synthesis of L-phenylglycine, L-phenylalanine and L-tyrosine, the specific production rate catalyzed by TryB were 0.28 g/(g x h), 0.31 g/(g x h) and 0.60 g/(g x h) and the specific production rate catalyzed by Aro8 were 0.61 g/(g x h), 0.48 g/(g x h) and 0.59 g/(g x h). The results obtained here were useful for applying the transaminases to asymmetric synthesis of L-amino acids by reversing the reaction balance in industry.

  6. Nucleic acids encoding plant glutamine phenylpyruvate transaminase (GPT) and uses thereof

    Energy Technology Data Exchange (ETDEWEB)

    Unkefer, Pat J.; Anderson, Penelope S.; Knight, Thomas J.

    2016-03-29

    Glutamine phenylpyruvate transaminase (GPT) proteins, nucleic acid molecules encoding GPT proteins, and uses thereof are disclosed. Provided herein are various GPT proteins and GPT gene coding sequences isolated from a number of plant species. As disclosed herein, GPT proteins share remarkable structural similarity within plant species, and are active in catalyzing the synthesis of 2-hydroxy-5-oxoproline (2-oxoglutaramate), a powerful signal metabolite which regulates the function of a large number of genes involved in the photosynthesis apparatus, carbon fixation and nitrogen metabolism.

  7. A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients

    Institute of Scientific and Technical Information of China (English)

    Shuichi Sato; Tatsuya Miyake; Hiroshi Tobita; Naoki Oshima; Junich Ishine; Takuya Hanaoka; Yuji Amano; Yoshikazu Kinoshita

    2009-01-01

    AIM:To examine whether a dose-up to 900 mg of ursodeoxycholic acid (UDCA) decreases transaminases in hepatitis C patients.METHODS:From January to December 2007,patients with chronic hepatitis C or compensated liver cirrhosis with hepatitis C virus (HCV) (43-80 years old) showing positive serum HCV-RNA who had already taken 600 mg/d of UDCA were recruited into this study.Blood parameters were examined at 4,8 and 24 wk after increasing the dose of oral UDCA from 600 to 900 mg/d.RESULTS:Serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),and gammaglutamyl transpeptidase (GGT) levels were significantly decreased following the administration of 900 mg/d as compared to 600 mg/d.The decrease in ALT from immediately before the dose-up of UDCA to 8 wk after the dose-up was 14.3 IU/L,while that for AST was 10.5 IU/L and for GGT was 9.8 IU/L.Platelet count tended to increase after the dose-up of UDCA,although it did not show a statistically significant level (P=0.05).Minor adverse events were observed in 3 cases,although no drop-outs from the study occurred.CONCLUSION:Oral administration of 900 mg/d of UDCA was more effective than 600 mg/d for reducing ALT,AST,and GGT levels in patients with HCV-related chronic liver disease.

  8. Asymmetric synthesis of aromatic β-amino acids using ω-transaminase: Optimizing the lipase concentration to obtain thermodynamically unstable β-keto acids.

    Science.gov (United States)

    Mathew, Sam; Jeong, Seong-Su; Chung, Taeowan; Lee, Sang-Hyeup; Yun, Hyungdon

    2016-01-01

    Synthesized aromatic β-amino acids have recently attracted considerable attention for their application as precursors in many pharmacologically relevant compounds. Previous studies on asymmetric synthesis of aromatic β-amino acids using ω-transaminases could not be done efficiently due to the instability of β-keto acids. In this study, a strategy to circumvent the instability problem of β-keto acids was utilized to generate β-amino acids efficiently via asymmetric synthesis. In this work, thermodynamically stable β-ketoesters were initially converted to β-keto acids using lipase, and the β-keto acids were subsequently aminated using ω-transaminase. By optimizing the lipase concentration, we successfully overcame the instability problem of β-keto acids and enhanced the production of β-amino acids. This strategy can be used as a general approach to efficiently generate β-amino acids from β-ketoesters.

  9. Deletion of the Saccharomyces cerevisiae ARO8 gene, encoding an aromatic amino acid transaminase, enhances phenylethanol production from glucose.

    Science.gov (United States)

    Romagnoli, Gabriele; Knijnenburg, Theo A; Liti, Gianni; Louis, Edward J; Pronk, Jack T; Daran, Jean-Marc

    2015-01-01

    Phenylethanol has a characteristic rose-like aroma that makes it a popular ingredient in foods, beverages and cosmetics. Microbial production of phenylethanol currently relies on whole-cell bioconversion of phenylalanine with yeasts that harbour an Ehrlich pathway for phenylalanine catabolism. Complete biosynthesis of phenylethanol from a cheap carbon source, such as glucose, provides an economically attractive alternative for phenylalanine bioconversion. In this study, synthetic genetic array (SGA) screening was applied to identify genes involved in regulation of phenylethanol synthesis in Saccharomyces cerevisiae. The screen focused on transcriptional regulation of ARO10, which encodes the major decarboxylase involved in conversion of phenylpyruvate to phenylethanol. A deletion in ARO8, which encodes an aromatic amino acid transaminase, was found to underlie the transcriptional upregulation of ARO10 during growth, with ammonium sulphate as the sole nitrogen source. Physiological characterization revealed that the aro8Δ mutation led to substantial changes in the absolute and relative intracellular concentrations of amino acids. Moreover, deletion of ARO8 led to de novo production of phenylethanol during growth on a glucose synthetic medium with ammonium as the sole nitrogen source. The aro8Δ mutation also stimulated phenylethanol production when combined with other, previously documented, mutations that deregulate aromatic amino acid biosynthesis in S. cerevisiae. The resulting engineered S. cerevisiae strain produced >3 mm phenylethanol from glucose during growth on a simple synthetic medium. The strong impact of a transaminase deletion on intracellular amino acid concentrations opens new possibilities for yeast-based production of amino acid-derived products.

  10. Mutations in γ-aminobutyric acid (GABA) transaminase genes in plants or Pseudomonas syringae reduce bacterial virulence.

    Science.gov (United States)

    Park, Duck Hwan; Mirabella, Rossana; Bronstein, Philip A; Preston, Gail M; Haring, Michel A; Lim, Chun Keun; Collmer, Alan; Schuurink, Robert C

    2010-10-01

    Pseudomonas syringae pv. tomato DC3000 is a bacterial pathogen of Arabidopsis and tomato that grows in the apoplast. The non-protein amino acid γ-amino butyric acid (GABA) is produced by Arabidopsis and tomato and is the most abundant amino acid in the apoplastic fluid of tomato. The DC3000 genome harbors three genes annotated as gabT GABA transaminases. A DC3000 mutant lacking all three gabT genes was constructed and found to be unable to utilize GABA as a sole carbon and nitrogen source. In complete minimal media supplemented with GABA, the mutant grew less well than wild-type DC3000 and showed strongly reduced expression of hrpL and avrPto, which encode an alternative sigma factor and effector, respectively, associated with the type III secretion system. The growth of the gabT triple mutant was weakly reduced in Arabidopsis ecotype Landberg erecta (Ler) and strongly reduced in the Ler pop2-1 GABA transaminase-deficient mutant that accumulates higher levels of GABA. Much of the ability to grow on GABA-amended minimal media or in Arabidopsis pop2-1 leaves could be restored to the gabT triple mutant by expression in trans of just gabT2. The ability of DC3000 to elicit the hypersensitive response (HR) in tobacco leaves is dependent upon deployment of the type III secretion system, and the gabT triple mutant was less able than wild-type DC3000 to elicit this HR when bacteria were infiltrated along with GABA at levels of 1 mm or more. GABA may have multiple effects on P. syringae-plant interactions, with elevated levels increasing disease resistance.

  11. Plasma membrane fatty acid-binding protein and mitochondrial glutamic-oxaloacetic transaminase of rat liver are related

    International Nuclear Information System (INIS)

    The hepatic plasma membrane fatty acid-binding protein (h-FABPPM) and the mitochondrial isoenzyme of glutamic-oxaloacetic transaminase (mGOT) of rat liver have similar amino acid compositions and identical amino acid sequences for residues 3-24. Both proteins migrate with an apparent molecular mass of 43 kDa on SDS/polyacrylamide gel electrophoresis, have a similar pattern of basic charge isomers on isoelectric focusing, are eluted similarly from four different high-performance liquid chromatographic columns, have absorption maxima at 435 nm under acid conditions and 354 nm at pH 8.3, and bind oleate. Sinusoidally enriched liver plasma membranes and purified h-FABPPM have GOT enzymatic activity. Monospecific rabbit antiserum against h-FABPPM reacts on Western blotting with mGOT, and vice versa. Antisera against both proteins produce plasma membrane immunofluorescence in rat hepatocytes and selectively inhibit the hepatocellular uptake of [3H]oleate but not that of [35S]sulfobromophthalein or [14C]taurocholate. The inhibition of oleate uptake produced by anti-h-FABPPM can be eliminated by preincubation of the antiserum with mGOT; similarly, the plasma membrane immunofluorescence produced by either antiserum can be eliminated by preincubation with the other antigen. These data suggest that h-FABPPM and mGOT are closely related

  12. Plasma membrane fatty acid-binding protein and mitochondrial glutamic-oxaloacetic transaminase of rat liver are related

    Energy Technology Data Exchange (ETDEWEB)

    Berk, P.D.; Potter, B.J.; Sorrentino, D.; Zhou, S.L.; Isola, L.M.; Stump, D.; Kiang, C.L.; Thung, S. (Mount Sinai School of Medicine, New York, NY (USA)); Wada, H.; Horio, Y. (Univ. of Osaka (Japan))

    1990-05-01

    The hepatic plasma membrane fatty acid-binding protein (h-FABP{sub PM}) and the mitochondrial isoenzyme of glutamic-oxaloacetic transaminase (mGOT) of rat liver have similar amino acid compositions and identical amino acid sequences for residues 3-24. Both proteins migrate with an apparent molecular mass of 43 kDa on SDS/polyacrylamide gel electrophoresis, have a similar pattern of basic charge isomers on isoelectric focusing, are eluted similarly from four different high-performance liquid chromatographic columns, have absorption maxima at 435 nm under acid conditions and 354 nm at pH 8.3, and bind oleate. Sinusoidally enriched liver plasma membranes and purified h-FABP{sub PM} have GOT enzymatic activity. Monospecific rabbit antiserum against h-FABP{sub PM} reacts on Western blotting with mGOT, and vice versa. Antisera against both proteins produce plasma membrane immunofluorescence in rat hepatocytes and selectively inhibit the hepatocellular uptake of ({sup 3}H)oleate but not that of ({sup 35}S)sulfobromophthalein or ({sup 14}C)taurocholate. The inhibition of oleate uptake produced by anti-h-FABP{sub PM} can be eliminated by preincubation of the antiserum with mGOT; similarly, the plasma membrane immunofluorescence produced by either antiserum can be eliminated by preincubation with the other antigen. These data suggest that h-FABP{sub PM} and mGOT are closely related.

  13. 2-(hydroxymethyl)aspartic acid: synthesis, crystal structure, and reaction with a transaminase

    Energy Technology Data Exchange (ETDEWEB)

    Walsh, J.J.; Metzler, D.E.; Powell, D.; Jacobson, R.A.

    1980-11-05

    The synthesis and x-ray crystal structure of 2-(hydroxymethyl) aspartic acid and the preliminary evaluation of its interaction with cytosolic aspartate aminotransferase of pig heart are described. A dissociation constant 1.4 mM for the L-2-(hydroxymethyl) aspartate complex with the enzyme was obtained. 2 figures. (DP)

  14. The 1.9 A Structure of the Branched-Chain Amino-Acid Transaminase (IlvE) from Mycobacterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Tremblay, L.; Blanchard, J

    2009-01-01

    Unlike mammals, bacteria encode enzymes that synthesize branched-chain amino acids. The pyridoxal 5'-phosphate-dependent transaminase performs the final biosynthetic step in these pathways, converting keto acid precursors into {alpha}-amino acids. The branched-chain amino-acid transaminase from Mycobacterium tuberculosis (MtIlvE) has been crystallized and its structure has been solved at 1.9 {angstrom} resolution. The MtIlvE monomer is composed of two domains that interact to form the active site. The biologically active form of IlvE is a homodimer in which each monomer contributes a substrate-specificity loop to the partner molecule. Additional substrate selectivity may be imparted by a conserved N-terminal Phe30 residue, which has previously been observed to shield the active site in the type IV fold homodimer. The active site of MtIlvE contains density corresponding to bound PMP, which is likely to be a consequence of the presence of tryptone in the crystallization medium. Additionally, two cysteine residues are positioned at the dimer interface for disulfide-bond formation under oxidative conditions. It is unknown whether they are involved in any regulatory activities analogous to those of the human mitochondrial branched-chain amino-acid transaminase.

  15. Suppression of γ-Aminobutyric Acid (GABA) Transaminases Induces Prominent GABA Accumulation, Dwarfism and Infertility in the Tomato (Solanum lycopersicum L.)

    OpenAIRE

    Koike, Satoshi; Matsukura, Chiaki; Takayama, Mariko; Asamizu, Erika; Ezura, Hiroshi

    2013-01-01

    Tomatoes accumulate γ-aminobutyric acid (GABA) at high levels in the immature fruits. GABA is rapidly converted to succinate during fruit ripening through the activities of GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH). Although three genes encoding GABA-T and both pyruvate- and α-ketoglutarate-dependent GABA-T activities have been detected in tomato fruits, the mechanism underlying the GABA-T-mediated conversion of GABA has not been fully understood. In this wor...

  16. Mutations in γ-aminobutyric acid (GABA) transaminase genes in plants or Pseudomonas syringae reduce bacterial virulence

    NARCIS (Netherlands)

    D.H. Park; R. Mirabella; P.A. Bronstein; G.M. Preston; M.A. Haring; C.K. Lim; A. Collmer; R.C. Schuurink

    2010-01-01

    Pseudomonas syringae pv. tomato DC3000 is a bacterial pathogen of Arabidopsis and tomato that grows in the apoplast. The non-protein amino acid γ-amino butyric acid (GABA) is produced by Arabidopsis and tomato and is the most abundant amino acid in the apoplastic fluid of tomato. The DC3000 genome h

  17. Analysis of an avtA::Mu d1(Ap lac) mutant: metabolic role of transaminase C.

    OpenAIRE

    Whalen, W A; Berg, C M

    1982-01-01

    Escherichia coli can synthesize alpha-ketoisovalerate, the precursor of valine, leucine, and pantothenate, by three routes: anabolically via dihydroxyacid dehydrase and catabolically via both the branched-chain amino acid transaminase (transaminase B) and the alanine-valine transaminase (transaminase C). An E. coli K-12 mutant devoid of transaminase C (avtA) was isolated by mutagenizing an isoleucine-requiring strain devoid of transaminase B (ilvE::Tn5) with Mu d1(Ap lac) and selecting for va...

  18. Substitution of glutamine for lysine at the pyridoxal phosphate binding site of bacterial D-amino acid transaminase. Effects of exogenous amines on the slow formation of intermediates.

    Science.gov (United States)

    Futaki, S; Ueno, H; Martinez del Pozo, A; Pospischil, M A; Manning, J M; Ringe, D; Stoddard, B; Tanizawa, K; Yoshimura, T; Soda, K

    1990-12-25

    In bacterial D-amino acid transaminase, Lys-145, which binds the coenzyme pyridoxal 5'-phosphate in Schiff base linkage, was changed to Gln-145 by site-directed mutagenesis (K145Q). The mutant enzyme had 0.015% the activity of the wild-type enzyme and was capable of forming a Schiff base with D-alanine; this external aldimine was formed over a period of minutes depending upon the D-alanine concentration. The transformation of the pyridoxal-5'-phosphate form of the enzyme to the pyridoxamine-5'-phosphate form (i.e. the half-reaction of transamination) occurred over a period of hours with this mutant enzyme. Thus, information on these two steps in the reaction and on the factors that influence them can readily be obtained with this mutant enzyme. In contrast, these reactions with the wild-type enzyme occur at much faster rates and are not easily studied separately. The mutant enzyme shows distinct preference for D- over L-alanine as substrates but it does so about 50-fold less effectively than the wild-type enzyme. Thus, Lys-145 probably acts in concert with the coenzyme and other functional side chain(s) to lead to efficient and stereochemically precise transamination in the wild-type enzyme. The addition of exogenous amines, ethanolamine or methyl amine, increased the rate of external aldimine formation with D-alanine and the mutant enzyme but the subsequent transformation to the pyridoxamine-5'-phosphate form of the enzyme was unaffected by exogenous amines. The wild-type enzyme displayed a large negative trough in the circular dichroic spectrum at 420 nm, which was practically absent in the mutant enzyme. However, addition of D-alanine to the mutant enzyme generated this negative Cotton effect (due to formation of the external aldimine with D-alanine). This circular dichroism band gradually collapsed in parallel with the transformation to the pyridoxamine-5'-phosphate enzyme. Further studies on this mutant enzyme, which displays the characteristics of the wild

  19. Attenuation of γ-aminobutyric acid (GABA) transaminase activity contributes to GABA increase in the cerebral cortex of mice exposed to β-cypermethrin.

    Science.gov (United States)

    Han, Y; Cao, D; Li, X; Zhang, R; Yu, F; Ren, Y; An, L

    2014-03-01

    The current study investigated the γ-aminobutyric acid (GABA) levels and GABA metabolic enzymes (GABA transaminase (GABA(T)) and glutamate decarboxylase (GAD)) activities at 2 and 4 h after treatment, using a high-performance liquid chromatography with ultraviolet detectors and colorimetric assay, in the cerebral cortex of mice treated with 20, 40 or 80 mg/kg β-cypermethrin by a single oral gavage, with corn oil as vehicle control. In addition, GABA protein (4 h after treatment), GABA(T) protein (2 h after treatment) and GABA receptors messenger RNA (mRNA) expression were detected by immunohistochemistry, Western blot and real-time quantitative reverse transcriptase polymerase chain reaction, respectively. β-Cypermethrin (80 mg/kg) significantly increased GABA levels in the cerebral cortex of mice, at both 2 and 4 h after treatment, compared with the control. Also, GABA immunohistochemistry results suggested that the number of positive granules was increased in the cerebral cortex of mice 4 h after exposure to 80 mg/kg β-cypermethrin when compared with the control. Furthermore, the results also showed that GABA(T) activity detected was significantly decreased in the cerebral cortex of mice 2 h after β-cypermethrin administration (40 or 80 mg/kg). No significant changes were found in GAD activity, or the expression of GABA(T) protein and GABAB receptors mRNA, in the cerebral cortex of mice, except that 80 mg/kg β-cypermethrin caused a significant decrease, compared with the vehicle control, in GABAA receptors mRNA expression 4 h after administration. These results suggested that attenuated GABA(T) activity induced by β-cypermethrin contributed to increased GABA levels in the mouse brain. The downregulated GABAA receptors mRNA expression is most likely a downstream event.

  20. Suppression of γ-aminobutyric acid (GABA) transaminases induces prominent GABA accumulation, dwarfism and infertility in the tomato (Solanum lycopersicum L.).

    Science.gov (United States)

    Koike, Satoshi; Matsukura, Chiaki; Takayama, Mariko; Asamizu, Erika; Ezura, Hiroshi

    2013-05-01

    Tomatoes accumulate γ-aminobutyric acid (GABA) at high levels in the immature fruits. GABA is rapidly converted to succinate during fruit ripening through the activities of GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH). Although three genes encoding GABA-T and both pyruvate- and α-ketoglutarate-dependent GABA-T activities have been detected in tomato fruits, the mechanism underlying the GABA-T-mediated conversion of GABA has not been fully understood. In this work, we conducted loss-of-function analyses utilizing RNA interference (RNAi) transgenic plants with suppressed pyruvate- and glyoxylate-dependent GABA-T gene expression to clarify which GABA-T isoforms are essential for its function. The RNAi plants with suppressed SlGABA-T gene expression, particularly SlGABA-T1, showed severe dwarfism and infertility. SlGABA-T1 expression was inversely associated with GABA levels in the fruit at the red ripe stage. The GABA contents in 35S::SlGABA-T1(RNAi) lines were 1.3-2.0 times and 6.8-9.2 times higher in mature green and red ripe fruits, respectively, than the contents in wild-type fruits. In addition, SlGABA-T1 expression was strongly suppressed in the GABA-accumulating lines. These results indicate that pyruvate- and glyoxylate-dependent GABA-T is the essential isoform for GABA metabolism in tomato plants and that GABA-T1 primarily contributes to GABA reduction in the ripening fruits.

  1. beta-Chloro-L-alanine inhibition of the Escherichia coli alanine-valine transaminase.

    OpenAIRE

    Whalen, W A; Wang, M D; Berg, C M

    1985-01-01

    beta-Chloro-L-alanine, an amino acid analog which inhibits a number of enzymes, reversibly inhibited the Escherichia coli K-12 alanine-valine transaminase, transaminase C. This inhibition, along with the inhibition of transaminase B, accounted for the isoleucine-plus-valine requirement of E. coli in the presence of beta-chloro-L-alanine.

  2. Development of Inhibitors of Salicylic Acid Signaling.

    Science.gov (United States)

    Jiang, Kai; Kurimoto, Tetsuya; Seo, Eun-kyung; Miyazaki, Sho; Nakajima, Masatoshi; Nakamura, Hidemitsu; Asami, Tadao

    2015-08-19

    Salicylic acid (SA) plays important roles in the induction of systemic acquired resistance (SAR) in plants. Determining the mechanism of SAR will extend our understanding of plant defenses against pathogens. We recently reported that PAMD is an inhibitor of SA signaling, which suppresses the expression of the pathogenesis-related PR genes and is expected to facilitate the understanding of SA signaling. However, PAMD strongly inhibits plant growth. To minimize the side effects of PAMD, we synthesized a number of PAMD derivatives, and identified compound 4 that strongly suppresses the expression of the PR genes with fewer adverse effects on plant growth than PAMD. We further showed that the adverse effects on plant growth were partially caused the stabilization of DELLA, which is also related to the pathogen responses. These results indicate that compound 4 would facilitate our understanding of SA signaling and its cross talk with other plant hormones.

  3. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies

    OpenAIRE

    Parviz, Mahsa; Vogel, Kara; Gibson, K Michael; Pearl, Phillip L.

    2014-01-01

    Clinical disorders known to affect inherited gamma-amino butyric acid (GABA) metabolism are autosomal recessively inherited succinic semialdehyde dehydrogenase and GABA-transaminase deficiency. The clinical presentation of succinic semialdehyde dehydrogenase deficiency includes intellectual disability, ataxia, obsessive-compulsive disorder and epilepsy with a nonprogressive course in typical cases, although a progressive form in early childhood as well as deterioration in adulthood with worse...

  4. Anacardic acid derived salicylates are inhibitors or activators of lipoxygenases

    NARCIS (Netherlands)

    Wisastra, Rosalina; Ghizzoni, Massimo; Boltjes, Andre; Haisma, Hidde J.; Dekker, Frank J.

    2012-01-01

    Lipoxygenases catalyze the oxidation of unsaturated fatty acids, such as linoleic acid, which play a crucial role in inflammatory responses. Selective inhibitors may provide a new therapeutic approach for inflammatory diseases. In this study, we describe the identification of a novel soybean lipoxyg

  5. Amino acids as corrosion inhibitors for copper in acidic medium: Experimental and theoretical study

    OpenAIRE

    Milošev Ingrid; Pavlinac Jasminka; Hodošček Milan; Lesar Antonija

    2013-01-01

    Experimental electrochemical methods combined with quantum chemical calculations and molecular dynamics simulations were used to investigate the possibility of use various amino acids as “green” corrosion inhibitors for copper in 0.5 M HCl solution. Among eleven amino acids studied, cysteine achieved the highest inhibitor effectiveness reaching 52% at 10 mM concentration. Other amino acids reached achieved effectiveness less than 25%, some of them even acte...

  6. Corrosion Inhibition of a Green Scale Inhibitor Polyepoxysuccinic Acid

    Institute of Scientific and Technical Information of China (English)

    Rong Chun XIONG; Qing ZHOU; Gang WEI

    2003-01-01

    The corrosion inhibition of a green scale inhibitor, polyepoxysuccinic acid (PESA) wasstudied based on dynamic tests. It is found that when PESA is used alone, it had good corrosioninhibition. So, PESA should be included in the category of corrosion inhibitors. It is not only akind of green scale inhibitor, but also a green corrosion inhibitor. The synergistic effect betweenPESA and Zn2+ or sodium gluconate is poor. However, the synergistic effect among PESA, Zn2+and sodium gluconate is excellent, and the corrosion inhibition efficiency for carbon steel is higherthan 99%. Further study of corrosion inhibition mechanism reveals that corrosion inhibition ofPESA is not affected by carboxyl group, but by the oxygen atom inserted The existence ofoxygen atom in PESA molecular structure makes it easy to form stable chelate with pentacyclicstructure.

  7. Hybridization of glutamate aspartate transaminase. Investigation of subunit interaction.

    Science.gov (United States)

    Boettcher, B; Martinez-Carrion, M

    1975-10-01

    Glutamate aspartate transaminase (EC 2.6.1.1) is a dimeric enzyme with identical subunits with each active site containing pyridoxal 5'-phosphate linked via an internal Shiff's base to a lysine residue. It is not known if these sites interact during catalysis but negative cooperativity has been reported for binding of the coenzyme (Arrio-Dupont, M. (1972), Eur. J. Biochem. 30, 307). Also nonequivalence of its subunits in binding 8-anilinonaphthalene-1-sulfonate (Harris, H.E., and Bayley, P. M. (1975), Biochem. J. 145, 125), in modification of only a single tyrosine with full loss of activity (Christen, P., and Riordan, J.F. (1970), Biochemistry 9, 3025), and following modification with 5,5'-dithiobis(2-nitrobenzoic acid) (Cournil, I., and Arrio-Dupont, M. (1973), Biochemie 55, 103) has been reported. However, steady-state and transient kinetic methods as well as direct titration of the active site chromophore with substrates and substrate analogs have not revealed any cooperative phenomena (Braunstein, A. E. (1973), Enzymes, 3rd Ed. 9, 379). It was therefore decided that a more direct approach should be used to clarify the quistion of subunit interaction during the covalent phase of catalysis. To this end a hybrid method was devised in which a hybrid transaminase was prepared which contained one subunit with a functional active site while the other subunit has the internal Shiff's base reduced with NaBH4. The specific activities and amount of "actively bound" pyridoxal 5'-phosphate are both in a 2:1 ratio for the native and hybrid forms. Comparison of the steady-state kinetic properties of the hybrid and native enzyme forms shows that both forms gave parallel double reciprocal plots which is characteristic of the Ping-Pong Bi-Bi mechanism of transamination. The Km values for the substrates L-aspartic acid and alpha-ketoglutaric acid are nearly identical while the Vmax value for the hybrid is one-half the value of the native transaminase. It therefore appears that

  8. Regulation of transaminase C synthesis in Escherichia coli: conditional leucine auxotrophy.

    Science.gov (United States)

    McGilvray, D; Umbarger, H E

    1974-11-01

    The regulation of synthesis of the valine-alanine-alpha-aminobutyrate transaminase (transaminase C) was studied in Escherichia coli mutants lacking the branched-chain amino acid transaminase (transaminase B). An investigation was made of two strains, CU2 and CU2002, each carrying the same transaminase B lesion but exhibiting different growth responses on a medium supplemented with branched-chain amino acids. Both had the absolute isoleucine requirement characteristic of ilvE auxotrophs, but growth of strain CU2 was stimulated by valine, whereas that of strain CU2002 was markedly inhibited by valine. Strain CU2002 behaved like a conditional leucine auxotroph in that the inhibition by valine was reversed by leucine. Results of enzymatic studies showed that synthesis of transaminase C was repressed by valine in strain CU2002 but not in strain CU2. Inhibition by valine in strain CU2002 appears to be the combined effect of repression on transaminase C synthesis and valine-dependent feedback inhibition of alpha-acetohydroxy acid synthase activity, causing alpha-ketoisovalerate (and hence leucine) limitation. The ilvE markers of strains CU2 and CU2002 were each transferred by transduction to a wild-type genetical background. All ilvE recombinants from both crosses resembled strain CU2002 and were inhibited by valine in the presence of isoleucine. Thus, strain CU2 carries an additional lesion that allows it to grow on a medium containing isoleucine plus valine. It is concluded that conditional leucine auxotrophy is characteristic of mutants carrying an ilvE lesion alone. PMID:4616947

  9. Factors associated with mortality in human immunodeficiency virus type 1-infected adults initiating protease inhibitor-containing therapy: role of education level and of early transaminase level elevation (APROCO-ANRS EP11 study). The Antiprotéases Cohorte Agence Nationale de Recherches sur le SIDA EP 11 study.

    Science.gov (United States)

    Lewden, Charlotte; Raffi, François; Cuzin, Lise; Cailleton, Valérie; Vildé, Jean-Louis; Chêne, Geneviève; Allavena, Clotilde; Salamon, Roger; Leport, Catherine

    2002-09-01

    This study attempted to identify factors associated with mortality among human immunodeficiency virus (HIV)-infected adults starting a protease inhibitor (PI)-containing therapy. Among 1155 patients consecutively enrolled in the APROCO study between May 1997 and June 1998, clinical characteristics were as follows: median age, 36 years; median baseline CD4 cell count, 288 cells/mm(3); and median baseline plasma HIV RNA load, 4.4 log(10) copies/mL. After a median follow-up of 27 months, 48 deaths had occurred, of which 44% were related to acquired immune deficiency syndrome. The mortality rate was 2.9% at 12 months. When both data at baseline and data at 4 months after the start of PI therapy were considered, factors independently associated with mortality were (Cox model) low baseline plasma creatinine level, low school education level, low CD4 cell count at 4 months, low hemoglobin level, and elevated hepatic transaminase levels. Thus, social context plus clinical and biologic data, including the 4-month response to treatment, must be considered in treatment of HIV-infected patients. PMID:12195361

  10. Purification, characterization, and molecular cloning of a novel amine:pyruvate transaminase from Vibrio fluvialis JS17.

    Science.gov (United States)

    Shin, J-S; Yun, H; Jang, J-W; Park, I; Kim, B-G

    2003-06-01

    A transaminase from Vibrio fluvialis JS17 showing activity toward chiral amines was purified to homogeneity and its enzymatic properties were characterized. The transaminase showed an apparent molecular mass of 100 kDa as determined by gel filtration chromatography and a subunit mass of 50 kDa by MALDI-TOF mass spectrometry, suggesting a dimeric structure. The enzyme had an isoelectric point of 5.4 and its absorption spectrum exhibited maxima at 320 and 405 nm. The optimal pH and temperature for enzyme activity were 9.2 and 37 degrees C, respectively. Pyruvate and pyridoxal 5'-phosphate increased enzyme stability whereas (S)-alpha-methylbenzylamine reversibly inactivated the enzyme. The transaminase gene was cloned from a V. fluvialis JS17 genomic library. The deduced amino acid sequence (453 residues) showed significant homology with omega-amino acid:pyruvate transaminases (omega-APT) from various bacterial strains (80 identical residues with four omega-APTs). However, of 159 conserved residues in the four omega-APTs, 79 were not conserved in the transaminase from V. fluvialis JS17. Taken together with the sequence homology results, and the lack of activity toward beta-alanine (a typical amino donor for the omega-APT), the results suggest that the transaminase is a novel amine:pyruvate transaminase that has not been reported to date. PMID:12687298

  11. Fatty acid synthase inhibitors isolated from Punica granatum L

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, He-Zhong [School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, (China); Ma, Qing-Yun; Liang, Wen-Juan; Huang, Sheng-Zhuo; Dai, Hao-Fu; Wang, Peng-Cheng; Zhao, You-Xing, E-mail: zhaoyx1011@163.com [Institute of Tropical Bioscience and Biotechnology, Chinese Academy of Tropical Agricultural Sciences, Haikou (China); Fan, Hui-Jin; Ma, Xiao-Feng, E-mail: maxiaofeng@gucas.ac.cn [College of Life Sciences, Graduate University of Chinese Academy of Sciences, Beijing (China)

    2012-05-15

    The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC{sub 50} value of 10.3 {mu}mol L{sup -1}. (author)

  12. Fatty acid synthase inhibitors isolated from Punica granatum L

    International Nuclear Information System (INIS)

    The aim of this work is the isolation of fatty acid synthase (FAS) inhibitors from the ethyl acetate extracts of fruit peels of Punica granatum L. Bioassay-guided chemical investigation of the fruit peels resulted in the isolation of seventeen compounds mainly including triterpenoids and phenolic compounds, from which one new oleanane-type triterpene (punicaone) along with fourteen known compounds were isolated for the first time from this plant. Seven isolates were evaluated for inhibitory activities of FAS and two compounds showed to be active. Particularly, flavogallonic acid exhibited strong FAS inhibitory activity with IC50 value of 10.3 μmol L-1. (author)

  13. Bisphosphonic acids as effective inhibitors of Mycobacterium tuberculosis glutamine synthetase.

    Science.gov (United States)

    Kosikowska, Paulina; Bochno, Marta; Macegoniuk, Katarzyna; Forlani, Giuseppe; Kafarski, Paweł; Berlicki, Łukasz

    2016-12-01

    Inhibition of glutamine synthetase (GS) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. Forty-three bisphosphonic and bis-H-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from Mycobacterium tuberculosis. Most of the studied compounds exhibited activities in micromolar range, with N-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, N-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic acid and N-(3,4-dichlorophenyl)-1-hydroxy-1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound - L-methionine-S-sulfoximine. Moreover, these inhibitors were found to be much more effective against pathogen enzyme than against the human ortholog. Thus, with the bone-targeting properties of the bisphosphonate compounds in mind, this activity/selectivity profile makes these compounds attractive agents for the treatment of bone tuberculosis.

  14. Polyethelene Glycol-Anthranilic Acid Composite as Corrosion Inhibitor for Mild Steel in Acid Medium

    Directory of Open Access Journals (Sweden)

    N. Banumathi

    2010-01-01

    Full Text Available The polymer PGA composite was prepared by chemical oxidative method of polyethylene glycol, anthranilic acid with ammonium persulphate in oxalic acid medium. The resulted polymer was characterized by FTIR spectroscopy. The performance of the polymer polyglycol anthranilic acid composite (PGA as corrosion inhibitor for mild steel in 1 M HCl has been studied by weight loss, potentiodynamic and impedance spectroscopy methods. The maximum IE was found to be 97%. Experimental results were fitted to Langmuir adsorption isotherm. Electrochemical studies confirmed the inhibitive nature of the PGA composite and also the mixed nature of the inhibitor. The polymer is found to be highly efficient non-toxic and environmentally safe.

  15. Role of alanine-valine transaminase in Salmonella typhimurium and analysis of an avtA::Tn5 mutant.

    OpenAIRE

    Berg, C M; Whalen, W A; Archambault, L B

    1983-01-01

    In Salmonella typhimurium, as in Escherichia coli, mutations in avtA, the gene encoding the alanine-valine transaminase (transaminase C), are silent unless they are combined with mutations involved in isoleucine-valine biosynthesis. avtA is repressed by leucine or alanine but not by valine. Transaminase C is found at reduced levels upon starvation for any one of several amino acids. We hypothesize that this is due to repression of avtA by the elevated alanine and leucine pools found in amino ...

  16. The enzyme 3-hydroxykynurenine transaminase as potential target for 1,2,4-oxadiazoles with larvicide activity against the dengue vector Aedes aegypti.

    Science.gov (United States)

    Oliveira, Vanessa S; Pimenteira, Cecília; da Silva-Alves, Diana C B; Leal, Laylla L L; Neves-Filho, Ricardo A W; Navarro, Daniela M A F; Santos, Geanne K N; Dutra, Kamilla A; dos Anjos, Janaína V; Soares, Thereza A

    2013-11-15

    The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.

  17. Genetic manipulation of the γ-aminobutyric acid (GABA) shunt in rice: overexpression of truncated glutamate decarboxylase (GAD2) and knockdown of γ-aminobutyric acid transaminase (GABA-T) lead to sustained and high levels of GABA accumulation in rice kernels.

    Science.gov (United States)

    Shimajiri, Yasuka; Oonishi, Takayuki; Ozaki, Kae; Kainou, Kumiko; Akama, Kazuhito

    2013-06-01

    Gamma-aminobutyric acid (GABA) is a non-protein amino acid commonly present in all organisms. Because cellular levels of GABA in plants are mainly regulated by synthesis (glutamate decarboxylase, GAD) and catabolism (GABA-transaminase, GABA-T), we attempted seed-specific manipulation of the GABA shunt to achieve stable GABA accumulation in rice. A truncated GAD2 sequence, one of five GAD genes, controlled by the glutelin (GluB-1) or rice embryo globulin promoters (REG) and GABA-T-based trigger sequences in RNA interference (RNAi) cassettes controlled by one of these promoters as well, was introduced into rice (cv. Koshihikari) to establish stable transgenic lines under herbicide selection using pyriminobac. T₁ and T₂ generations of rice lines displayed high GABA concentrations (2-100 mg/100 g grain). In analyses of two selected lines from the T₃ generation, there was a strong correlation between GABA level and the expression of truncated GAD2, whereas the inhibitory effect of GABA-T expression was relatively weak. In these two lines both with two T-DNA copies, their starch, amylose, and protein levels were slightly lower than non-transformed cv. Koshihikari. Free amino acid analysis of mature kernels of these lines demonstrated elevated levels of GABA (75-350 mg/100 g polished rice) and also high levels of several amino acids, such as Ala, Ser, and Val. Because these lines of seeds could sustain their GABA content after harvest (up to 6 months), the strategy in this study could lead to the accumulation GABA and for these to be sustained in the edible parts.

  18. Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

    DEFF Research Database (Denmark)

    Kornhuber, Johannes; Muehlbacher, Markus; Trapp, Stefan;

    2011-01-01

    of ASM, such as Alzheimer's disease, major depression, radiation-and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 mu M drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups......We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity...... with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate...

  19. cis-Cinnamic acid selective suppressors distinct from auxin inhibitors.

    Science.gov (United States)

    Okuda, Katsuhiro; Nishikawa, Keisuke; Fukuda, Hiroshi; Fujii, Yoshiharu; Shindo, Mitsuru

    2014-01-01

    The activity of cis-cinnamic acid (cis-CA), one of the allelochemicals, in plants is very similar to that of indole-3-acetic acid (IAA), a natural auxin, and thus cis-CA has long been believed to be an analog of auxin. We have reported some structure-activity relationships studies by synthesizing over 250 cis-CA derivatives and estimating their inhibitory activities on root growth inhibition in lettuce. In this study, the compounds that showed low- or no-activity on root growth inhibition were recruited as candidates suppressors against cis-CA and/or auxin and tested for their activity. In the presence of cis-CA, lettuce root growth was inhibited; however, the addition of some cis-CA derivatives restored control-level root growth. Four compounds, (Z)-3-(4-isopropylphenyl)acrylic acid, (Z)-3-(3-butoxyphenyl)acrylic acid, (Z)-3-[3-(pentyloxy)phenyl]acrylic acid, and (Z)-3-(naphthalen-1-yl)acrylic acid were selected as candidates for a cis-CA selective suppressor they allowed the recovery of root growth from inhibition by cis-CA treatment without any effects on the IAA-induced effect or elongating activity by themselves. Three candidates significantly ameliorated the root shortening by the potent inhibitor derived from cis-CA. In brief, we have found some cis-CA selective suppressors which have never been reported from inactive cis-CA derivatives for root growth inhibition. cis-CA selective suppressors will play an important role in elucidating the mechanism of plant growth regulation. PMID:24881667

  20. Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines

    OpenAIRE

    Chavez-Blanco, Alma; Perez-Plasencia, Carlos; Perez-Cardenas, Enrique; Carrasco-Legleu, Claudia; Rangel-Lopez, Edgar; Segura-Pacheco, Blanca; Taja-Chayeb, Lucia; Trejo-Becerril, Catalina; Gonzalez-Fierro, Aurora; Candelaria, Myrna; Cabrera, Gustavo; Duenas-Gonzalez, Alfonso

    2006-01-01

    Background Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines. Results Hydralazi...

  1. Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines

    OpenAIRE

    Candelaria Myrna; Gonzalez-Fierro Aurora; Trejo-Becerril Catalina; Taja-Chayeb Lucia; Segura-Pacheco Blanca; Rangel-Lopez Edgar; Carrasco-Legleu Claudia; Perez-Cardenas Enrique; Perez-Plasencia Carlos; Chavez-Blanco Alma; Cabrera Gustavo; Duenas-Gonzalez Alfonso

    2006-01-01

    Abstract Background Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines. Results ...

  2. Identification of novel functional inhibitors of acid sphingomyelinase.

    Directory of Open Access Journals (Sweden)

    Johannes Kornhuber

    Full Text Available We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM. These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse, therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78% compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66% drugs licensed for medical use in humans.

  3. Corrosion Inhibition of Aluminum in Acidic Solution by Aqueous Extract of Ajowan Plant as Green Inhibitor

    OpenAIRE

    Aisha M. Al-Turkustani; Mona M. Al-Solmi

    2011-01-01

    The inhibition of aluminum corrosion in 0.5 M hydrochloric acid by Ajowan plant was studied using chemical (weight loss) and ectrochemical (impedance and polarization) methods. The Ajowan plant extract was found to be good inhibitor for aluminum corrosion in 0.5 M hydrochloric acid in the studied concentration range of inhibitor. Corrosion inhibition could be explained by considering an interaction between metal surface and the inhibitor molecules. Electrochemical measurements showed that Ajo...

  4. A β-Alanine Catabolism Pathway Containing a Highly Promiscuous ω-Transaminase in the 12-Aminododecanate-Degrading Pseudomonas sp. Strain AAC

    OpenAIRE

    Wilding, Matthew; Thomas S Peat; Newman, Janet; Scott, Colin

    2016-01-01

    ABSTRACT We previously isolated the transaminase KES23458 from Pseudomonas sp. strain AAC as a promising biocatalyst for the production of 12-aminododecanoic acid, a constituent building block of nylon-12. Here, we report the subsequent characterization of this transaminase. It exhibits activity with a broad substrate range which includes α-, β-, and ω-amino acids, as well as α,ω-diamines and a number of other industrially relevant compounds. It is therefore a prospective candidate for the bi...

  5. TRANSAMINASES ACTIVITY IN THE SAND LIZARD’S SERUM UNDER INFLUENCE OF INDUSTRIAL POLLUTION

    OpenAIRE

    O. Y. Klymenko; V. Y. Gasso

    2009-01-01

    Influence of the environmental pollution on the alanine aminotransferase and aspartate aminotransferase activity in the blood serum of the sand lizard has been studied. Aminotransferases (ALT and AST) are similar by the mechanism of action. These enzymes take part in the amino acids metabolism. The increase of the transaminases activities under conditions of the pollution is found. It may be a proof of a damage of relevant organs: namely, the liver.

  6. Characterization of a novel amine transaminase from Halomonas elongata

    OpenAIRE

    Cerioli, Lorenzo; Planchestainer, Matteo; Cassidy, Jennifer; Tessaro, Davide; Paradisi, Francesca

    2015-01-01

    Chiral amines are indispensable building blocks in the production of biologically active compounds. They are fundamental for the pharmaceutical industry, both as active molecules themselves and as chiral auxiliaries in asymmetric synthesis; however, the available synthetic strategies often present disadvantages. ω-Transaminases (ω-TAs) appear as an attractive alternative by driving the stereoselective amination of prochiral ketones. HEWT is a novel amine transaminase from the moderate halophi...

  7. Amino acids as corrosion inhibitors for copper in acidic medium: Experimental and theoretical study

    Directory of Open Access Journals (Sweden)

    Milošev Ingrid

    2013-01-01

    Full Text Available Experimental electrochemical methods combined with quantum chemical calculations and molecular dynamics simulations were used to investigate the possibility of use various amino acids as “green” corrosion inhibitors for copper in 0.5 M HCl solution. Among eleven amino acids studied, cysteine achieved the highest inhibitor effectiveness reaching 52% at 10 mM concentration. Other amino acids reached achieved effectiveness less than 25%, some of them even acted as corrosion accelerators. Based on the experimental results, theoretical calculations and simulations were focused on cysteine and alanine. The electronic and reactivity parameters of their protonated forms in electrical double layer were evaluated by density functional calculations. In addition, molecular dynamic simulations were introduced to follow the adsorption behaviour of these two amino acids at the Cu(111 surface in the electrolyte solution. The results indicate that the orientation of both molecules is nearly parallel to the surface except of ammonium group which is directed away from the surface. Therefore, as the orientation of the cysteine and alanine molecules at the surface is similar, thiol functional group is responsible for superior inhibition efficiency of cysteine.

  8. GREWIA TILIAEFOLIA BARK EXTRACT AS GREEN INHIBITOR OF MILD STEEL C ORROSION IN SULPHURIC ACID MEDIUM

    OpenAIRE

    V.N. Sheeja; S. Subhashini

    2015-01-01

    This paper presents the inhibitory properties of Grewia tiliaefolia bark extract on the corrosion of mild steel in sulphuric acid medium. The corrosion rates and inhibition efficiencies were evaluated by weight loss measurements. The adsorption of inhibitor obeyed Langmuir isotherm and the negative values of Gibbs energy indicate the nature of interactions between inhibitor molecules and metal surface. Further...

  9. Kynurenine aminotransferase III and glutamine transaminase L are identical enzymes that have cysteine S-conjugate β-lyase activity and can transaminate L-selenomethionine.

    Science.gov (United States)

    Pinto, John T; Krasnikov, Boris F; Alcutt, Steven; Jones, Melanie E; Dorai, Thambi; Villar, Maria T; Artigues, Antonio; Li, Jianyong; Cooper, Arthur J L

    2014-11-01

    Three of the four kynurenine aminotransferases (KAT I, II, and IV) that synthesize kynurenic acid, a neuromodulator, are identical to glutamine transaminase K (GTK), α-aminoadipate aminotransferase, and mitochondrial aspartate aminotransferase, respectively. GTK/KAT I and aspartate aminotransferase/KAT IV possess cysteine S-conjugate β-lyase activity. The gene for the former enzyme, GTK/KAT I, is listed in mammalian genome data banks as CCBL1 (cysteine conjugate beta-lyase 1). Also listed, despite the fact that no β-lyase activity has been assigned to the encoded protein in the genome data bank, is a CCBL2 (synonym KAT III). We show that human KAT III/CCBL2 possesses cysteine S-conjugate β-lyase activity, as does mouse KAT II. Thus, depending on the nature of the substrate, all four KATs possess cysteine S-conjugate β-lyase activity. These present studies show that KAT III and glutamine transaminase L are identical enzymes. This report also shows that KAT I, II, and III differ in their ability to transaminate methyl-L-selenocysteine (MSC) and L-selenomethionine (SM) to β-methylselenopyruvate (MSP) and α-ketomethylselenobutyrate, respectively. Previous studies have identified these seleno-α-keto acids as potent histone deacetylase inhibitors. Methylselenol (CH3SeH), also purported to have chemopreventive properties, is the γ-elimination product of SM and the β-elimination product of MSC catalyzed by cystathionine γ-lyase (γ-cystathionase). KAT I, II, and III, in part, can catalyze β-elimination reactions with MSC generating CH3SeH. Thus, the anticancer efficacy of MSC and SM will depend, in part, on the endogenous expression of various KAT enzymes and cystathionine γ-lyase present in target tissue coupled with the ability of cells to synthesize in situ either CH3SeH and/or seleno-keto acid metabolites.

  10. Azorhodanine derivatives as inhibitors for acidic corrosion of nickel.

    Science.gov (United States)

    Fouda, Abd El-Aziz S; Al-Sarawy, Ahmed A; Omar, Tark M

    2005-01-01

    Azorhodanine derivatives (HL1-HL5) were tested as corrosion inhibitors for nickel in 2M HNO3 solution using weight loss and galvanostatic polarization techniques. The results showed that these derivatives act as inhibitors for nickel in this medium. The inhibition was assumed to occur via adsorption of the inhibitor molecule on the metal surface. Polarization measurements indicated that these compounds act as mixed-type inhibitors, but the cathode is more polarized when an external current was applied. This means that these compounds retard the rate of hydrogen evolution and the rate of dissolution of the metal. Results showed that azorhodanine derivatives are adsorbed on the nickel surface following Temkin's adsorption isotherm. The activation energy and thermodynamic parameters were calculated and discussed at different temperatures (30-45 degrees C).

  11. Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines

    Directory of Open Access Journals (Sweden)

    Candelaria Myrna

    2006-01-01

    Full Text Available Abstract Background Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines. Results Hydralazine showed no growth inhibitory effect on cervical, colon, breast, sarcoma, glioma, and head & neck cancer cell lines when used alone. On the contrary, valproic acid showed a strong growth inhibitory effect that is potentiated by hydralazine in some cell lines. Individually, hydralazine and valproic acid displayed distinctive effects upon global gene over-expression but the number of genes over-expressed increased when cells were treated with the combination. Treatment of HeLa cells with hydralazine and valproic acid lead to an increase in the cytotoxicity of gemcitabine, cisplatin and adriamycin. A higher antitumor effect of adriamycin was observed in mice xenografted with human fibrosarcoma cells when the animals were co-treated with hydralazine and valproic acid. Conclusion Hydralazine and valproic acid, two widely used drugs for cardiovascular and neurological conditions respectively have promising antineoplastic effects when used concurrently and may increase the antitumor efficacy of current cytotoxic agents.

  12. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

    DEFF Research Database (Denmark)

    Sørensen, Mette G; Henriksen, Kim; Sørensen, Mette Guldmann;

    2010-01-01

    Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we...... screened a protein kinase inhibitor library in human osteoclasts....

  13. Development of Ecofriendly Corrosion Inhibitors for Application in Acidization of Petroleum Oil Well

    Directory of Open Access Journals (Sweden)

    M. Yadav

    2013-01-01

    Full Text Available In the present investigation the protective ability of 1-(2-aminoethyl-2-octadecylimidazoline (AEODI and 1-(2-octadecylamidoethyl-2-octadecylimidazoline (ODAEODI as corrosion inhibitors for N80 steel in 15% hydrochloric acid has been studied, which may find application as ecofriendly corrosion inhibitors in acidizing processes in petroleum industry. Different concentration of synthesized inhibitors AEODI and ODAEODI was added to test solution (15% HCl, and corrosion inhibition of N80 steel was tested by weight loss, potentiodynamic polarization, and AC impedance measurements. Influence of temperature (298 to 323 K on the inhibition behaviour was studied. Surface studies were performed by using SEM. It was found that both the inhibitors were effective inhibitors, and their inhibition efficiency was significantly increased with increasing their concentration. Polarization curves revealed that the used inhibitors represent mixed-type inhibitors. The adsorption of used inhibitors led to a reduction in the double-layer capacitance and an increase in the charge transfer resistance. The adsorption of used compounds was found to obey Langmuir isotherm. The adsorption of the corrosion inhibitors at the surface of N80 steel is the root cause of corrosion inhibition.

  14. [Effect of proteolysis inhibitors on the incorporation of labelled amino acids into proteins].

    Science.gov (United States)

    Konikova, A S; Korotkina, R N

    1975-01-01

    Role of peptide bond breaks in the incorporation of amino acids into proteins in a "protein--amino acid" system is investigated. For this purpose the incorporation of labelled amino acids into trypsin under the inhibition of its autolysis by a specific inhibitor from soybean and epsilon-amino-caproic acid is studied. The trypsin inhibitor from soybean is found to suppress considerably the incorporation of 14C-glycine, 14C-lysine and 14C-methionine into crystal trypsin and not to affect the incorporation of labelled amino acids into chomotrypsin, papain and carboxypeptidase. Epsilon-Aminocaproic acid inhibited 14C-glycine incorporation into crystal trypsin by 40% and did not change its incorporation level into serum albumin. The dependency of amino acid incorporation level into trypsin on the activity of autolysis in the "protein--amino acid" system is demonstrated. PMID:1212456

  15. 2-Aminoimidazole Amino Acids as Inhibitors of the Binuclear Manganese Metalloenzyme Human Arginase I

    Energy Technology Data Exchange (ETDEWEB)

    Ilies, M.; Di Costanzo, L; North, M; Scott, J; Christianson, D

    2010-01-01

    Arginase, a key metalloenzyme of the urea cycle that converts L-arginine into L-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant L-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl)pentanoic acid (A1P, 10), binds to human arginase I with K{sub d} = 2 {micro}M and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles.

  16. Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

    Science.gov (United States)

    Ogawa, Shintaro; Kunugi, Hiroshi

    2015-01-01

    Cannabis and analogs of Δ9-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors' therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted. PMID:26630956

  17. Inhibitors

    Science.gov (United States)

    ... wrong place in the body. Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor reaction from ... body to accept clotting factor concentrate treatments. With ITI therapy, people receive large amounts of clotting factor ...

  18. Chitosan as a green inhibitor for copper corrosion in acidic medium.

    Science.gov (United States)

    El-Haddad, Mahmoud N

    2013-04-01

    The behavior of copper in 0.5 M HCl acid containing different concentrations of chitosan has been studied by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS) and electrochemical frequency modulation (EFM) measurements. Potentiodynamic polarization measurements show that the chitosan acts essentially as a mixed-type inhibitor. EFM can be used as a rapid and non destructive technique for corrosion rate measurements without prior knowledge of Tafel constants. The results of EIS indicate that the value of CPEs tends to decrease and both charge transfer resistance and inhibition efficiency tend to increase by increasing the inhibitor concentration. The investigated inhibitor has shown good inhibition efficiency in 0.5 M HCl. The adsorption of inhibitor on the copper surface obeys Langmuir's isotherm. Metal surface characterization was performed using scanning electron microscope (SEM) and Fourier transform infrared spectroscopy (FT-IR). Also, the relationship between quantum chemical calculations and experimental inhibition efficiency of the inhibitor was discussed. PMID:23298849

  19. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    Science.gov (United States)

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.

  20. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    Science.gov (United States)

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors. PMID:26864638

  1. Inhibitors of fatty acid biosynthesis in sunflower seeds.

    Science.gov (United States)

    Pleite, Rafael; Martínez-Force, Enrique; Garcés, Rafael

    2006-09-01

    During de novo fatty acid synthesis in sunflower seeds, saturated fatty acid production is influenced by the competition between the enzymes of the principal pathways and the saturated acyl-ACP thioesterases. Genetic backgrounds with more efficient saturated acyl-ACP thioesterase alleles only express their phenotypic effects when the alleles for the enzymes in the main pathway are less efficient. For this reason, we studied the incorporation of [2-(14)C]acetate into the lipids of developing sunflower seeds (Helianthus annuus L.) from several mutant lines in vivo. The labelling of different triacylglycerol fatty acids in different oilseed mutants reflects the fatty acid composition of the seed and supports the channelling theory of fatty acid biosynthesis. Incubation with methyl viologen diminished the conversion of stearoyl-ACP to oleoyl-ACP in vivo through a decrease in the available reductant power. In turn, this led to the accumulation of stearoyl-ACP to the levels detected in seeds from high stearic acid mutants. The concomitant reduction of oleoyl-ACP content inside the plastid allowed us to study the activity of acyl-ACP thioesterases on saturated fatty acids. In these mutants, we verified that the accumulation of saturated fatty acids requires efficient thioesterase activity on saturated-ACPs. By studying the effects of cerulenin on the in vivo incorporation of [2-(14)C]acetate into lipids and on the in vitro activity of beta-ketoacyl-ACP synthase II, we found that elongation to very long chain fatty acids can occur both inside and outside of the plastid in sunflower seeds. PMID:16500723

  2. Inhibitors of amino acids biosynthesis as antifungal agents.

    Science.gov (United States)

    Jastrzębowska, Kamila; Gabriel, Iwona

    2015-02-01

    Fungal microorganisms, including the human pathogenic yeast and filamentous fungi, are able to synthesize all proteinogenic amino acids, including nine that are essential for humans. A number of enzymes catalyzing particular steps of human-essential amino acid biosynthesis are fungi specific. Numerous studies have shown that auxotrophic mutants of human pathogenic fungi impaired in biosynthesis of particular amino acids exhibit growth defect or at least reduced virulence under in vivo conditions. Several chemical compounds inhibiting activity of one of these enzymes exhibit good antifungal in vitro activity in minimal growth media, which is not always confirmed under in vivo conditions. This article provides a comprehensive overview of the present knowledge on pathways of amino acids biosynthesis in fungi, with a special emphasis put on enzymes catalyzing particular steps of these pathways as potential targets for antifungal chemotherapy.

  3. Fatty Acid Synthase Inhibitor C75 Ameliorates Experimental Colitis

    OpenAIRE

    Matsuo, Shingo; Yang, Weng-Lang; Aziz, Monowar; Kameoka, Shingo; Wang, Ping

    2013-01-01

    Abnormalities of lipid metabolism through overexpression of fatty acid synthase (FASN), which catalyzes the formation of long-chain fatty acids, are associated with the development of inflammatory bowel disease (IBD). C75 is a synthetic α-methylene-γ-butyrolactone compound that inhibits FASN activity. We hypothesized that C75 treatment could effectively reduce the severity of experimental colitis. Male C57BL/6 mice were fed 4% dextran sodium sulfate (DSS) for 7 d. C75 (5 mg/kg body weight) or...

  4. Sodium phthalamates as corrosion inhibitors for carbon steel in aqueous hydrochloric acid solution

    International Nuclear Information System (INIS)

    Highlights: → N-Alkyl-sodium phthalamates as corrosion inhibitors for industry in acidic medium. → Compounds behaved as mixed type inhibitors and followed Langmuir adsorption isotherm. → Efficiencies were proportional to aliphatic chain length and inhibitor concentration. → Iron complexes and chelates with phthalamates contributed to carbon steel protection. - Abstract: Three compounds of N-alkyl-sodium phthalamates were synthesized and tested as corrosion inhibitors for carbon steel in 0.5 M aqueous hydrochloric acid. Tests showed that inhibitor efficiencies were related to aliphatic chain length and dependent on concentration. N-1-n-tetradecyl-sodium phthalamate displayed moderate efficiency against uniform corrosion, 42-86% at 25 deg. C and 25-60% at 40 oC. Tests indicated that compounds behave as mixed type inhibitors where molecular adsorption on steel followed Langmuir isotherm, whereas thermodynamic suggested that a physisorption process occurred. XPS analysis confirmed film formation on surface, where Fe+2 complexes and Fe+2 chelates with phthalamates prevented steel from further corrosion.

  5. Impacts of lignocellulose-derived inhibitors on L-lactic acid fermentation by Rhizopus oryzae.

    Science.gov (United States)

    Zhang, Li; Li, Xin; Yong, Qiang; Yang, Shang-Tian; Ouyang, Jia; Yu, Shiyuan

    2016-03-01

    Inhibitors generated in the pretreatment and hydrolysis of corn stover and corn cob were identified. In general, they inhibited cell growth, lactate dehydrogenase, and lactic acid production but with less or no adverse effect on alcohol dehydrogenase and ethanol production in batch fermentation by Rhizopus oryzae. Furfural and 5-hydroxymethyl furfural (HMF) were highly toxic at 0.5-1 g L(-1), while formic and acetic acids at less than 4 g L(-1) and levulinic acid at 10 g L(-1) were not toxic. Among the phenolic compounds at 1 g L(-1), trans-cinnamic acid and syringaldehyde had the highest toxicity while syringic, ferulic and p-coumaric acids were not toxic. Although these inhibitors were present at concentrations much lower than their separately identified toxic levels, lactic acid fermentation with the hydrolysates showed much inferior performance compared to the control without inhibitor, suggesting synergistic or compounded effects of the lignocellulose-degraded compounds on inhibiting lactic acid fermentation. PMID:26724548

  6. Binding of [alpha, alpha]-Disubstituted Amino Acids to Arginase Suggests New Avenues for Inhibitor Design

    Energy Technology Data Exchange (ETDEWEB)

    Ilies, Monica; Di Costanzo, Luigi; Dowling, Daniel P.; Thorn, Katherine J.; Christianson, David W. (MIT); (Episcopal U); (Rutgers); (Drexel); (Penn)

    2011-10-21

    Arginase is a binuclear manganese metalloenzyme that hydrolyzes L-arginine to form L-ornithine and urea, and aberrant arginase activity is implicated in various diseases such as erectile dysfunction, asthma, atherosclerosis, and cerebral malaria. Accordingly, arginase inhibitors may be therapeutically useful. Continuing our efforts to expand the chemical space of arginase inhibitor design and inspired by the binding of 2-(difluoromethyl)-L-ornithine to human arginase I, we now report the first study of the binding of {alpha},{alpha}-disubstituted amino acids to arginase. Specifically, we report the design, synthesis, and assay of racemic 2-amino-6-borono-2-methylhexanoic acid and racemic 2-amino-6-borono-2-(difluoromethyl)hexanoic acid. X-ray crystal structures of human arginase I and Plasmodium falciparum arginase complexed with these inhibitors reveal the exclusive binding of the L-stereoisomer; the additional {alpha}-substituent of each inhibitor is readily accommodated and makes new intermolecular interactions in the outer active site of each enzyme. Therefore, this work highlights a new region of the protein surface that can be targeted for additional affinity interactions, as well as the first comparative structural insights on inhibitor discrimination between a human and a parasitic arginase.

  7. Curcumin Derivatives as Green Corrosion Inhibitors for α-Brass in Nitric Acid Solution

    Science.gov (United States)

    Fouda, A. S.; Elattar, K. M.

    2012-11-01

    1,7- Bis-(4-hydroxy-3-methoxy-phenyl)-hepta-1,6-diene-4-arylazo-3,5-dione I-V have been investigated as corrosion inhibitors for α-brass in 2 M nitric acid solution using weight-loss and galvanostatic polarization techniques. The efficiency of the inhibitors increases with the increase in the inhibitor concentration but decreases with a rise in temperature. The conjoint effect of the curcumin derivatives and KSCN has also been studied. The apparent activation energy ( E a*) and other thermodynamic parameters for the corrosion process have also been calculated. The galvanostatic polarization data indicated that the inhibitors were of mixed-type, but the cathode is more polarized than the anode. The slopes of the cathodic and anodic Tafel lines ( b c and b a) are maintained approximately equal for various inhibitor concentrations. However, the value of the Tafel slopes increases together as inhibitor concentration increases. The adsorption of these compounds on α-brass surface has been found to obey the Frumkin's adsorption isotherm. The mechanism of inhibition was discussed in the light of the chemical structure of the undertaken inhibitors.

  8. Trypsin inhibitors from ridged gourd (Luffa acutangula Linn.) seeds: purification, properties, and amino acid sequences.

    Science.gov (United States)

    Haldar, U C; Saha, S K; Beavis, R C; Sinha, N K

    1996-02-01

    Two trypsin inhibitors, LA-1 and LA-2, have been isolated from ridged gourd (Luffa acutangula Linn.) seeds and purified to homogeneity by gel filtration followed by ion-exchange chromatography. The isoelectric point is at pH 4.55 for LA-1 and at pH 5.85 for LA-2. The Stokes radius of each inhibitor is 11.4 A. The fluorescence emission spectrum of each inhibitor is similar to that of the free tyrosine. The biomolecular rate constant of acrylamide quenching is 1.0 x 10(9) M-1 sec-1 for LA-1 and 0.8 x 10(9) M-1 sec-1 for LA-2 and that of K2HPO4 quenching is 1.6 x 10(11) M-1 sec-1 for LA-1 and 1.2 x 10(11) M-1 sec-1 for LA-2. Analysis of the circular dichroic spectra yields 40% alpha-helix and 60% beta-turn for La-1 and 45% alpha-helix and 55% beta-turn for LA-2. Inhibitors LA-1 and LA-2 consist of 28 and 29 amino acid residues, respectively. They lack threonine, alanine, valine, and tryptophan. Both inhibitors strongly inhibit trypsin by forming enzyme-inhibitor complexes at a molar ratio of unity. A chemical modification study suggests the involvement of arginine of LA-1 and lysine of LA-2 in their reactive sites. The inhibitors are very similar in their amino acid sequences, and show sequence homology with other squash family inhibitors. PMID:8924202

  9. N-heterocyclic Amine Derivatives as Efficient Corrosion Inhibitors for Carbon Steel in Acidic Medium

    International Nuclear Information System (INIS)

    A novel heterocyclic amine derivatives, namely N, N'-substituted pyridinyl ethylene diamine tetra acetic acid sodium salt (A) and ethylene diamine N, N'-diacetic acid di (2-methylene tetra hydro furfuryl) acetate (B) were synthesized and their structure confirmations were performed by FTIR, HNMR and CNMR spectra. The inhibition effectiveness was evaluated against the corrosion of carbon steel in 1 M HCl by weight loss and polarization techniques. The results showed that the synthesized derivatives are good corrosion inhibitors for carbon steel in 1 M HCl medium, their inhibition efficiency, increased with inhibitor concentration, and (A) is slightly more effective than (B). The potentiostatic polarization study showed that (A) and (B) are mixed-type inhibitors in 1 M HCl. These compounds prevent carbon steel from corrosion by adsorption to the steel surface and forming insoluble complexes with ferrous species. The weight loss results and potentiostatic polarization studies were in reasonable agreement. (author)

  10. Influence of containing of asphaltenes and naphthenic acids over organic deposition inhibitor performance

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Geiza E.; Mansur, Claudia R.E.; Pires, Renata V.; Passos, Leonardo B.; Lucas, Elizabete F. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Inst. de Macromoleculas; Alvares, Dellyo R.S.; Gonzalez, Gaspar [PETROBRAS, Rio de Janeiro, RJ (Brazil). Centro de Pesquisas (CENPES)

    2004-07-01

    Organic deposition is a serious problem confronted by the petroleum industry in Brazil and worldwide. Among the main petroleum components that may cause deposition problems are waxes and asphaltenes. This work aims at evaluating the influence of petroleum fractions (asphaltenes and naphthenic acids) on the organic deposition phenomenon as well as on organic deposition inhibitors performance. The influence of the organic fractions was evaluated by their ability to change wax crystals, to lower the pour point and to alter the initial wax appearance temperature. The efficiency of the additives was tested by pour point measurements. The results show that asphaltenes seem to act as organic deposition inhibitors, while naphthenic acids do not significantly change the system. Moreover, employing both of them produces no synergic effect. Among polymeric inhibitors, all of the chemically modified EVA copolymer presented better results than the non-modified commercial EVA copolymer. The best result was observed for EVA28C{sub 16}. (author)

  11. Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies.

    Science.gov (United States)

    Bach, Anders; Pizzirani, Daniela; Realini, Natalia; Vozella, Valentina; Russo, Debora; Penna, Ilaria; Melzig, Laurin; Scarpelli, Rita; Piomelli, Daniele

    2015-12-10

    Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads. PMID:26560855

  12. THE STUDY OF HENNA LEAVES EXTRACT AS GREEN CORROSION INHIBITOR FOR MILD STEEL IN ACETIC ACID.

    OpenAIRE

    H. G. Chaudhari; R. T. Vashi

    2016-01-01

    The inhibitive action of henna leaves extract on mild steel in acetic acid solution have been investigated by weight-loss, A C impedence and potentiodynamic polarization measurements. The study indicates that as acid concentration increases corrosion rate increases. The corrosion inhibition efficiency increases with increase in concentration of extract. The result obtained revealed that henna leaves extract act as efficient inhibitor. The adsorption of the henna leaves extract obeyed Langmuir...

  13. Synergism of antifungal activity between mitochondrial respiration inhibitors and kojic acid

    Science.gov (United States)

    Co-application of certain types of compounds with conventional antimicrobial drugs results in the enhancement of efficacy of drugs through a mechanism termed chemosensitization. We show that kojic acid (KA), a natural product, is a potent chemosensitizer to complex III inhibitors of mitochondrial re...

  14. The identification and optimization of 2,4-diketobutyric acids as flap endonuclease 1 inhibitors.

    Science.gov (United States)

    Tumey, L Nathan; Huck, Bayard; Gleason, Elizabeth; Wang, Jianmin; Silver, Daniel; Brunden, Kurt; Boozer, Sherry; Rundlett, Stephen; Sherf, Bruce; Murphy, Steven; Bailey, Andrew; Dent, Tom; Leventhal, Christina; Harrington, John; Bennani, Youssef L

    2004-10-01

    There have been several recent reports of chemopotentiation via inhibition of DNA repair processes. Flap endonuclease 1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. In this report, we describe the identification and SAR of a series of 2,4-diketobutyric acid FEN1 inhibitors. PMID:15341951

  15. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose

    OpenAIRE

    Huan Huang; McIntosh, Avery L.; Martin, Gregory G.; Petrescu, Anca D.; Landrock, Kerstin K.; Danilo Landrock; Kier, Ann B.; Friedhelm Schroeder

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-α (PPARα) in the nucleus, was found to bind TOFA and its activated CoA th...

  16. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

    Energy Technology Data Exchange (ETDEWEB)

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David (UCLA); (UWASH); (UL); (Kansas); (Ulm)

    2011-09-20

    Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-{beta}-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

  17. Alteration of the Donor/Acceptor Spectrum of the (S-Amine Transaminase from Vibrio fluvialis

    Directory of Open Access Journals (Sweden)

    Maika Genz

    2015-11-01

    Full Text Available To alter the amine donor/acceptor spectrum of an (S-selective amine transaminase (ATA, a library based on the Vibrio fluvialis ATA targeting four residues close to the active site (L56, W57, R415 and L417 was created. A 3DM-derived alignment comprising fold class I pyridoxal-5′-phosphate (PLP-dependent enzymes allowed identification of positions, which were assumed to determine substrate specificity. These positions were targeted for mutagenesis with a focused alphabet of hydrophobic amino acids to convert an amine:α-keto acid transferase into an amine:aldehyde transferase. Screening of 1200 variants revealed three hits, which showed a shifted amine donor/acceptor spectrum towards aliphatic aldehydes (mainly pentanal, as well as an altered pH profile. Interestingly, all three hits, although found independently, contained the same mutation R415L and additional W57F and L417V substitutions.

  18. Cathepsin D-mediated yolk protein degradation is blocked by acid phosphatase inhibitors.

    Science.gov (United States)

    Fialho, Eliane; Nakamura, Angelica; Juliano, Luiz; Masuda, Hatisaburo; Silva-Neto, Mário A C

    2005-04-15

    Vitellin (VT) is a lipoglycophosphoprotein stored inside the eggs of every oviparous organism during oogenesis. In the blood-sucking bug Rhodnius prolixus, VT is deposited inside growing oocytes together with two acid hydrolases: acid phosphatase (AP) and cathepsin D (CD). Egg fertilization triggers AP activity and VT proteolysis in vivo [Insect Biochem. Mol. Biol. 2002 (32) 847]. Here, we show that CD is the main protease targeting VT proteolysis during egg development. CD activity in total egg homogenates is blocked by the classical aspartyl protease inhibitor, pepstatin A. Surprisingly, AP inhibitors such as NaF, Na+/K+ tartrate, and inorganic phosphate also block VT proteolysis, whereas this effect is not observed when tyrosine phosphatase inhibitors such as vanadate and phenylarsine oxide or an inhibitor of alkaline phosphatases such as levamisole are used in a VT proteolysis assay. NaF concentrations that block isolated AP activity do not affect the activity of partially purified CD. Therefore, a specific repressor of VT proteolysis must be dephosphorylated by AP in vivo. In conclusion, these results demonstrate for the first time that acid hydrolases act cooperatively to promote yolk degradation during egg development in arthropods. PMID:15797237

  19. Study of Plant Cordia Dichotoma as Green Corrosion Inhibitor for Mild Steel in Different Acid Media

    Directory of Open Access Journals (Sweden)

    R. Khandelwal

    2011-01-01

    Full Text Available The corrosion inhibition of mild steel using extracts of Cordia dichotoma in different acid media was investigated by mass loss and thermometric methods. The experiments were carried out at 299±0.2 K in presence of different concentrations of dry fruit, leaves and stem extracts of Cordia dichotoma. The results reveal that the alcoholic extracts of Cordia dichotoma is a better corrosion inhibitor than that of toxic chemicals. The fruit extract is more potent than leaves and stem extracts to inhibit the corrosion rate. The study seeks to investigate the possibility of using extracts of Cordia dichotoma as a green corrosion inhibitor for mild steel.

  20. Molecular design, synthesis and biological activities of amidines as new ketol-acid reductoisomerase inhibitors

    Institute of Scientific and Technical Information of China (English)

    Bao Lei Wang; Yong Hong Li; Jian Guo Wang; Yi Ma; Zheng Ming Li

    2008-01-01

    Diamidine (A) was identified in our in vitro bio-assay as a possible inhibitor of ketol-acid reductoisomerase (KARI) from the ACD database search based on the known three-dimensional crystal structure of KARI. An investigation on interaction of A on KARI active sites, led to the design and synthesis of 15 novel monoamidines. Some of those showed better biological activity than A on rice KARI (in vitro) and in greenhouse herbicidal tests (in vivo). The structure-biological activity relationship was investigated, which provides valuable information to further study of potential KARI inhibitors.

  1. EFFECT OF INHIBITORS ON ENZYMATIC HYDROLYSIS AND SIMULTANEOUS SACCHARIFICATION FERMENTATION FOR LACTIC ACID PRODUCTION FROM STEAM EXPLOSION PRETREATED LESPEDEZA STALKS

    OpenAIRE

    Yue Feng; Xiang Qi,; Hong-lei Jian,; Run-cang Sun; Jian-xin Jiang

    2012-01-01

    The effects on both cellulose conversion rate and lactic acid yield were studied by adding inhibitors, including formic acid, acetic acid, furfural, and vanillin into the hydrolysate of steam-pretreated Lespedeza stalks. The results suggest that formic acid has a significant influence on the enzyme activity and poisoned bacterial cells, resulting in the reduction of cellulose conversion rate and lactic acid yield by 21% and 16.4%, respectively. Acetic acid showed a strong inhibition on simult...

  2. Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application.

    Science.gov (United States)

    Cozza, Giorgio; Bonvini, Paolo; Zorzi, Elisa; Poletto, Giorgia; Pagano, Mario A; Sarno, Stefania; Donella-Deana, Arianna; Zagotto, Giuseppe; Rosolen, Angelo; Pinna, Lorenzo A; Meggio, Flavio; Moro, Stefano

    2006-04-20

    Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase whose abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other diseases. Using a virtual screening approach, we have identified the ellagic acid, a naturally occurring tannic acid derivative, as a novel potent CK2 inhibitor. At present, ellagic acid represents the most potent known CK2 inhibitor (K(i) = 20 nM). PMID:16610779

  3. Lichen secondary metabolite evernic acid as potential quorum sensing inhibitor against Pseudomonas aeruginosa.

    Science.gov (United States)

    Gökalsın, Barış; Sesal, Nüzhet Cenk

    2016-09-01

    Cystic Fibrosis is a genetic disease and it affects the respiratory and digestive systems. Pseudomonas aeruginosa infections in Cystic Fibrosis are presented as the main cause for high mortality and morbidity rates. Pseudomonas aeruginosa populations can regulate their virulence gene expressions via the bacterial communication system: quorum sensing. Inhibition of quorum sensing by employing quorum sensing inhibitors can leave the bacteria vulnerable. Therefore, determining natural sources to obtain potential quorum sensing inhibitors is essential. Lichens have ethnobotanical value for their medicinal properties and it is possible that their secondary metabolites have quorum sensing inhibitor properties. This study aims to investigate an alternative treatment approach by utilizing lichen secondary metabolite evernic acid to reduce the expressions of Pseudomonas aeruginosa virulence factors by inhibiting quorum sensing. For this purpose, fluorescent monitor strains were utilized for quorum sensing inhibitor screens and quantitative reverse-transcriptase PCR analyses were conducted for comparison. Results indicate that evernic acid is capable of inhibiting Pseudomonas aeruginosa quorum sensing systems. PMID:27465850

  4. Seed Extract of Psidium guajava as Ecofriendly Corrosion Inhibitor for Carbon Steel in Hydrochloric Acid Medium

    Institute of Scientific and Technical Information of China (English)

    K.P.Vinod Kumar; M. Sankara Narayana Pillai; G. Rexin Thusnavis

    2011-01-01

    The anticorrosion characteristics of the seeds of Psidium guajava (P. Guajava) fruits on carbon steel in acid medium were examined with weight loss data and subsequently thermodynamic factors such as heat of adsorption of the inhibitor on the metal surface (Q), change in entropy (△S), change in free energy of the reaction (△G), corrosion rate (CR) and energy of activation for corrosion reaction of carbon steel (E) were also evaluated. Adsorption isotherm was plotted to study the adsorption of the inhibitor on the metal surface with increasing concentration of the inhibitor. The functional groups responsible for inhibition were investigated using Fourier transform infrared (FT-IR) spectra. Electrochemical parameters were evaluated through the potentiodynamic Tafel polarization and impedance spectral studies. Scanning electron microscopy (SEM) micrographs were recorded to investigate the change in surface morphology. The complete study reveals the efficiency of seed extract of P. Guajava as a safe, ecofriendly and alternate corrosion inhibitor for carbon steel in acid medium.

  5. Synthesis and Application of Phenyl Nitrone Derivatives as Acidic and Microbial Corrosion Inhibitors

    OpenAIRE

    Shijun Chen; Kang Zhao; Gang Chen

    2015-01-01

    Nitrone has drawn great attention due to its wide applications as a 1,3-dipole in heterocyclic compounds synthesis and the bioactivities. With the special structure, nitrone can also be used as ligand in inorganic chemistry. Based on the current research, the nitrones are anticipated to be effective inhibitors against acidic and microbial corrosion. The aim of this work is to investigate the inhibitory action of nitrones. In this work, a series of phenyl nitrone derivatives (PN) was synthesiz...

  6. Predictive QSPR analysis of corrosion inhibitors for super 13% Cr steel in hydrochloric acid

    OpenAIRE

    S. P. Cardoso; J. A. C. P. Gomes; L. E. P. Borges; E. Hollauer

    2007-01-01

    An experimental and theoretical study on the inhibition corrosion efficiencies of twenty three compounds in hydrochloric acid (15% w/v) on 13% Cr modified stainless steel (martensitic) has been carried out. This inhibitor set includes amines, thiourea derivatives and acetylenic alcohols. Experimental weight losses at 60ºC were correlated with group and quantum AM1 descriptors obtained from QSPR analysis. Such data, for a large set of molecules, offer a unique opportunity for searching for cor...

  7. INHIBITIVE EFFECT OF WRIGHTIA TINCTORIA LEAVES AS GREEN INHIBITOR FOR MILD STEEL IN ACID MEDIUM

    OpenAIRE

    P. Deivanayagam*; I. Malarvizhi; Selvaraj, S

    2016-01-01

    The inhibition efficacy of Wrightia tinctoria leaves (WTL) extract on mild steel in 1.0N hydrochloric acid with various exposure time (24 to 360hrs) and temperature (313 to 333K) are investigated by mass loss measurements. The value of inhibition efficiency is increased with increase of inhibitor concentration and gradually decreased with rise in temperature is suggestive of physisorption. The adsorption of WTL onto the mild steel surface is found to follow the Langmuir adsorption isotherm. B...

  8. Study of Plant Cordia Dichotoma as Green Corrosion Inhibitor for Mild Steel in Different Acid Media

    OpenAIRE

    Khandelwal, R; Arora, S. K.; Mathur, S P

    2011-01-01

    The corrosion inhibition of mild steel using extracts of Cordia dichotoma in different acid media was investigated by mass loss and thermometric methods. The experiments were carried out at 299±0.2 K in presence of different concentrations of dry fruit, leaves and stem extracts of Cordia dichotoma. The results reveal that the alcoholic extracts of Cordia dichotoma is a better corrosion inhibitor than that of toxic chemicals. The fruit extract is more potent than leaves and stem extracts to in...

  9. Glutamic oxaloacetic transaminase isozymes from rat liver. Purification and physicochemical characterization.

    Science.gov (United States)

    Huynh, Q K; Sakakibara, R; Watanabe, T; Wada, H

    1980-07-01

    Glutamic oxaloacetic transaminase isozymes were purified simultaneously to homogeneity from rat liver with high yields. Three subforms of mitochondrial isozyme and three subforms of cytosolic isozyme were separated by chromatography on CM-Sephadex and electrophoresis on polyacrylamide gel. The general enzymatic properties of the purified isozymes such as their kinetic parameters, isoelectric points, molecular weights, amino acid compositions, NH2-terminal amino acid sequences and COOH-terminal amino acids were determined. Most of these properties of the isozymes are similar to those of the corresponding isozymes from other sources, such as rat brain and pig and human heart. In amino acid compositions, cytosolic isozyme from rat liver has more proline and glycine and less arginine, threonine and leucine than pig heart cytosolic isozyme; the mitochondrial isozyme has more glutamic acid and glycine and less serine than the corresponding pig heart isozyme. The NH2-terminal amino acid sequences of GOT isozymes from rat liver were identical with those of the GOT isozymes from pig heart up to the 10th residues except for the 5th residues. The subforms of mitochondrial isozyme from rat liver were generated on storage at 4 degrees C for 4-8 weeks.

  10. Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

    DEFF Research Database (Denmark)

    Bach, Anders

    2015-01-01

    Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may...... examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic...

  11. Garcinia indica as an Environmentally Safe Corrosion Inhibitor for Aluminium in 0.5 M Phosphoric Acid

    OpenAIRE

    Deepa Prabhu; Padmalatha Rao

    2013-01-01

    The Inhibitive and adsorption properties of aqueous extract of seeds of Garcinia indica extract (GIE) have been studied for corrosion control of aluminium in 0.5 M phosphoric acid solution using potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques at 30∘C to 50∘C. The effects of inhibitor concentration on the inhibition action were investigated. Polarization measurements showed that the GIE acted as mixed inhibitor and the inhibitor molecules followed chemi...

  12. Comparative Study of Elaeis Guiniensis Exudates (Palm Wine as a Corrosion Inhibitor for Mild Steel in Acidic and Basic Solutions

    Directory of Open Access Journals (Sweden)

    S.C. Nwigbo

    2012-01-01

    Full Text Available This study has explored the possibility of using a typical plant extract other than the use of conventional materials as corrosion inhibitor. Elaeis guinensis exudates (Palm wine, which contains carbonyl groups, double bonds and triple bonds as shown by the FTIR, Gas chromatography-mass spectrometry and phytochemical tests is a one of good natural materials as corrosion inhibitor. This paper was focused on the behaviour of palm wine as corrosion inhibitor for mild steel in (0.1 and 0.5 M H2SO4 and NaOH solutions at 303 and 333 K temperatures and inhibitor concentrations using weight loss measurement. Results showed that weight loss decreases as concentration of both solutions studied increase. The inhibitor performs better under the basic solution compared to the acidic solution. The kinetics results showed that activation energy increases as temperature and inhibitors concentration increase. Palm wine inhibitor adsorbed on the surface of mild steel through physical adsorption.

  13. The antiviral drug acyclovir is a slow-binding inhibitor of (D)-amino acid oxidase.

    Science.gov (United States)

    Katane, Masumi; Matsuda, Satsuki; Saitoh, Yasuaki; Sekine, Masae; Furuchi, Takemitsu; Koyama, Nobuhiro; Nakagome, Izumi; Tomoda, Hiroshi; Hirono, Shuichi; Homma, Hiroshi

    2013-08-20

    d-Amino acid oxidase (DAO) is a degradative enzyme that is stereospecific for d-amino acids, including d-serine and d-alanine, which are believed to be coagonists of the N-methyl-d-aspartate (NMDA) receptor. To identify a new class of DAO inhibitor(s) that can be used to elucidate the molecular details of the active site environment of DAO, manifold biologically active compounds of microbial origin and pre-existing drugs were screened for their ability to inhibit DAO activity, and several compounds were identified as candidates. One of these compounds, acyclovir (ACV), a well-known antiviral drug used for the treatment of herpesvirus infections, was characterized and evaluated as a novel DAO inhibitor in vitro. Analysis showed that ACV acts on DAO as a reversible slow-binding inhibitor, and interestingly, the time required to achieve equilibrium between DAO, ACV, and the DAO/ACV complex was highly dependent on temperature. The binding mechanism of ACV to DAO was investigated in detail by several approaches, including kinetic analysis, structural modeling of DAO complexed with ACV, and site-specific mutagenesis of an active site residue postulated to be involved in the binding of ACV. The results confirm that ACV is a novel, active site-directed inhibitor of DAO that can be a valuable tool for investigating the structure-function relationships of DAO, including the molecular details of the active site environment of DAO. In particular, it appears that ACV can serve as an active site probe to study the structural basis of temperature-induced conformational changes of DAO.

  14. Applying Enzymatic Cascades for ISCPR in ω-transaminase Systems

    DEFF Research Database (Denmark)

    Janes, Kresimir; Woodley, John; Tufvesson, Pär;

    Filtration Membrane Reactor) as a viable process design option and charge analysis showed that ISPR is possible via ion exchange resins or electrodialysis. An ISPR example showed that process intensification could yield significant reductions in the required ω-transaminase activity improvement (up to five fold......Biocatalysis complements the classical organic synthesis, and in many cases the superior selectivity of a biocatalyst is a strong driver explaining why there are an increasing number of processes where traditional organic synthesis has been replaced or combined with biocatalytic industrial process...... steps. An important fact is also that different types of selectivity make biocatalysis an excellent tool for overcoming difficulties typically associated with organic synthesis. Regioselectivity of the biocatalysts offers potential process simplification compared to the organic synthesis routes...

  15. Zoledronic acid cooperates with a cyclooxygenase-2 inhibitor and gefitinib in inhibiting breast and prostate cancer.

    Science.gov (United States)

    Melisi, Davide; Caputo, Rosa; Damiano, Vincenzo; Bianco, Roberto; Veneziani, Bianca Maria; Bianco, A Raffaele; De Placido, Sabino; Ciardiello, Fortunato; Tortora, Giampaolo

    2005-12-01

    Biphosphonates (BPs) are widely used to inhibit osteoclastic activity in malignant diseases such as bone metastatic breast and prostate carcinoma. Recent studies reported that BPs could also cause a direct antitumor effect, probably due to their ability to interfere with several intracellular signalling molecules. The enzyme cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) play an important role in the control of cancer cell growth and inhibitors of COX-2 and EGFR have shown antitumor activity in vitro and in vivo in several tumor types. We, and others, have previously shown that EGFR and COX-2 may be directly related to each other and that their selective inhibitors may have a cooperative effect. In the present study we have evaluated the combined effect of zoledronic acid, the most potent nitrogen-containing BP, with the COX-2 inhibitor SC-236 and the selective EGFR-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. We show that combination of zoledronic acid with SC-236 and gefitinib causes a cooperative antitumor effect accompanied by induction of apoptosis and regulation of the expression of mitogenic factors, proangiogenic factors and cell cycle controllers both in vitro and in xenografted nude mice. The modulatory effect on protein expression and the inhibitory effect on tumor growth is much more potent when the three agents are used together. Since studies are ongoing to explore the antitumor effect of zoledronic acid, our results provide new insights into the mechanism of action of these agents and a novel rationale to translate this feasible combination treatment strategy into a clinical setting.

  16. Chemical Genetics Uncovers Novel Inhibitors of Lignification, Including p-Iodobenzoic Acid Targeting CINNAMATE-4-HYDROXYLASE.

    Science.gov (United States)

    Van de Wouwer, Dorien; Vanholme, Ruben; Decou, Raphaël; Goeminne, Geert; Audenaert, Dominique; Nguyen, Long; Höfer, René; Pesquet, Edouard; Vanholme, Bartel; Boerjan, Wout

    2016-09-01

    Plant secondary-thickened cell walls are characterized by the presence of lignin, a recalcitrant and hydrophobic polymer that provides mechanical strength and ensures long-distance water transport. Exactly the recalcitrance and hydrophobicity of lignin put a burden on the industrial processing efficiency of lignocellulosic biomass. Both forward and reverse genetic strategies have been used intensively to unravel the molecular mechanism of lignin deposition. As an alternative strategy, we introduce here a forward chemical genetic approach to find candidate inhibitors of lignification. A high-throughput assay to assess lignification in Arabidopsis (Arabidopsis thaliana) seedlings was developed and used to screen a 10-k library of structurally diverse, synthetic molecules. Of the 73 compounds that reduced lignin deposition, 39 that had a major impact were retained and classified into five clusters based on the shift they induced in the phenolic profile of Arabidopsis seedlings. One representative compound of each cluster was selected for further lignin-specific assays, leading to the identification of an aromatic compound that is processed in the plant into two fragments, both having inhibitory activity against lignification. One fragment, p-iodobenzoic acid, was further characterized as a new inhibitor of CINNAMATE 4-HYDROXYLASE, a key enzyme of the phenylpropanoid pathway synthesizing the building blocks of the lignin polymer. As such, we provide proof of concept of this chemical biology approach to screen for inhibitors of lignification and present a broad array of putative inhibitors of lignin deposition for further characterization. PMID:27485881

  17. Synergism of Antifungal Activity between Mitochondrial Respiration Inhibitors and Kojic Acid

    Directory of Open Access Journals (Sweden)

    Ronald P. Haff

    2013-01-01

    Full Text Available Co-application of certain types of compounds to conventional antimicrobial drugs can enhance the efficacy of the drugs through a process termed chemosensitization. We show that kojic acid (KA, a natural pyrone, is a potent chemosensitizing agent of complex III inhibitors disrupting the mitochondrial respiratory chain in fungi. Addition of KA greatly lowered the minimum inhibitory concentrations of complex III inhibitors tested against certain filamentous fungi. Efficacy of KA synergism in decreasing order was pyraclostrobin > kresoxim-methyl > antimycin A. KA was also found to be a chemosensitizer of cells to hydrogen peroxide (H2O2, tested as a mimic of reactive oxygen species involved in host defense during infection, against several human fungal pathogens and Penicillium strains infecting crops. In comparison, KA-mediated chemosensitization to complex III inhibitors/H2O2 was undetectable in other types of fungi, including Aspergillus flavus, A. parasiticus, and P. griseofulvum, among others. Of note, KA was found to function as an antioxidant, but not as an antifungal chemosensitizer in yeasts. In summary, KA could serve as an antifungal chemosensitizer to complex III inhibitors or H2O2 against selected human pathogens or Penicillium species. KA-mediated chemosensitization to H2O2 seemed specific for filamentous fungi. Thus, results indicate strain- and/or drug-specificity exist during KA chemosensitization.

  18. Steel Corrosion Inhibition by Acid Garlic Essential Oil as a Green Corrosion Inhibitor a nd Sorption Behavior

    OpenAIRE

    Afia, L.; Benali, O.; Salghi, R.; Ebenso, Eno E.; Jodeh, S.; Zougagh, M.; Hammouti, B.

    2014-01-01

    The aim of this work was to investigate the inhibition effect of acid garlic essential oil (GO oil) as an inhibitor on the corrosion of carbon steel in a 1M HCl solution at different temperatures by weight loss,electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization methods. The GO oil acts as an effective corrosion inhibitor for carbon steel in a hydrochloric acid medium. The inhibition process is attributed to the formatio...

  19. Effect of carbonyl inhibitors and their H₂O₂ detoxification on lactic acid fermentation.

    Science.gov (United States)

    Li, Jing; Zhu, Caiqing; Tu, Maobing; Han, Pingping; Wu, Yonnie

    2015-04-01

    Biomass degradation compounds significantly inhibit biochemical conversion of biomass prehydrolysates to biofuels and chemicals, such as lactic acid. To characterize the structure-activity relationship of carbonyl inhibition on lactic acid fermentation, we examined effects of eight carbonyl compounds (furfural, 5-hydroxymethyl furfural, vanillin, syringaldehyde, 4-hydroxybenzaldehyde, phthalaldehyde, benzoic acid, and pyrogallol aldehyde) and creosol on lactic acid production by Lactobacillus delbrueckii. Pyrogallol aldehyde reduced the cell growth rate by 35 % at 1.0 mM and inhibited lactic acid production completely at 2.0 mM. By correlating the molecular descriptors to the inhibition constants in lactic acid fermentation, we found a good relationship between the hydrophobicity (Log P) of aldehydes and their inhibition constants in fermentation. The inhibitory effect of carbonyl inhibitors appeared to correlate with their thiol reactivity as well. In addition, we found that H2O2 detoxified pyrogallol aldehyde and phthalaldehyde inhibitory activity. H2O2 detoxification was applied to real biomass prehydrolysates in lactic acid fermentation. PMID:25666370

  20. Mangrove tannins and their flavanoid monomers as alternative steel corrosion inhibitors in acidic medium

    International Nuclear Information System (INIS)

    The inhibitive behaviour on steel of flavanoid monomers that constitute mangrove tannins namely catechin, epicatechin, epigallocatechin and epicatechingallate was investigated in an aerated HCl solution via electrochemical methods. The monomers were found to be mainly cathodic inhibitors and the inhibition efficiency was dependent on concentration. To explain the adsorptive behaviour of the molecules on the steel surface, a semiempirical approach involving quantum chemical calculations using HyperChem 6.0 was undertaken. The HOMO electronic density of the molecule was used to explain the inhibiting mechanism. The most probable adsorption centers were found in the vicinity of the phenolic groups. In a second part, the use of mangrove tannin, extracted from the mangrove barks as steel corrosion inhibitors in acidic media was investigated and its inhibitive efficiency was compared with that of commercial mimosa, quebracho and chestnut tannins. The inhibitive performance of mangrove tannins was comparable to the other tannins investigated, indicating their potential in corrosion protection

  1. Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents.

    Science.gov (United States)

    Wang, Hao; Gill, Charles J; Lee, Sang H; Mann, Paul; Zuck, Paul; Meredith, Timothy C; Murgolo, Nicholas; She, Xinwei; Kales, Susan; Liang, Lianzhu; Liu, Jenny; Wu, Jin; Santa Maria, John; Su, Jing; Pan, Jianping; Hailey, Judy; Mcguinness, Debra; Tan, Christopher M; Flattery, Amy; Walker, Suzanne; Black, Todd; Roemer, Terry

    2013-02-21

    Innovative strategies are needed to combat drug resistance associated with methicillin-resistant Staphylococcus aureus (MRSA). Here, we investigate the potential of wall teichoic acid (WTA) biosynthesis inhibitors as combination agents to restore β-lactam efficacy against MRSA. Performing a whole-cell pathway-based screen, we identified a series of WTA inhibitors (WTAIs) targeting the WTA transporter protein, TarG. Whole-genome sequencing of WTAI-resistant isolates across two methicillin-resistant Staphylococci spp. revealed TarG as their common target, as well as a broad assortment of drug-resistant bypass mutants mapping to earlier steps of WTA biosynthesis. Extensive in vitro microbiological analysis and animal infection studies provide strong genetic and pharmacological evidence of the potential effectiveness of WTAIs as anti-MRSA β-lactam combination agents. This work also highlights the emerging role of whole-genome sequencing in antibiotic mode-of-action and resistance studies.

  2. Molecular Structure of Phenylthiourea as a Corrosion Inhibitor for Mild Steel in Hydrochloric Acid

    Institute of Scientific and Technical Information of China (English)

    Anees A, Khadom

    2011-01-01

    The application of statistical analysis and quantum chemical models on the corrosion inhibition of mild steel in hydrochloric acid in presence of phenylthiourea (PTU) as corrosion inhibitor have been investigated. Two mathematical models were used, second order polynomial model and Arrhenius type equation model. STATISTICA software based on Levenberg-Marquardt estimation method was used to evaluate the coefficients of two Models. It follows that the two models were suitable to represent the corrosion rate data at different conditions. The correlation coefficient of second order polynomial model was 0.973, while for the Arrhenius type model was 0.919. The structure of inhibitor was optimized by ArgusLab 4.0.1 package. The quantum chemical parameters (EHoMO, ELUMO, AE, and dipole moment μ) were estimated by PM3-SCF method.

  3. Mangrove tannins and their flavanoid monomers as alternative steel corrosion inhibitors in acidic medium

    Energy Technology Data Exchange (ETDEWEB)

    Rahim, Afidah A. [School of Chemical Sciences, University Sains Malaysia, 11800 Penang (Malaysia)]. E-mail: afidah@usm.my; Rocca, E. [Laboratoire de Chimie du Solide Mineral, Universite Henri Poincare, Nancy I BP 239, 54506 Vandoeuvre Les Nancy (France); Steinmetz, J. [Laboratoire de Chimie du Solide Mineral, Universite Henri Poincare, Nancy I BP 239, 54506 Vandoeuvre Les Nancy (France); Kassim, M.J. [School of Chemical Sciences, University Sains Malaysia, 11800 Penang (Malaysia); Adnan, R. [School of Chemical Sciences, University Sains Malaysia, 11800 Penang (Malaysia); Sani Ibrahim, M. [School of Chemical Sciences, University Sains Malaysia, 11800 Penang (Malaysia)

    2007-02-15

    The inhibitive behaviour on steel of flavanoid monomers that constitute mangrove tannins namely catechin, epicatechin, epigallocatechin and epicatechingallate was investigated in an aerated HCl solution via electrochemical methods. The monomers were found to be mainly cathodic inhibitors and the inhibition efficiency was dependent on concentration. To explain the adsorptive behaviour of the molecules on the steel surface, a semiempirical approach involving quantum chemical calculations using HyperChem 6.0 was undertaken. The HOMO electronic density of the molecule was used to explain the inhibiting mechanism. The most probable adsorption centers were found in the vicinity of the phenolic groups. In a second part, the use of mangrove tannin, extracted from the mangrove barks as steel corrosion inhibitors in acidic media was investigated and its inhibitive efficiency was compared with that of commercial mimosa, quebracho and chestnut tannins. The inhibitive performance of mangrove tannins was comparable to the other tannins investigated, indicating their potential in corrosion protection.

  4. Punica granatum leave extract as green corrosion inhibitor for mild steel in Hydrochloric acid

    Directory of Open Access Journals (Sweden)

    Abboud Y.

    2013-09-01

    Full Text Available Leave of Punica granatum extract (LPGE as green inhibitor for the corrosion of mild steel in 1M HCl solution was studied using weight-loss and potentiodynamic polarization measurements. The results obtained revealed that LPGE has fairly good inhibiting properties for mild steel corrosion in 1M HCl solution, with efficiency of around 94 % at a concentration of 1 g/l. The inhibition was of a mixed anodic–cathodic nature. The film which is formed over the metal surface was analysed by FT-IR spectroscopy. Further examination using X-ray diffraction confirms the role of LPGE as an effective corrosion inhibitor for mild steel in acid media.

  5. Solution structure of the squash aspartic acid proteinase inhibitor (SQAPI) and mutational analysis of pepsin inhibition.

    Science.gov (United States)

    Headey, Stephen J; Macaskill, Ursula K; Wright, Michele A; Claridge, Jolyon K; Edwards, Patrick J B; Farley, Peter C; Christeller, John T; Laing, William A; Pascal, Steven M

    2010-08-27

    The squash aspartic acid proteinase inhibitor (SQAPI), a proteinaceous proteinase inhibitor from squash, is an effective inhibitor of a range of aspartic proteinases. Proteinaceous aspartic proteinase inhibitors are rare in nature. The only other example in plants probably evolved from a precursor serine proteinase inhibitor. Earlier work based on sequence homology modeling suggested SQAPI evolved from an ancestral cystatin. In this work, we determined the solution structure of SQAPI using NMR and show that SQAPI shares the same fold as a plant cystatin. The structure is characterized by a four-strand anti-parallel beta-sheet gripping an alpha-helix in an analogous manner to fingers of a hand gripping a tennis racquet. Truncation and site-specific mutagenesis revealed that the unstructured N terminus and the loop connecting beta-strands 1 and 2 are important for pepsin inhibition, but the loop connecting strands 3 and 4 is not. Using ambiguous restraints based on the mutagenesis results, SQAPI was then docked computationally to pepsin. The resulting model places the N-terminal strand of SQAPI in the S' side of the substrate binding cleft, whereas the first SQAPI loop binds on the S side of the cleft. The backbone of SQAPI does not interact with the pepsin catalytic Asp(32)-Asp(215) diad, thus avoiding cleavage. The data show that SQAPI does share homologous structural elements with cystatin and appears to retain a similar protease inhibitory mechanism despite its different target. This strongly supports our hypothesis that SQAPI evolved from an ancestral cystatin.

  6. Relation of circulating liver transaminase concentrations to risk of new-onset atrial fibrillation

    NARCIS (Netherlands)

    Sinner, Moritz F.; Wang, Na; Fox, Caroline S.; Fontes, Joao D.; Rienstra, Michel; Magnani, Jared W.; Vasan, Ramachandran S.; Calderwood, Audrey H.; Pencina, Michael; Sullivan, Lisa M.; Ellinor, Patrick T.; Benjamin, Emelia J.

    2013-01-01

    Heart failure, a strong risk factor for atrial fibrillation (AF), is often accompanied by elevated liver transaminases. The aim of this study was to test the hypothesis that elevated transaminases are associated with the risk for incident AF in the community. A total of 3,744 participants (mean age

  7. Stearic Acid Serves as a Potent Inhibitor of Protein Tyrosine Phosphatase 1B

    Directory of Open Access Journals (Sweden)

    Ayako Tsuchiya

    2013-11-01

    Full Text Available Background/Aims: Free fatty acids (FFAs are implicated in diverse signal transduction pathways. The present study investigated the effects of the saturated FFA stearic acid on protein tyrosine phosphatase 1B (PTP1B activity, Akt activity, and glucose uptake into cells relevant to insulin signal. Methods: PTP1B activity was assayed under the cell-free conditions. Phosphorylation of insulin receptor and Akt and glucose uptake into cells were monitored in differentiated 3T3-L1-GLUT4myc adipocytes. Results: In the cell-free PTP1B assay, stearic acid suppressed PTP1B activity in a concentration (1-30 µM-dependent manner. For 3T3-L1-GLUT4myc adipocytes insulin phosphorylated insulin receptor at Tyr1185 and Akt at Thr308 and Ser473 in a concentration (100 fM-100 nM-dependent manner and stimulated glucose uptake into cells in a concentration (0.1-100 nM-dependent manner. Stearic acid (30 µM significantly increased insulin-induced phosphorylation of insulin receptor at Tyr1185, but insulin-induced phosphorylation of Akt was not significantly enhanced. Stearic acid (30 µM by itself promoted glucose uptake into adipocytes. Conclusion: The results of the present study indicate that stearic acid serves as a potent PTP1B inhibitor, possibly causing an enhancement in the insulin receptor signaling to stimulate glucose uptake into adipocytes.

  8. Synthesis and characterization of phosphocitric acid, a potent inhibitor of hydroxylapatite crystal growth.

    Science.gov (United States)

    Tew, W P; Mahle, C; Benavides, J; Howard, J E; Lehninger, A L

    1980-04-29

    Human urine and extracts of rat liver mitochondria contain apparently identical agents capable of inhibiting the precipitation or crystallization of calcium phosphate. Its general properties, as well as 1H NMR and mass spectra, have suggested that the agent is phosphocitric acid. This paper reports the synthesis of phosphocitric acid via the phosphorylation of triethyl citrate with o-phenylene phosphochloridate, hydrogenolysis of the product to yield triethyl phosphocitrate, hydrolytic removal of the blocking ethyl groups and also chromatographic purification. An enzymatic assay of phosphocitrate is described. Synthetic phosphocitrate was found to be an exceedingly potent inhibitor of the growth of hydroxylapatite seed crystals in a medium supersaturated with respect to Ca2+ and phosphate. Comparative assays showed phosphocitrate to be much more potent than the most active precipitation-crystallization inhibitors previously reported, which include pyrophosphate and ATP. 14C-Labeled phosphocitrate was bound very tightly to hydroxylapatite crystals. Such binding appeared to be essential for its inhibitory activity on crystal growth. Citrate added before but not after, phosphocitrate greatly enhanced the inhibitory potency of the latter. This enhancement effect was not given by other tricarboxylic acids. The monoethyl ester of phosphocitrate had no inhibitory effect on hydroxylapatite crystal growth. PMID:7378389

  9. Inhibition of Pig Phosphoenolpyruvate Carboxykinase Isoenzymes by 3-Mercaptopicolinic Acid and Novel Inhibitors

    Science.gov (United States)

    Hidalgo, Jorge; Latorre, Pedro; Carrodeguas, José Alberto; Velázquez-Campoy, Adrián; Sancho, Javier; López-Buesa, Pascual

    2016-01-01

    There exist two isoforms of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in pig populations that differ in a single amino acid (Met139Leu). The isoenzymes have different kinetic properties, affecting more strongly the Km and Vmax of nucleotides. They are associated to different phenotypes modifying traits of considerable economic interest. In this work we use inhibitors of phosphoenolpyruvate carboxykinase activity to search for further differences between these isoenzymes. On the one hand we have used the well-known inhibitor 3-mercaptopicolinic acid. Its inhibition patterns were the same for both isoenzymes: a three-fold decrease of the Ki values for GTP in 139Met and 139Leu (273 and 873 μM, respectively). On the other hand, through screening of a chemical library we have found two novel compounds with inhibitory effects of a similar magnitude to that of 3-mercaptopicolinic acid but with less solubility and specificity. One of these novel compounds, (N'1-({5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-thienyl}methylidene)-2,4-dichlorobenzene-1-carbohydrazide), exhibited significantly different inhibitory effects on either isoenzyme: it enhanced threefold the apparent Km value for GTP in 139Met, whereas in 139Leu, it reduced it from 99 to 69 μM. The finding of those significant differences in the binding of GTP reinforces the hypothesis that the Met139Leu substitution affects strongly the nucleotide binding site of PEPCK-C. PMID:27391465

  10. THE STUDY OF HENNA LEAVES EXTRACT AS GREEN CORROSION INHIBITOR FOR MILD STEEL IN ACETIC ACID.

    Directory of Open Access Journals (Sweden)

    H. G. Chaudhari

    2016-05-01

    Full Text Available The inhibitive action of henna leaves extract on mild steel in acetic acid solution have been investigated by weight-loss, A C impedence and potentiodynamic polarization measurements. The study indicates that as acid concentration increases corrosion rate increases. The corrosion inhibition efficiency increases with increase in concentration of extract. The result obtained revealed that henna leaves extract act as efficient inhibitor. The adsorption of the henna leaves extract obeyed Langmuir adsorption isotherm. The calculated thermodynamic parameters indicated that the adsorption was a spontaneous, exothermic process accompanied by an increase in entropy. Cathodic and anodic polarization curves show that henna leaves extract is a mixed-type inhibitor. Normal 0 false false false EN-IN X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}   ABSTRACT:    The inhibitive action of henna leaves extract on mild steel in acetic acid solution have been investigated by weight-loss, A C impedence and potentiodynamic polarization measurements. The study indicates that as acid concentration increases corrosion rate increases. The corrosion inhibition efficiency increases with increase in concentration of extract. The result obtained revealed that henna leaves extract act as efficient inhibitor. The adsorption of the henna leaves

  11. Benzimidazole as corrosion inhibitor for heat treated 6061 Al- SiCp composite in acetic acid

    Science.gov (United States)

    Chacko, Melby; Nayak, Jagannath

    2015-06-01

    6061 Al-SiCpcomposite was solutionizedat 350 °C for 30 minutes and water quenched. It was then underaged at 140 °C (T6 treatment). The aging behaviour of the composite was studied using Rockwell B hardness measurement. Corrosion behaviour of the underaged sample was studied in different concentrations of acetic acid and at different temperatures. Benzimidazole at different concentrations was used for the inhibition studies. Inhibition efficiency of benzimidazole was calculated for different experimental conditions. Thermodynamic parameters were found out which suggested benzimidazole is an efficient inhibitor and it adsorbed on to the surface of composite by mixed adsorption where chemisorption is predominant.

  12. Induction of aromatic-L-amino acid decarboxylase by decarboxylase inhibitors in idiopathic parkinsonism.

    Science.gov (United States)

    Boomsma, F; Meerwaldt, J D; Man in 't Veld, A J; Hovestadt, A; Schalekamp, M A

    1989-06-01

    We evaluated the effect of administration of L-dopa, alone or in combination with a peripheral decarboxylase inhibitor, on plasma levels of aromatic-L-amino acid decarboxylase (ALAAD). After single-dose administration of L-dopa plus benserazide (Madopar) in healthy subjects and in chronically treated patients with parkinsonism, plasma ALAAD followed for 2 to 3 hours fell, but returned to predosing levels within 90 minutes. Four groups of patients with idiopathic parkinsonism were studied during chronic treatment: Group I, no L-dopa treatment (n = 31); Group II, L-dopa alone (n = 15); Group III, L-dopa plus benserazide (n = 28); and Group IV, L-dopa plus carbidopa (Sinemet, n = 30). Plasma ALAAD 2 hours after dosing was normal in Groups I and II. ALAAD was increased threefold in Groups III and IV, suggesting induction of ALAAD by the coadministration of a peripheral decarboxylase inhibitor. In a study of 3 patients in whom L-dopa/benserazide was started, plasma ALAAD rose gradually over 3 to 4 weeks. Further detailed pharmacokinetic studies of L-dopa, dopamine, and ALAAD in plasma and cerebrospinal fluid are required to determine if the apparent ALAAD induction by a peripheral decarboxylase inhibitor may be related to the loss of clinical efficacy of combination therapy in some patients and how it is related to end-of-dose deterioration and on-off phenomena.

  13. Antibacterial drugs as corrosion inhibitors for bronze surfaces in acidic solutions

    International Nuclear Information System (INIS)

    Graphical abstract: - Highlights: • All four investigated antibacterial drugs act as corrosion inhibitors for bronze surface. • In the presence of antibiotics, a 3RC electric circuit simulates the corrosion system. • The electrochemical results indicate as best inhibitors Doxy, followed by Strepto. • HOMO–LUMO energy gap increases in the order: Doxy > Strepto > Cipro > Amoxi. • The thin protective film on bronze is reinforced by the presence of the antibiotics. - Abstract: The present study is aiming to investigate the effect of four antibiotics (amoxicillin, ciprofloxacin, doxycycline and streptomycin,) belonging to different classes of antibacterial drugs on bronze corrosion in a solution simulating an acid rain (pH 4). Due to their ability to form protective films on the metal surface, the tested antibiotics act as corrosion inhibitors for bronze. The antibiotics were tested at various concentrations in order to determine the optimal concentration range for the best corrosion inhibiting effect. In evaluating the inhibition efficiency, polarization curves, electrochemical impedance spectroscopy, SEM and XPS measurements were used. Moreover, a correlation between the inhibition efficiency of some antibacterial drugs and certain molecular parameters was determined by quantum chemical computations. Parameters like energies EHOMO and ELUMO and HOMO–LUMO energy gap were used for correlation with the corrosion data

  14. Antibacterial drugs as corrosion inhibitors for bronze surfaces in acidic solutions

    Energy Technology Data Exchange (ETDEWEB)

    Rotaru, Ileana [Department of Chemical Engineering, “Babes-Bolyai” University, 11 Arany-Janos St., 400028 Cluj-Napoca (Romania); Varvara, Simona, E-mail: svarvara@uab.ro [Department of Exact Sciences and Engineering, “1 Decembrie 1918” University, 11-13 Nicolae Iorga St., 510009 Alba Iulia (Romania); Gaina, Luiza [Department of Chemical Engineering, “Babes-Bolyai” University, 11 Arany-Janos St., 400028 Cluj-Napoca (Romania); Muresan, Liana Maria, E-mail: limur@chem.ubbcluj.ro [Department of Chemical Engineering, “Babes-Bolyai” University, 11 Arany-Janos St., 400028 Cluj-Napoca (Romania)

    2014-12-01

    Graphical abstract: - Highlights: • All four investigated antibacterial drugs act as corrosion inhibitors for bronze surface. • In the presence of antibiotics, a 3RC electric circuit simulates the corrosion system. • The electrochemical results indicate as best inhibitors Doxy, followed by Strepto. • HOMO–LUMO energy gap increases in the order: Doxy > Strepto > Cipro > Amoxi. • The thin protective film on bronze is reinforced by the presence of the antibiotics. - Abstract: The present study is aiming to investigate the effect of four antibiotics (amoxicillin, ciprofloxacin, doxycycline and streptomycin,) belonging to different classes of antibacterial drugs on bronze corrosion in a solution simulating an acid rain (pH 4). Due to their ability to form protective films on the metal surface, the tested antibiotics act as corrosion inhibitors for bronze. The antibiotics were tested at various concentrations in order to determine the optimal concentration range for the best corrosion inhibiting effect. In evaluating the inhibition efficiency, polarization curves, electrochemical impedance spectroscopy, SEM and XPS measurements were used. Moreover, a correlation between the inhibition efficiency of some antibacterial drugs and certain molecular parameters was determined by quantum chemical computations. Parameters like energies E{sub HOMO} and E{sub LUMO} and HOMO–LUMO energy gap were used for correlation with the corrosion data.

  15. Combination Therapy of PPAR Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jordi Tauler

    2008-01-01

    Full Text Available Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPAR. Targeting LOX/COX enzymes and inducing activation of PPAR have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPAR activation through synthetic ligands (TZDs has revealed a great mechanistic complexity since effects are produced through PPAR-dependent and -independent mechanisms. Furthermore, PPAR could also be involved in regulation of COX-2. Overexpression of PPAR has reported to play a role in control of invasion and differentiation. Exploring the function of PPAR, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

  16. [Application of aspartic acid as a non-specific binding inhibitor in the enrichment of phosphopeptides with titanium dioxide].

    Science.gov (United States)

    Chi, Ming; Bi, Wei; Lu, Zhuang; Song, Lina; Jia, Wei; Zhang, Yangjun; Qian, Xiaohong; Cai, Yun

    2010-02-01

    Titanium dioxide (TiO2) is one of metal oxides widely used for phosphopeptide enrichment in phosphoproteomic research nowadays. However it can bind to some non-phosphorylated peptides containing one or more aspartic acid residues and/or glutamic acid residues. These non-phosphorylated peptides can be eluted along with phosphorylated peptides and cause the reduction of the selectivity. Conventional inhibitors for the non-specific binding of non-phosphorylated peptides can often contaminate the ion source of mass spectrometry and therefore their applications are limited in liquid chromatography-mass spectrometry (LC-MS). In this study, aspartic acid was reported as a novel non-specific binding inhibitor for phosphopeptide enrichment by titanium dioxide. Firstly, the tryptic peptide mixtures of 3 and 9 standard proteins were used for the comparison of the enrichment efficiency of titanium dioxide. The effects with the presence of aspartic acid, glutamic acid and no-inhibitor in the enrichment systems were compared separately. The results showed that aspartic acid can greatly improve the selectivity of titanium dioxide for phosphopeptide enrichment. Then, aspartic acid was used for the enrichment of tryptic peptide mixture of C57BL/6J mouse liver lysate and good results were also obtained which demonstrated that aspartic acid was a promising non-specific binding inhibitor for complex biological samples. Besides, no contamination in the ion source occurred during the mass spectrometric analysis.

  17. Synthesis of water soluble glycosides of pentacyclic dihydroxytriterpene carboxylic acids as inhibitors of α-glucosidase.

    Science.gov (United States)

    Xu, Jiancong; Nie, Xuliang; Hong, Yanping; Jiang, Yan; Wu, Guoqiang; Yin, Xiaoli; Wang, Chunrong; Wang, Xiaoqiang

    2016-04-01

    A series of compounds were synthesized by glycosylation of maslinic acid (MA) and corosolic acid (CA) with monosaccharides and disaccharides, and the structures of the derivatives were elucidated by standard spectroscopic methods including (1)H NMR, (13)C NMR and HRMS. The α-glucosidase inhibitory activities of all the novel compounds were evaluated in vitro. The solubility and inhibitory activity of α-glucosidase assays showed that the bis-disaccharide glycosides of triterpene acids possessed higher water solubility and α-glucosidase inhibitory activities than the bis-monosaccharide glycosides. Among these compounds, maslinic acid bis-lactoside (8e, IC50 = 684 µM) and corosolic acid bis-lactoside (9e, IC50 = 428 µM) had the best water solubility, and 9e exhibited a better inhibitory activity than acarbose (IC50 = 478 µM). However, most of glycosylated derivatives possessed lower inhibitory activities than the parent compounds, although their water solubility was enhanced obviously. Moreover, the kinetic inhibition studies indicated that 9e was a non-competitive inhibitor, and structure-activity relationships of the derivatives are also discussed. PMID:26974355

  18. New insights into the metabolism of organomercury compounds: mercury-containing cysteine S-conjugates are substrates of human glutamine transaminase K and potent inactivators of cystathionine γ-lyase.

    Science.gov (United States)

    Bridges, Christy C; Krasnikov, Boris F; Joshee, Lucy; Pinto, John T; Hallen, André; Li, Jianyong; Zalups, Rudolfs K; Cooper, Arthur J L

    2012-01-01

    Anthropogenic practices and recycling in the environment through natural processes result in release of potentially harmful levels of mercury into the biosphere. Mercury, especially organic forms, accumulates in the food chain. Mercury reacts readily with sulfur-containing compounds and often exists as a thiol S-conjugate, such as the l-cysteine (Cys)-S-conjugate of methylmercury (CH(3)Hg-S-Cys) or inorganic mercury (Cys-S-Hg-S-Cys). These S-conjugates are structurally similar to l-methionine and l-cystine/l-cystathionine, respectively. Bovine and rat glutamine transaminase K (GTK) catalyze transamination of sulfur-containing amino acids. Recombinant human GTK (rhGTK) has a relatively open catalytic active site, and we report here that this enzyme, like the rat and bovine enzymes, can also utilize sulfur-containing l-amino acids, including l-methionine, l-cystine, and l-cystathionine as substrates. The current study extends this list to include mercuric S-conjugates, and shows that CH(3)Hg-S-Cys and Cys-S-Hg-S-Cys are substrates and reversible inhibitors of rhGTK. The homocysteine S-conjugates, Hcy-S-Hg-S-Hcy and CH(3)Hg-S-Hcy, are also inhibitors. Finally, we show that HgCl(2), CH(3)Hg-S-Cys and Cys-S-Hg-S-Cys are potent irreversible inhibitors of rat cystathionine γ-lyase. The present study broadens our knowledge of the biochemistry of mercury compounds by showing that Cys S-conjugates of mercury interact with enzymes that catalyze transformations of biologically important sulfur-containing amino acids.

  19. Hydrophobic amino acids as a new class of kinetic inhibitors for gas hydrate formation

    Science.gov (United States)

    Sa, Jeong-Hoon; Kwak, Gye-Hoon; Lee, Bo Ram; Park, Da-Hye; Han, Kunwoo; Lee, Kun-Hong

    2013-08-01

    As the foundation of energy industry moves towards gas, flow assurance technology preventing pipelines from hydrate blockages becomes increasingly significant. However, the principle of hydrate inhibition is still poorly understood. Here, we examined natural hydrophobic amino acids as novel kinetic hydrate inhibitors (KHIs), and investigated hydrate inhibition phenomena by using them as a model system. Amino acids with lower hydrophobicity were found to be better KHIs to delay nucleation and retard growth, working by disrupting the water hydrogen bond network, while those with higher hydrophobicity strengthened the local water structure. It was found that perturbation of the water structure around KHIs plays a critical role in hydrate inhibition. This suggestion of a new class of KHIs will aid development of KHIs with enhanced biodegradability, and the present findings will accelerate the improved control of hydrate formation for natural gas exploitation and the utilization of hydrates as next-generation gas capture media.

  20. Bee Wax Propolis Extract as Eco-Friendly Corrosion Inhibitors for 304SS in Sulfuric Acid

    Directory of Open Access Journals (Sweden)

    Femiana Gapsari

    2015-01-01

    Full Text Available The inhibition properties of bee wax propolis (BWP extract on the 304SS in 0.5 M sulfuric acid were conducted using potentiodynamic polarization, EIS, and XRD. Quercetin (2-(3.4-dihydroxy phenyl-3.5.7-trihydroxy-4H-chromen-4-one was identified as the main compound in the BWP extract based on FTIR and HPLC analysis. The results showed that the inhibitor could retard the corrosion rate of 304SS in 0.5 M sulfuric acid which reached 97.29% and 91.42% at 2000 ppm based on potentiodynamic polarization and EIS measurement, respectively. The inhibition efficiency decreased with increasing temperature. The inhibition mechanism of BWP extract on the 304SS was physisorption and obeyed Temkin adsorption isotherm equation. The thin protective layer on the 304SS surface was confirmed by XRD.

  1. Proton pump inhibitor-responsive chronic cough without acid reflux: a case report

    Directory of Open Access Journals (Sweden)

    Nobata Kouichi

    2007-08-01

    Full Text Available Abstract Background Because 24-h esophageal pH monitoring is quite invasive, the diagnosis of gastroesophageal reflux disease (GERD-associated cough has usually been made based merely on the clinical efficacy of treatment with proton pump inhibitor (PPI. Case presentation We recently encountered two patients with PPI-responsive chronic non-productive cough for whom switching from bronchodilators and glucocorticosteroids to PPI resulted in improvement of cough. The cough returned nearly to pre-administration level a few weeks after discontinuation of PPI. Though GERD-associated cough was suspected, 24-h esophageal pH monitoring revealed that the cough rarely involved gastric acid reflux. Following re-initiation of PPI, the cough disappeared again. Conclusion PPI may improve cough unrelated to gastric acid reflux.

  2. Adsorptive removal of fermentation inhibitors from concentrated acid hydrolyzates of lignocellulosic biomass.

    Science.gov (United States)

    Sainio, Tuomo; Turku, Irina; Heinonen, Jari

    2011-05-01

    Adsorptive purification of concentrated acid hydrolyzate of lignocellulose was investigated. Cation exchange resin (CS16GC), neutral polymer adsorbent (XAD-16), and granulated activated carbon (GAC) were studied to remove furfural, HMF, and acetic acid from a synthetic hydrolyzate containing 20 wt.% H(2)SO(4). Adsorption isotherms were determined experimentally. Loading and regeneration were investigated in a laboratory scale column. GAC has the highest adsorption capacity, but regeneration with water was not feasible. XAD-16 and CS16GC had lower adsorption capacities but also shorter cycle times due to easier regeneration. Productivity increased when regenerating with 50 wt.% EtOH(aq) solution. To compare adsorbents, process performance was quantified by productivity and fraction of inhibitors removed. GAC yields highest performance when high purity is required and ethanol can be used in regeneration. For lower purities, XAD-16 and GAC yield approximately equal performance. When using ethanol must be avoided, CS16GC offers highest productivity. PMID:21441022

  3. Adaptive laboratory evolution of ethanologenic Zymomonas mobilis strain tolerant to furfural and acetic acid inhibitors.

    Science.gov (United States)

    Shui, Zong-Xia; Qin, Han; Wu, Bo; Ruan, Zhi-yong; Wang, Lu-shang; Tan, Fu-Rong; Wang, Jing-Li; Tang, Xiao-Yu; Dai, Li-Chun; Hu, Guo-Quan; He, Ming-Xiong

    2015-07-01

    Furfural and acetic acid from lignocellulosic hydrolysates are the prevalent inhibitors to Zymomonas mobilis during cellulosic ethanol production. Developing a strain tolerant to furfural or acetic acid inhibitors is difficul by using rational engineering strategies due to poor understanding of their underlying molecular mechanisms. In this study, strategy of adaptive laboratory evolution (ALE) was used for development of a furfural and acetic acid-tolerant strain. After three round evolution, four evolved mutants (ZMA7-2, ZMA7-3, ZMF3-2, and ZMF3-3) that showed higher growth capacity were successfully obtained via ALE method. Based on the results of profiling of cell growth, glucose utilization, ethanol yield, and activity of key enzymes, two desired strains, ZMA7-2 and ZMF3-3, were achieved, which showed higher tolerance under 7 g/l acetic acid and 3 g/l furfural stress condition. Especially, it is the first report of Z. mobilis strain that could tolerate higher furfural. The best strain, Z. mobilis ZMF3-3, has showed 94.84% theoretical ethanol yield under 3-g/l furfural stress condition, and the theoretical ethanol yield of ZM4 is only 9.89%. Our study also demonstrated that ALE method might also be used as a powerful metabolic engineering tool for metabolic engineering in Z. mobilis. Furthermore, the two best strains could be used as novel host for further metabolic engineering in cellulosic ethanol or future biorefinery. Importantly, the two strains may also be used as novel-tolerant model organisms for the genetic mechanism on the "omics" level, which will provide some useful information for inverse metabolic engineering.

  4. Identification of a mutation affecting an alanine-alpha-ketoisovalerate transaminase activity in Escherichia coli K-12.

    Science.gov (United States)

    Falkinham, J O

    1979-10-01

    A mutation affecting alanine-alpha-ketoisovalerate transaminase activity has been shown to be cotransducible with ilv gene cluster. The transaminase deficiency results in conditional isoleucine auxotrophy in the presence of alanine. PMID:396446

  5. Synthesis and Application of Phenyl Nitrone Derivatives as Acidic and Microbial Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    Shijun Chen

    2015-01-01

    Full Text Available Nitrone has drawn great attention due to its wide applications as a 1,3-dipole in heterocyclic compounds synthesis and the bioactivities. With the special structure, nitrone can also be used as ligand in inorganic chemistry. Based on the current research, the nitrones are anticipated to be effective inhibitors against acidic and microbial corrosion. The aim of this work is to investigate the inhibitory action of nitrones. In this work, a series of phenyl nitrone derivatives (PN was synthesized and used as acidic and microbial corrosion inhibitors. The results indicate that several compounds show moderate to high inhibition efficiency (IE in 3% HCl. Accompanied with HMTA or BOZ, the IEs greatly increase, and the highest efficiency of 98.5% was obtained by using PN4 + BOZ. Investigation of the antibacterial activity against oilfield microorganism shows that the nitrone derivatives can inhibit SRB, IB, and TGB with moderate to high efficiency under 1,000 mg/L, which makes them potential to be used as bifunctional oilfield chemicals.

  6. Inhibitors from Carob (Ceratonia siliqua L.) I. Nature of the Interaction With Gibberellic Acid on Shoot Growth.

    Science.gov (United States)

    Corcoran, M R; West, C A

    1968-06-01

    Concentrated whole extracts of the immature fruit of carob and 3 fractions derived from this extract have been shown to inhibit the gibberellic acid induced growth of pea seedlings. The inhibition can be completely reversed by increasing the amount of gibberellic acid. The inhibitors do not reduce the endogenous growth of seedlings but only that induced by gibberellic acid. One of the fractions is a newly separated one not previously reported.

  7. Theoretical study of inhibition efficiencies of some amino acids on corrosion of carbon steel in acidic media: green corrosion inhibitors.

    Science.gov (United States)

    Dehdab, Maryam; Shahraki, Mehdi; Habibi-Khorassani, Sayyed Mostafa

    2016-01-01

    Inhibition efficiencies of three amino acids [tryptophan (B), tyrosine (c), and serine (A)] have been studied as green corrosion inhibitors on corrosion of carbon steel using density functional theory (DFT) method in gas and aqueous phases. Quantum chemical parameters such as EH OMO (highest occupied molecular orbital energy), E LUMO (lowest unoccupied molecular orbital energy), hardness (η), polarizability ([Formula: see text]), total negative charges on atoms (TNC), molecular volume (MV) and total energy (TE) have been calculated at the B3LYP level of theory with 6-311++G** basis set. Consistent with experimental data, theoretical results showed that the order of inhibition efficiency is tryptophan (B) > tyrosine (C) > serine (A). In order to determine the possible sites of nucleophilic and electrophilic attacks, local reactivity has been evaluated through Fukui indices.

  8. Theoretical study of inhibition efficiencies of some amino acids on corrosion of carbon steel in acidic media: green corrosion inhibitors.

    Science.gov (United States)

    Dehdab, Maryam; Shahraki, Mehdi; Habibi-Khorassani, Sayyed Mostafa

    2016-01-01

    Inhibition efficiencies of three amino acids [tryptophan (B), tyrosine (c), and serine (A)] have been studied as green corrosion inhibitors on corrosion of carbon steel using density functional theory (DFT) method in gas and aqueous phases. Quantum chemical parameters such as EH OMO (highest occupied molecular orbital energy), E LUMO (lowest unoccupied molecular orbital energy), hardness (η), polarizability ([Formula: see text]), total negative charges on atoms (TNC), molecular volume (MV) and total energy (TE) have been calculated at the B3LYP level of theory with 6-311++G** basis set. Consistent with experimental data, theoretical results showed that the order of inhibition efficiency is tryptophan (B) > tyrosine (C) > serine (A). In order to determine the possible sites of nucleophilic and electrophilic attacks, local reactivity has been evaluated through Fukui indices. PMID:26347374

  9. Amino acid amides of piperic acid (PA) and 4-ethylpiperic acid (EPA) as NorA efflux pump inhibitors of Staphylococcus aureus.

    Science.gov (United States)

    Wani, Naiem Ahmad; Singh, Samsher; Farooq, Saleem; Shankar, Sudha; Koul, Surrinder; Khan, Inshad Ali; Rai, Rajkishor

    2016-09-01

    A total of eighteen piperic acid (PA) and 4-ethylpiperic acid (EPA) amides (C1-C18) with α-, β- and γ-amino acids were synthesized, characterized and evaluated for their efflux pump inhibitory activity against ciprofloxacin resistant Staphylococcus aureus. The amides were screened against NorA overexpressing S. aureus SA-1199B and wild type S. aureus SA-1199 using ethidium bromide as NorA efflux pump substrate. EPI C6 was found to be most potent and reduced the MIC of ciprofloxacin by 16 fold followed by C18 which showed 4 fold reduction of MIC. Ethidium bromide efflux inhibition and accumulation assay proved these compounds as NorA inhibitors. PMID:27503686

  10. Inhibition of leukemic cells by valproic acid, an HDAC inhibitor, in xenograft tumors

    Directory of Open Access Journals (Sweden)

    Zhang Z

    2013-06-01

    Full Text Available Zhihua Zhang,1 Changlai Hao,1 Lihong Wang,1 Peng Liu,2 Lei Zhao,1 Cuimin Zhu,1 Xia Tian31Hematology Department, Affiliated Hospital of Chengde Medical College, Chengde, Hebei Province, 2Department of Medical Oncology, Shijiazhuang Municipal No 1 Hospital, Hebei Province, 3Department of Medical Oncology, Rizhao Municipal People’s Hospital, Shandong Province, People's Republic of ChinaAbstract: The chimeric fusion protein, AML1-ETO, generated by translocation of t(8;21, abnormally recruits histone deacetylase (HDAC to the promoters of AML1 target genes, resulting in transcriptional repression of the target genes and development of t(8;21 acute myeloid leukemia. Abnormal expression of cyclin-dependent kinase inhibitors, especially p21, is considered a possible mechanism of the arrested maturation and differentiation seen in leukemia cells. A new generation of HDAC inhibitors is becoming an increasing focus of attention for their ability to induce differentiation and apoptosis in tumor cells and to block the cell cycle. Our previous research had demonstrated that valproic acid induces G0/G1 arrest of Kasumi-1 cells in t(8;21 acute myeloid leukemia. In this study, we further confirmed that valproic acid inhibits the growth of Kasumi-1 cells in a murine xenograft tumor model, and that this occurs via upregulation of histone acetylation in the p21 promoter region, enhancement of p21 expression, suppression of phosphorylation of retinoblastoma protein, blocking of transcription activated by E2F, and induction of G0/G1 arrest.Keywords: valproic acid, acute myeloid leukemia, AML1-ETO, p21, E2F

  11. Inhibiting properties and adsorption of an amine based fatty acid corrosion inhibitor on carbon steel in aqueous carbon dioxide solutions

    Energy Technology Data Exchange (ETDEWEB)

    Buchweishaija, Joseph

    1997-12-31

    Carbon dioxide corrosion is a major corrosion problem in oil and gas production systems and many organic inhibitors have been tested and used to protect the substrate from corrosion. This thesis studies the mechanism of interaction of the inhibitor molecule with the metallic substrate and how this affects the dissolution rate of the metal. The performance of a commercial amine based fatty acid corrosion inhibitor has been investigated using rotating cylinder electrodes and carbon steel electrodes in CO{sub 2} saturated formation water in the temperature range between 35 to 80{sup o}C. The corrosion process was monitored by electrochemical impedance measurements, and at the end of each experiment full polarization curves were recorded. When the inhibitor was applied on noncorroded electrodes, high inhibitor performance, over 99.7%, was observed independent of temperature. On precorroded electrodes inhibitor performance was found to depend on temperature and time of precorrosion. Above 60{sup o}C, the inhibitor performance decreased with increasing time of precorrosion, presumably because of the formation of a corrosion film of either iron carbonate or a combination of iron carbonate and iron carbide which prevent the inhibitor from reaching the surface. The inhibitor protection efficiency was assumed to be associated with the degree of inhibitor coverage at the material surface, and adsorption isotherms have been calculated in the concentration range between 0.1 ppm and 100 ppm. A Langmuir isotherm was found to give the best fit. The inhibitor performance on a 2 days precorroded rotating electrode was investigated at different solution pH ranging between 4.5 and 6.5 at 35{sup o}C. 130 refs., 80 figs., 22 tabs.

  12. Valproic Acid as a Potential Inhibitor of Plasmodium falciparum Histone Deacetylase 1 (PfHDAC1: An in Silico Approach

    Directory of Open Access Journals (Sweden)

    Mohamed A. Abdallah Elbadawi

    2015-02-01

    Full Text Available A new Plasmodium falciparum histone deacetylase1 (PfHDAC1 homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.

  13. Structure Activity Relationship of Phenolic Acid inhibitors of α-Synuclein Fibril Formation and Toxicity

    Directory of Open Access Journals (Sweden)

    Mustafa eArdah

    2014-08-01

    Full Text Available The aggregation of α-synuclein (α-syn is considered the key pathogenic event in many neurological disorders such as Parkinson’s disease (PD, dementia with Lewy bodies and multiple system atrophy, giving rise to a whole category of neurodegenerative diseases known as synucleinopathies. Although the molecular basis of α-syn toxicity has not been precisely elucidated, a great deal of effort has been put into identifying compounds that could inhibit or even reverse the aggregation process. Previous reports indicated that many phenolic compounds are potent inhibitors of α-syn aggregation. The aim of the present study was to assess the anti-aggregating effect of gallic acid (GA (3,4,5-trihydroxybenzoic acid, a benzoic acid derivative that belongs to a group of phenolic compounds known as phenolic acids. By employing an array of biophysical and biochemical techniques and a cell-viability assay, GA was shown not only to inhibit α-syn fibrillation and toxicity but also to disaggregate preformed α-syn amyloid fibrils. Interestingly, GA was found to bind to soluble, non-toxic oligomers with no β-sheet content, and to stabilize their structure. The binding of GA to the oligomers may represent a potential mechanism of action. Additionally, by using structure activity relationship data obtained from fourteen structurally similar benzoic acid derivatives, it was determined that the inhibition of α-syn fibrillation by GA is related to the number of hydroxyl moieties and their position on the phenyl ring. GA may represent the starting point for designing new molecules that could be used for the treatment of PD and related disorders.

  14. Eclipta Alba as Corrosion Pickling Inhibitor on Mild Steel in Hydrochloric Acid

    Institute of Scientific and Technical Information of China (English)

    M. Shyamala; A. Arulanantham

    2009-01-01

    Due to ease of application, cost effectiveness and environmentally safe, in this study, the corrosion inhibition effect of aqueous extract of Eclipta alba in 1 N hydrochloric acid has been investigated by weight loss, potentiodynamic polarization and impedance methods and the extracts of Eclipta alba were found to be effective corrosion pickling inhibitor. The effect of immersion time and temperature revealed that the extracts of Eclipta alba with an optimum concentration of 8.0% v/v showed maximum inhibition efficiency of 99.6% at 3 h immersion time and 30℃. Arrhenius plots for mild steel immersed in 1 N HCI solution in the absence and presence of optimum concentration (8.0% in v/v) of Eclipta alba extract showed the effect of temperature. Polarization studies indicate that this plant extract acts as a mixed type inhibitor. The adsorption of Eclipta alba follows Langmuir adsorption isotherm. The inhibition action may be due to the presence of the Wedelactone and also the alkaloid Ecliptine present in the leaves of Eclipta alba.

  15. Herbs as new type of green inhibitors for acidic corrosion of steel

    Energy Technology Data Exchange (ETDEWEB)

    Khamis, E. [Faculty of Science, Chemistry Department, Alexandria University, P.O. Box 426 Ibrahimia Alexandria 21321 (Egypt); AlAndis, N. [College of Science, Chemistry Department, King Saud University (Saudi Arabia)

    2002-09-01

    Corrosion inhibition of steel in sulphuric acid by six different herb plants has been studied using a.c and d.c electrochemical techniques. The environmentally friendly investigated compounds are namely: thyme, coriander, hibiscus, anis, black cumin and Garden cress. Electrochemical impedance spectroscopy has been successfully used to evaluate the performance of these compounds. The ac measurements showed that the dissolution process is activation controlled. Bode and theta diagrams show only one time constant ({tau}). Potentiodynamic polarization curves indicate that the studied compounds are mixed-type inhibitors. The order of increasing inhibition efficiency was correlated with the change of the constituent active materials of the compounds. Thyme, which contains the powerful antiseptic thymol as the active ingredient, offers excellent protection for steel surface. (Abstract Copyright [2002], Wiley Periodicals, Inc.)

  16. Quantitative structure activity relationships of some pyridine derivatives as corrosion inhibitors of steel in acidic medium.

    Science.gov (United States)

    El Ashry, El Sayed H; El Nemr, Ahmed; Ragab, Safaa

    2012-03-01

    Quantum chemical calculations using the density functional theory (B3LYP/6-31G DFT) and semi-empirical AM1 methods were performed on ten pyridine derivatives used as corrosion inhibitors for mild steel in acidic medium to determine the relationship between molecular structure and their inhibition efficiencies. Quantum chemical parameters such as total negative charge (TNC) on the molecule, energy of highest occupied molecular orbital (E (HOMO)), energy of lowest unoccupied molecular orbital (E (LUMO)) and dipole moment (μ) as well as linear solvation energy terms, molecular volume (Vi) and dipolar-polarization (π) were correlated to corrosion inhibition efficiency of ten pyridine derivatives. A possible correlation between corrosion inhibition efficiencies and structural properties was searched to reduce the number of compounds to be selected for testing from a library of compounds. It was found that theoretical data support the experimental results. The results were used to predict the corrosion inhibition of 24 related pyridine derivatives.

  17. Development of Cholinesterase Inhibitors Using (a)-Lipoic Acid-benzyl Piperazine Hybrid Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Beomcheol; Lee, Seunghwan; Jang, Mi; Shon, Min Young; Park, Jeong Ho [Hanbat National Univ., Daejeon (Korea, Republic of)

    2013-11-15

    A series of hybrid molecules between (α)-lipoic acid (ALA) and benzyl piperazines were synthesized and their in vitro cholinesterase [acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)] inhibitory activities were evaluated. Even though the parent compounds did not show any inhibitory activity against cholinesterase (ChE), all hybrid molecules showed BuChE inhibitory activity. Some hybrid compounds also displayed AChE inhibitory activity. Specifically, ALA-1-(3-methylbenzyl)piperazine (15) was shown to be an effective inhibitor of both BuChE (IC{sub 50} = 2.3 ± 0.7 μM) and AChE (IC{sub 50} = 30.31 ± 0.64 μM). An inhibition kinetic study using compound 15 indicated a mixed inhibition type. Its binding affinity (K{sub i}) value to BuChE is 2.91 ± 0.15 μM.

  18. EFFECT OF INHIBITORS ON ENZYMATIC HYDROLYSIS AND SIMULTANEOUS SACCHARIFICATION FERMENTATION FOR LACTIC ACID PRODUCTION FROM STEAM EXPLOSION PRETREATED LESPEDEZA STALKS

    Directory of Open Access Journals (Sweden)

    Yue Feng,

    2012-06-01

    Full Text Available The effects on both cellulose conversion rate and lactic acid yield were studied by adding inhibitors, including formic acid, acetic acid, furfural, and vanillin into the hydrolysate of steam-pretreated Lespedeza stalks. The results suggest that formic acid has a significant influence on the enzyme activity and poisoned bacterial cells, resulting in the reduction of cellulose conversion rate and lactic acid yield by 21% and 16.4%, respectively. Acetic acid showed a strong inhibition on simultaneous saccharification fermentation (SSF process, but little effect on enzymatic hydrolysis. Hydrolysis and SSF were less affected by furfural and vanillin compared with weak acids. The lactic acid yield of Lespedeza stalks rinsed with water increased from 64.0% to 89.4%, and the time to reach the maximum concentration was shortened from 96 hours to 48 hours when compared with the unwashed materials.

  19. Synchronization by Food Access Modifies the Daily Variations in Expression and Activity of Liver GABA Transaminase

    Directory of Open Access Journals (Sweden)

    Dalia De Ita-Pérez

    2014-01-01

    Full Text Available Daytime restricted feeding (DRF is an experimental protocol that influences the circadian timing system and underlies the expression of a biological clock known as the food entrained oscillator (FEO. Liver is the organ that reacts most rapidly to food restriction by adjusting the functional relationship between the molecular circadian clock and the metabolic networks. γ-Aminobutyric acid (GABA is a signaling molecule in the liver, and able to modulate the cell cycle and apoptosis. This study was aimed at characterizing the expression and activity of the mostly mitochondrial enzyme GABA transaminase (GABA-T during DRF/FEO expression. We found that DRF promotes a sustained increase of GABA-T in the liver homogenate and mitochondrial fraction throughout the entire day-night cycle. The higher amount of GABA-T promoted by DRF was not associated to changes in GABA-T mRNA or GABA-T activity. The GABA-T activity in the mitochondrial fraction even tended to decrease during the light period. We concluded that DRF influences the daily variations of GABA-T mRNA levels, stability, and catalytic activity of GABA-T. These data suggest that the liver GABAergic system responds to a metabolic challenge such as DRF and the concomitant appearance of the FEO.

  20. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

    Science.gov (United States)

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

  1. Inhibitors from carob (Ceratonia siliqua L.) : III. Comparisons with abscisic acid.

    Science.gov (United States)

    Corcoran, M R

    1970-06-01

    Inhibitory extracts of carob and abscisic acid (ABA) were compared and found to behave differently in three types of tests. The carob inhibitors remained at the origin upon thin-layer chromatography in two different solvent systems while a cis-trans mixture of ABA had Rf's of 2.5 and 3.5 in the first system (chloroform:acetic acid, 95:5), and 3.5 and 4.5 in the second system (benzene:acetic acid:water, 8:3:5). When ABA and carob extract were mixed and then chromatographed, the ABA had the same Rf values as ABA chromatographed alone.Assays utilizing light-grown, dwarf peas showed that a weight ratio of 1000: 1 ABA:gibberellic acid (GA3) was necessary to inhibit GA3-induced growth by 50% while carob fraction C is inhibitory to GA3 at a ratio of 17:1. The amount of ABA which inhibited 50% of the growth induced by 0.05 μg GA3 reduced the endogenous growth of both dwarf and non-dwarf pea seedlings; in contrast, concentrations of carob extract up to 100 times greater than the amount necessary for 50% inhibition of the growth response caused by 0.05 μg GA3 did not affect endogenous growth.Only very small amounts of inhibitory activity from carob extract were transferred from water to chloroform at a pH (2.0) at which most of the ABA was transferred.

  2. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors.

    Science.gov (United States)

    Vuille-dit-Bille, Raphael N; Camargo, Simone M; Emmenegger, Luca; Sasse, Tom; Kummer, Eva; Jando, Julia; Hamie, Qeumars M; Meier, Chantal F; Hunziker, Schirin; Forras-Kaufmann, Zsofia; Kuyumcu, Sena; Fox, Mark; Schwizer, Werner; Fried, Michael; Lindenmeyer, Maja; Götze, Oliver; Verrey, François

    2015-04-01

    Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression.

  3. Tranexamic acid, an inhibitor of plasminogen activation, reduces urinary collagen cross-link excretion in both experimental and rheumatoid arthritis

    NARCIS (Netherlands)

    Ronday, H.K.; TeKoppele, J.M.; Greenwald, R.A.; Moak, S.A.; Roos, J.A.D.M. de; Dijkmans, B.A.C.; Breedveld, F.C.; Verheijen, J.H.

    1998-01-01

    The plasminogen activation system is one of the enzyme systems held responsible for bone and cartilage degradation in rheumatoid arthritis (RA). In this study, we evaluated the effect of tranexamic acid (TEA), an inhibitor of plasminogen activation, on urinary collagen cross-link excretion and radio

  4. Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors.

    Science.gov (United States)

    Cozza, Giorgio; Gianoncelli, Alessandra; Bonvini, Paolo; Zorzi, Elisa; Pasquale, Riccardo; Rosolen, Angelo; Pinna, Lorenzo A; Meggio, Flavio; Zagotto, Giuseppe; Moro, Stefano

    2011-12-01

    Casein kinase 2 (CK2) is a ubiquitous, essential, and highly pleiotropic protein kinase; its abnormally high constitutive activity is suspected to underlie its pathogenic potential in neoplasia and other relevant diseases. Previously, using different in silico screening approaches, two potent and selective CK2 inhibitors were identified by our group: ellagic acid, a naturally occurring tannic acid derivative (K(i)=20 nM) and 3,8-dibromo-7-hydroxy-4-methylchromen-2-one (DBC, K(i)=60 nM). Comparing the crystallographic binding modes of both ellagic acid and DBC, an X-ray structure-driven merging approach was taken to design novel CK2 inhibitors with improved target affinity. A urolithin moiety is proposed as a possible bridging scaffold between the two known CK2 inhibitors, ellagic acid and DBC. Optimization of urolithin A as the bridging moiety led to the identification of 4-bromo-3,8-dihydroxy-benzo[c]chromen-6-one as a novel, potent and selective CK2 inhibitor, which shows a K(i) value of 7 nM against the protein kinase, representing a significant improvement in affinity for the target compared with the two parent fragments. PMID:21972104

  5. Treatment with the Hyaluronic Acid Synthesis Inhibitor 4-Methylumbelliferone Suppresses SEB-Induced Lung Inflammation

    Directory of Open Access Journals (Sweden)

    Olga N. Uchakina

    2013-10-01

    Full Text Available Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB, can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS. To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU on staphylococcal enterotoxin B (SEB induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.

  6. Experimental study on scale inhibition performance of a green scale inhibitor polyaspartic acid

    Institute of Scientific and Technical Information of China (English)

    QUAN ZhenHua; CHEN YongChang; WANG XiuRong; SHI Cheng; LIU YunJie; MA ChongFang

    2008-01-01

    Static and dynamic experiments were carried out to validate scale inhibition performance of a green scale inhibitor-polyaspartic acid (PASP). From the static experiment, it was shown that below 60℃, polyaspartic acid is very effective in scale inhibition, with the scale inhibition ratio exceeding 90% with only 3 mg/L PASP for the 600 mg/L hardness solution. For a higher hardness solution of 800 mg/L, the scale inhibition ratio can also reach 90% with 6 and 12 mg/L PASP at 30 and 60℃ respectively. The SEM photographs of CaCO3 crystals indicate that the crystal structure transforms from a compact stick-shape to a loose shape so that the scale can be washed away easily instead of being deposited on the heat transfer surface. The dynamic experimental results show that almost no scales formed on the heat trans-fer surface and the fouling thermal resistance decreases extraordinarily if PASP is added in the solution.

  7. Treatment with the hyaluronic Acid synthesis inhibitor 4-methylumbelliferone suppresses LPS-induced lung inflammation.

    Science.gov (United States)

    McKallip, Robert J; Ban, Hao; Uchakina, Olga N

    2015-01-01

    Exposure to bacterial endotoxins, such as lipopolysaccharide (LPS), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for LPS-induced inflammation. In the current study, we investigated the potential use of the hyaluronic acid (HA) synthesis inhibitor 4-methylumbelliferone (4-MU) on LPS-induced acute lung inflammation. Culturing LPS-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production, and an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from LPS-induced lung injury. Specifically, 4-MU treatment led to a reduction in LPS-induced hyaluronic acid synthase (HAS) messenger RNA (mRNA) levels, reduction in lung permeability, and reduction in proinflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target HA production may be an effective treatment for the inflammatory response following exposure to LPS.

  8. Two Distinctive Binding Modes of Endonuclease Inhibitors to the N-Terminal Region of Influenza Virus Polymerase Acidic Subunit.

    Science.gov (United States)

    Fudo, Satoshi; Yamamoto, Norio; Nukaga, Michiyoshi; Odagiri, Takato; Tashiro, Masato; Hoshino, Tyuji

    2016-05-10

    Influenza viruses are global threat to humans, and the development of new antiviral agents are still demanded to prepare for pandemics and to overcome the emerging resistance to the current drugs. Influenza polymerase acidic protein N-terminal domain (PAN) has endonuclease activity and is one of the appropriate targets for novel antiviral agents. First, we performed X-ray cocrystal analysis on the complex structures of PAN with two endonuclease inhibitors. The protein crystallization and the inhibitor soaking were done at pH 5.8. The binding modes of the two inhibitors were different from a common binding mode previously reported for the other influenza virus endonuclease inhibitors. We additionally clarified the complex structures of PAN with the same two endonuclease inhibitors at pH 7.0. In one of the crystal structures, an additional inhibitor molecule, which chelated to the two metal ions in the active site, was observed. On the basis of the crystal structures at pH 7.0, we carried out 100 ns molecular dynamics (MD) simulations for both of the complexes. The analysis of simulation results suggested that the binding mode of each inhibitor to PAN was stable in spite of the partial deviation of the simulation structure from the crystal one. Furthermore, crystal structure analysis and MD simulation were performed for PAN in complex with an inhibitor, which was already reported to have a high compound potency for comparison. The findings on the presence of multiple binding sites at around the PAN substrate-binding pocket will provide a hint for enhancing the binding affinity of inhibitors. PMID:27088785

  9. Development of Better Analogs of Valproic Acid for the Treatment of Epilepsy by CADD

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Mahto

    2012-01-01

    Full Text Available Epilepsy is one of the major neurological disorders occurring due to the abnormal functioning of the various receptors and enzymes in the central nervous system. Many potentials drugs were developed in recent times which act on ion channels like sodium (Na+, calcium (Ca2+, chloride (Cl-, and receptors like GABA receptor and enzymes like GABA transaminase. Some drugs act as enzyme, ion channel inhibitors or blockers, and some drugs as receptor agonist like barbiturates, benzodiazepines acting on GABA receptors. In the present study performed computational techniques in order to develop better inhibitors for the enzyme GABA transaminase by modifying the terminal ‘methyl’ group of the Valproic acid structure with electrophilic, nucleophile and neutral pharmacophoric features. Molecular mechanics studies has been carried out for the analogs and protein – ligand interactions of these analogs was identified through docking studies using GOLD 4.1 software against the enzyme 4-aminobutyrate-aminotransferase(GABA transaminase. From the docking studies we found that replacement of methyl with amine, hydrogen and hydroxyl groups (hydrophilic groups, are showing better fitness than that of the valproic acid.

  10. Sargassum Wightii Extract as a Green Inhibitor for Corrosion of Brass in 0.1 N Phosphoric Acid Solution

    Directory of Open Access Journals (Sweden)

    R. Selva Kumar

    2015-06-01

    Full Text Available The effect of marine algae Sargassum wightii extract on corrosion inhibition of brass in phosphoric acid was investigated by weight-loss method, potentiodynamic polarization and electrochemical impedance spectroscopy studies. The inhibition efficiency is found to increase with increasing concentration of extract and decreases with rise in temperature. The inhibitive effect could be attributed to the phytochemical constituents present in the inhibitor containing N, S, O atoms. The activation energy, thermodynamic parameters (free energy, enthalpy and entropy change and kinetic parameters (rate constant and half-life for inhibition process were calculated. These thermodynamic and kinetic parameters indicate a strong interaction between the inhibitor and the brass surface. The inhibition is assumed to occur via adsorption of inhibitor molecules on the brass surface, which obeys Temkin adsorption isotherm. The adsorption of inhibitor on the brass surface is exothermic, physical, and spontaneous, follows first order kinetics. The polarization measurements showed that the inhibitor behaves as a mixed type inhibitor. Inhibition efficiency values were found to show good trend with weight-loss method, potentiodynamic polarization and electrochemical impedance spectroscopy studies. Surface study techniques (FT-IR and SEM were carried out to ascertain the inhibitive nature of the algal extract on the brass surface.

  11. Aqueous Extract of Kalmegh (Andrographis paniculata Leaves as Green Inhibitor for Mild Steel in Hydrochloric Acid Solution

    Directory of Open Access Journals (Sweden)

    Ambrish Singh

    2010-01-01

    Full Text Available The inhibition of the corrosion of mild steel in hydrochloric acid solution by the extract of Kalmegh (Andrographis paniculata leaves extract has been studied using weight loss, electrochemical impedance spectroscopy, linear polarization, and potentiodynamic polarization techniques. Inhibition was found to increase with increasing concentration of the extract. The effect of temperature, immersion time, and acid concentration on the corrosion behavior of mild steel in 1 M HCl with addition of extract was also studied. The inhibition was assumed to occur via adsorption of the inhibitor molecules on the metal surface. The adsorption of the molecules of the extract on the mild steel surface obeyed the Langmuir adsorption isotherm. The protective film formed on the metal surface was analyzed by FTIR spectroscopy. The results obtained showed that the extract of Kalmegh (Andrographis paniculata leaves extract could serve as an effective inhibitor of the corrosion of mild steel in hydrochloric acid media.

  12. Second-generation sulfonamide inhibitors of D-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of D-glutamic acid.

    Science.gov (United States)

    Sosič, Izidor; Barreteau, Hélène; Simčič, Mihael; Sink, Roman; Cesar, Jožko; Zega, Anamarija; Grdadolnik, Simona Golič; Contreras-Martel, Carlos; Dessen, Andréa; Amoroso, Ana; Joris, Bernard; Blanot, Didier; Gobec, Stanislav

    2011-07-01

    D-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities. PMID:21524830

  13. Novel 2-oxoimidazolidine-4-carboxylic acid derivatives as Hepatitis C virus NS3-4A serine protease inhibitors: synthesis, activity, and X-ray crystal structure of an enzyme inhibitor complex

    Energy Technology Data Exchange (ETDEWEB)

    Arasappan, Ashok; Njoroge, F. George; Parekh, Tejal N.; Yang, Xiaozheng; Pichardo, John; Butkiewicz, Nancy; Prongay, Andrew; Yao, Nanhua; Girijavallabhan, Viyyoor (SPRI)

    2008-06-30

    Synthesis and HCV NS3 serine protease inhibitory activity of some novel 2-oxoimidazolidine-4-carboxylic acid derivatives are reported. Inhibitors derived from this new P2 core exhibited activity in the low {micro}M range. X-ray structure of an inhibitor, 15c bound to the protease is presented.

  14. Characterization of the corrosion products formed on mild steel in acidic medium with N-octadecylpyridinium bromide as corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Nava, N., E-mail: tnava@imp.mx; Likhanova, N. V. [Direccion de Investigacion y Posgrado, Instituto Mexicano del Petroleo (Mexico); Olivares-Xometl, O. [Benemerita Universidad Autonoma de Puebla, Facultad de Ingenieria Quimica (Mexico); Flores, E. A. [Direccion de Investigacion y Posgrado, Instituto Mexicano del Petroleo (Mexico); Lijanova, I. V. [CIITEC, Instituto Politecnico Nacional (Mexico)

    2011-11-15

    The characterization of the corrosion products formed on mild steel SAE 1018 after 2 months exposure in aqueous sulfuric acid with and without corrosion inhibitor N-octadecylpyridinium bromide has been carried out by means of transmission {sup 57}Fe Moessbauer spectroscopy and X-ray powder diffraction (XRD). The major constituent of the rust formed in this environment without corrosion inhibitor is goethite ({alpha}-FeOOH). The samples with N-octadecylpyridinium bromide contain rozenite and large amounts of melanterite in the corrosion layers.

  15. Multicomponent click synthesis of new 1,2,3-triazole derivatives of pyrimidine nucleobases: promising acidic corrosion inhibitors for steel.

    Science.gov (United States)

    González-Olvera, Rodrigo; Espinoza-Vázquez, Araceli; Negrón-Silva, Guillermo E; Palomar-Pardavé, Manuel E; Romero-Romo, Mario A; Santillan, Rosa

    2013-12-06

    A series of new mono-1,2,3-triazole derivatives of pyrimidine nucleobases were synthesized by one-pot copper(I)-catalyzed 1,3-dipolar cycloaddition reactions between N-1-propargyluracil and thymine, sodium azide and several benzyl halides. The desired heterocyclic compounds were obtained in good yields and characterized by NMR, IR, and high resolution mass spectrometry. These compounds were investigated as corrosion inhibitors for steel in 1 M HCl solution, using electrochemical impedance spectroscopy (EIS) technique. The results indicate that these heterocyclic compounds are promising acidic corrosion inhibitors for steel.

  16. Baphia nitida Leaves Extract as a Green Corrosion Inhibitor for the Corrosion of Mild Steel in Acidic Media

    OpenAIRE

    Njoku, V. O.; E. E. Oguzie; Obi, C.; Ayuk, A. A.

    2014-01-01

    The inhibiting effect of Baphia nitida (BN) leaves extract on the corrosion of mild steel in 1 M H2SO4 and 2 M HCl was studied at different temperatures using gasometric and weight loss techniques. The results showed that the leaves extract is a good inhibitor for mild steel corrosion in both acid media and better performances were obtained in 2 M HCl solutions. Inhibition efficiency was found to increase with increasing inhibitor concentration and decreasing temperature. The addition of hali...

  17. Characterization of the corrosion products formed on mild steel in acidic medium with N-octadecylpyridinium bromide as corrosion inhibitor

    International Nuclear Information System (INIS)

    The characterization of the corrosion products formed on mild steel SAE 1018 after 2 months exposure in aqueous sulfuric acid with and without corrosion inhibitor N-octadecylpyridinium bromide has been carried out by means of transmission 57Fe Mössbauer spectroscopy and X-ray powder diffraction (XRD). The major constituent of the rust formed in this environment without corrosion inhibitor is goethite (α-FeOOH). The samples with N-octadecylpyridinium bromide contain rozenite and large amounts of melanterite in the corrosion layers.

  18. In silico analysis for predicting fatty acids of black cumin oil as inhibitors of P-glycoprotein

    Directory of Open Access Journals (Sweden)

    Babar Ali

    2015-01-01

    Full Text Available Background: Black cumin oil is obtained from the seeds of Nigella sativa L. which belongs to family Ranunculaceae. The seed oil has been reported to possess antitumor, antioxidant, antibacterial, anti-inflammatory, hypoglycemic, central nervous system depressant, antioxidant, and immunostimulatory activities. These bioactivities have been attributed to the fixed oil, volatile oil, or their components. Seed oil consisted of 15 saturated fatty acids (17% and 17 unsaturated fatty acids (82.9%. Long chain fatty acids and medium chain fatty acids have been reported to increase oral bioavailability of peptides, antibiotics, and other important therapeutic agents. In earlier studies, permeation enhancement and bioenhancement of drugs has been done with black cumin oil. Objective: In order to recognize the mechanism of binding of fatty acids to P-glycoprotein (P-gp, linoleic acid, oleic acid, margaric acid, cis-11, 14-eicosadienoic acid, and stearic acid were selected for in silico studies, which were carried out using AutoDock 4.2, based on the Lamarckian genetic algorithm principle. Materials and Methods: Template search with BLAST and HHblits has been performed against the SWISS-MODEL template library. The target sequence was searched with BLAST against the primary amino acid sequence of P-gp from Rattus norvegicus. Results: The amount of energy needed by linoleic acid, oleic acid, eicosadienoic acid, margaric acid, and stearic acid to bind with P-gp were found to be − 10.60, −10.48, −9.95, −11.92, and − 10.37 kcal/mol, respectively. The obtained data support that all the selected fatty acids have contributed to inhibit P-gp activity thereby enhances the bioavailability of drugs. Conclusion: This study plays a significant role in finding hot spots in P-gp and may offer the further scope of designing potent and specific inhibitors of P-gp.

  19. Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Saini, Nipun; Black, Paul N.; Montefusco, David; DiRusso, Concetta C., E-mail: cdirusso2@unl.edu

    2015-09-25

    The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC{sub 50} 8–11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC{sub 50} 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of {sup 13}C-oleate demonstrating its potential as a therapeutic agent. - Highlights: • Grassofermata is a small compound inhibitor of FATP2. • Uptake inhibition is specific for long chain fatty acids. • Uptake kinetics shows low specificity for adipocytes compared to other cell types. • Inhibition is by a non-competitive mechanism. • Atypical antipsychotics do not inhibit FA uptake by comparison with Grassofermata.

  20. The histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates human astrocyte neurotoxicity induced by interferon-γ

    Directory of Open Access Journals (Sweden)

    Hashioka Sadayuki

    2012-05-01

    Full Text Available Abstract Backgrounds Increasing evidence shows that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA possesses potent anti-inflammatory and immunomodulatory properties. It is tempting to evaluate the potential of SAHA as a therapeutic agent in various neuroinflammatory and neurodegenerative disorders. Methods We examined the effects of SAHA on interferon (IFN-γ-induced neurotoxicity of human astrocytes and on IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT 3 in human astrocytes. We also studied the effects of SAHA on the astrocytic production of two representative IFN-γ-inducible inflammatory molecules, namely IFN-γ-inducible T cell α chemoattractant (I-TAC and intercellular adhesion molecule-1 (ICAM-1. Results SAHA significantly attenuated the toxicity of astrocytes activated by IFN-γ towards SH-SY5Y human neuronal cells. In the IFN-γ-activated astrocytes, SAHA reduced the STAT3 phosphorylation. SAHA also inhibited the IFN-γ-induced astrocytic production of I-TAC, but not ICAM-1. These results indicate that SAHA suppresses IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. Conclusion Due to its anti-neurotoxic and anti-inflammatory properties, SAHA appears to have the therapeutic or preventive potential for a wide range of neuroinflammatory disorders associated with activated astrocytes.

  1. Salubrinal, ER stress inhibitor, attenuates kainic acid-induced hippocampal cell death.

    Science.gov (United States)

    Kim, Jung Soo; Heo, Rok Won; Kim, Hwajin; Yi, Chin-Ok; Shin, Hyun Joo; Han, Jong Woo; Roh, Gu Seob

    2014-10-01

    Kainic acid (KA)-induced neuronal death is closely linked to endoplasmic reticulum (ER) and mitochondrial dysfunction. Parkin is an ubiquitin E3 ligase that mediates the ubiquitination of the Bcl-2 family of proteins and its mutations are associated with neuronal apoptosis in neurodegenerative diseases. We investigated the effect of salubrinal, an ER stress inhibitor, on the regulation of ER stress and mitochondrial apoptosis induced by KA, in particular, by controlling parkin expression. We showed that salubrinal significantly reduced seizure activity and increased survival rates of mice with KA-induced seizures. We found that salubrinal protected neurons against apoptotic death by reducing expression of mitochondrial apoptotic factors and elF2α-ATF4-CHOP signaling proteins. Interestingly, we showed that salubrinal decreased the KA-induced parkin expression and inhibited parkin translocation to mitochondria, which suggests that parkin may regulate a cross-talk between ER and mitochondria. Collectively, inhibition of ER stress attenuates mitochondrial apoptotic and ER stress pathways and controls parkin-mediated neuronal death following KA-induced seizures. PMID:24728926

  2. Diagnosis of Infectious Mononucleosis by Combined Detection of Atypical Lymphocytes and Transaminase

    Institute of Scientific and Technical Information of China (English)

    HU Lihua; YANG Juhong; CUI Tianpen; XING Hui; CAI Pengcheng

    2006-01-01

    In order to explore the value of combined detection of atypical lymphocytes (ATL) and transaminase (alanine aminotransferase, ALT; asparate aminotransferase, AST) in the diagnosis of infectious mononucleosis (IM), The data of blood routine and liver function were collected from 54 IM patients, 34 acute hepatitis (AH) patients, 44 upper respiratory infection (URI) patients in Union Hospital during March 2002 to March 2005. Same data were also collected from 40 healthy children as normal control. These data were analyzed retrospectively. Both proportion of atypical lymphocytes and enzyme activity of transaminase were elevated simultaneously (ALT>40 IU/L,AST>45 IU/L) in 57.4% (31/54) IM patients. There was significant difference (P<0.01) between IM group and the other groups. Combined detection of atypical lymphocytes and transaminase can be regarded as a diagnostic marker of infectious mononucleosis.

  3. Impact of plasma transaminase levels on the peripheral blood glutamate levels and memory functions in healthy subjects ☆

    OpenAIRE

    Kamada, Yoshihiro; Hashimoto, Ryota; Yamamori, Hidenaga; Yasuda, Yuka; Takehara, Tetsuo; Fujita, Yuko; Hashimoto, Kenji; Miyoshi, Eiji

    2016-01-01

    Background & aims Blood aspartate aminotransferase (AST) and alanine transaminase (ALT) levels are the most frequently reliable biomarkers of liver injury. Although AST and ALT play central roles in glutamate production as transaminases, peripheral blood levels of AST and ALT have been regarded only as liver injury biomarkers. Glutamate is a principal excitatory neurotransmitter, which affects memory functions in the brain. In this study, we investigated the impact of blood transaminase level...

  4. Amino Acid Composition, Urease Activity and Trypsin Inhibitor Activity after Toasting of Soybean in Thick and Thin Layer

    Directory of Open Access Journals (Sweden)

    Tajana Krička

    2009-12-01

    Full Text Available The objective of this study was to determine amino acid content, urease activity and trypsin inhibitor activity in soybean grain for polygastric animals’ feed aft er toasting with the aim to introduce thick layer in toasting technology. Hence, soybean was toasted both in thick and thin layer at 130 oC during 10 minutes. In order to properly monitor the technological process of soybean thermal processing, it was necessary to study crude protein content, urease activity, trypsin inhibitor activity and amino acid composition of soybean in natural and toasted samples. Results demonstrate that protein content in soybean toasted in thick and thin layer was found to be slightly increased while urease activity was reduced in relation to non-treated sample. Study also established a significant reduction of trypsin inhibitor activity aft er toasting, at higher extent in thin layer toasting. Amino acid content of soybean was slightly increased in relation to natural sample, as well as difference between amino acid content in samples toasted in thick and thin layers.

  5. Mechanism for release of arachidonic acid during guinea pig platelet aggregation: a role for the diacylglycerol lipase inhibitor RHC 80267

    International Nuclear Information System (INIS)

    The mechanism of the release of arachidonic acid from phospholipids after the stimulation of guinea pig platelets with collagen, thrombin and platelet activating factor (PAF) was studied. RHC 80267, a diacylglycerol lipase inhibitor, and indomethacin, a cyclooxygenase inhibitor, were used. Various in vitro assays for enzymes involved in arachidonic acid release and metabolism were conducted. Platelet aggregation and simultaneous release of ADP from platelets were monitored using a Chrono-log Lumiaggregometer. Platelets were labeled with (14C)arachidonic acid to facilitate sensitive determination of small changes in platelet phospholipids during platelet aggregation. In the present investigation it is shown that collagen, thrombin and PAF increased phospholipase C activity. It was also discovered that cyclooxygenase products were responsible for further stimulation (a positive feed-back) of phospholipase C activity, while diacylglycerol provided a negative feed-back control over receptor-stimulated phospholipase C activity and inhibited ADP release. The guinea pig platelet is an ideal model to study phospholipase C-diacylglycerol lipase pathway for the release of arachidonic acid from platelet phospholipids because it does not have any phospholipase A2 activity. It was observed that cyclooxygenase products were responsible for collagen-induced guinea pig platelet aggregation. Indomethacin completely inhibited collagen-induced platelet aggregation, was less effective against thrombin, and had no effect on PAF-induced platelet aggregation. On the other hand, RHC 80267 was a powerful inhibitor of aggregation and ADP release induced by all three of these potent aggregating agents

  6. Chronic hepatitis E virus infection in a patient with leukemia and elevated transaminases: a case report

    Directory of Open Access Journals (Sweden)

    Gauss Annika

    2012-10-01

    Full Text Available Abstract Introduction Acute hepatitis E virus infection may cause mild, self-limiting hepatitis, either as epidemic outbreaks or sporadic cases, the latter of which have been reported in industrialized countries. Chronic infections are uncommon and have been reported in immunosuppressed patients, patients with human immunodeficiency virus infection, and patients with hematological malignancies. Case presentation A 46-year-old Caucasian man was admitted to the gastroenterology clinic with a history of increasing transaminases, persistent exhaustion, and occasional right-side abdominal pain over the course of a 6-month period. B-cell chronic lymphocytic leukemia had been diagnosed several years earlier, and the patient was treated with rituximab, pentostatin, and cyclophosphamide. A diagnostic workup ruled out autoimmune and metabolic liver disease, hepatitis A-C, and herpes virus infection. A physical examination revealed enlarged axillary lymph nodes. The results of an abdominal ultrasound examination were otherwise unremarkable. Hepatitis E virus infection was diagnosed by detection of hepatitis E virus-specific antibodies. Blood samples were positive for hepatitis E virus ribonucleic acid with high viral loads for at least 8 months, demonstrating a rare chronic hepatitis E virus infection. Sequencing and phylogenetic analysis revealed hepatitis E virus genotype 3c with homologies to other European isolates from humans and swine, indicating an autochthonous infection. Conclusions Usually, hepatitis E virus infection appears as an acute infection; rare chronic infections have been reported for transplant patients, patients with human immunodeficiency virus, and patients with hematological malignancies. The chronic nature of hepatitis E infection in our patient was most likely induced by the immunosuppressive B-cell chronic lymphocytic leukemia treatment. The differential diagnosis in patients with unexplained hepatitis should include hepatitis E

  7. Determination of human serum alpha1-acid glycoprotein and albumin binding of various marketed and preclinical kinase inhibitors.

    Science.gov (United States)

    Zsila, Ferenc; Fitos, Ilona; Bencze, Gyula; Kéri, György; Orfi, László

    2009-01-01

    There are about 380 protein kinase inhibitors in drug development as of today and 15 drugs have been marketed already for the treatment of cancer. This time 139 validated kinase targets are in the focus of drug research of pharmaceutical companies and big efforts are made for the development of new, druglike kinase inhibitors. Plasma protein binding is an important factor of the ADME profiling of a drug compound. Human serum albumin (HSA) and alpha(1)-acid glycoprotein (AAG) are the most relevant drug carriers in blood plasma. Since previous literature data indicated that AAG is the principal plasma binding component of some kinase inhibitors the present work focuses on the comprehensive evaluation of AAG binding of a series of marketed and experimental kinase inhibitors by using circular dichroism (CD) spectroscopy approach. HSA binding was also evaluated by affinity chromatography. Protein binding interactions of twenty-six kinase inhibitors are characterized. The contribution of AAG and HSA binding data to the pharmacokinetic profiles of the investigated therapeutic agents is discussed. Structural, biological and drug binding properties of AAG as well as the applicability of the CD method in studying drug-protein binding interactions are also briefly reviewed.

  8. Some aromatic hydrazone derivatives as inhibitors for the corrosion of C-steel in phosphoric acid solution.

    Science.gov (United States)

    Fouda, Abd El-Aziz S; Al-Sarawy, Ahmed A; Radwan, Mohamed S

    2006-01-01

    The effect of furfural benzoylhydrazone and its derivatives (I-VII) as corrosion inhibitors for C-steel in 1M phosphoric acid solution has been studied by weight-loss and galvanostatic polarization techniques. A significant decrease in the corrosion rate of C-steel was observed in the presence of the investigated inhibitors. This study revealed that, the inhibition efficiency increases with increasing the inhibitor concentration, and the addition of iodide ions enhances it to a considerable extent. The effect of temperature on the inhibition efficiency of these compounds was studied using weight-loss method. Activation energy (E(a)*) and other thermodynamic parameters for the corrosion process were calculated and discussed. The galvanostatic polarization data indicated that, the inhibitors were of mixed-type, but the cathode is more polarized than the anode. The adsorption of these compounds on C-steel surface has been found to obey Frumkin's adsorption isotherm. The mechanism of inhibition was discussed in the light of the chemical structure of the undertaken inhibitors.

  9. Valoniopsis pachynema Extract as a Green Inhibitor for Corrosion of Brass in 0.1 N Phosphoric Acid Solution

    Science.gov (United States)

    Selva Kumar, R.; Chandrasekaran, V.

    2016-04-01

    The effect of marine alga Valoniopsis pachynema extract on corrosion inhibition of brass in phosphoric acid was investigated by weight-loss method, potentiodynamic polarization, and electrochemical impedance spectroscopy studies. The inhibition efficiency is found to increase with increasing concentration of extract and decreases with rise in temperature. The activation energy, thermodynamic parameters (free energy, enthalpy, and entropy change) and kinetic parameters (rate constant and half-life) for inhibition process were calculated. These thermodynamic and kinetic parameters indicate a strong interaction between the inhibitor and the brass surface. The inhibition is assumed to occur via adsorption of inhibitor molecules on brass surface, which obeys Temkin adsorption isotherm. The adsorption of inhibitor on the brass surface is exothermic, physical, and spontaneous, and follows first-order kinetics. The polarization measurements showed that the inhibitor behaves as a mixed type inhibitor and the higher inhibition surface coverage on the brass was predicted. Inhibition efficiency values were found to show good trend with weight-loss method, potentiodynamic polarization, and electrochemical impedance spectroscopy studies. Surface study techniques (FT-IR and SEM) were carried out to ascertain the inhibitive nature of the algal extract on the brass surface.

  10. Biophysical Investigation of the Mode of Inhibition of Tetramic Acids, the Allosteric Inhibitors of Undecaprenyl Pyrophosphate Synthase

    OpenAIRE

    Lee, Lac V.; Granda, Brian; Dean, Karl; Tao, Jianshi; Liu, Eugene; Zhang, Rui; Peukert, Stefan; Wattanasin, Sompong; XIE, XIAOLING; Ryder, Neil S.; Tommasi, Ruben; Deng, Gejing

    2010-01-01

    Undecaprenyl pyrophosphate synthase (UPPS) catalyzes the consecutive condensation of eight molecules of isopentenyl pyrophosphate (IPP) with farnesyl pyrophosphate (FPP) to generate the C55 undecaprenyl pyrophosphate (UPP). It has been demonstrated that tetramic acids (TAs) are selective and potent inhibitors of UPPS, but the mode of inhibition was unclear. In this work, we used a fluorescent FPP probe to study possible TA binding at the FPP binding site. A photosensitive TA analogue was desi...

  11. Pomegranate (Punica granatum) Peel Extract as a Green Corrosion Inhibitor for Mild Steel in Hydrochloric Acid Solution

    OpenAIRE

    Habib Ashassi-Sorkhabi; Shoja Mirzaee; Taghi Rostamikia; Robabeh Bagheri

    2015-01-01

    The inhibition effect of pomegranate peel extract (PPE) on the corrosion of mild steel in hydrochloric acid (HCl) solution was investigated. The polarization, mass loss, and electrochemical impendence techniques were used to evaluate the corrosion inhibition performance of the pomegranate peel extract. The results revealed that PPE acts as a corrosion inhibitor in HCl solution. The inhibition efficiency increased with the increase of extract concentration. The inhibition action was attributed...

  12. Rhabdovirus-induced apoptosis in a fish cell line is inhibited by a human endogenous acid cysteine proteinase inhibitor.

    Science.gov (United States)

    Björklund, H V; Johansson, T R; Rinne, A

    1997-07-01

    To determine the mechanisms of cell death in rhabdovirus-infected cells, we studied the infection of the epithelial papilloma of carp cell line with spring viremia of carp virus. Studies using electron microscopy, confocal microscopy, and agarose gel electrophoresis revealed changes in cell morphology and DNA fragmentation indicative of apoptosis. The virus-induced apoptosis was inhibited in cells treated with a human endogenous acid cysteine proteinase inhibitor. PMID:9188644

  13. Rhabdovirus-induced apoptosis in a fish cell line is inhibited by a human endogenous acid cysteine proteinase inhibitor.

    OpenAIRE

    Björklund, H V; Johansson, T R; Rinne, A

    1997-01-01

    To determine the mechanisms of cell death in rhabdovirus-infected cells, we studied the infection of the epithelial papilloma of carp cell line with spring viremia of carp virus. Studies using electron microscopy, confocal microscopy, and agarose gel electrophoresis revealed changes in cell morphology and DNA fragmentation indicative of apoptosis. The virus-induced apoptosis was inhibited in cells treated with a human endogenous acid cysteine proteinase inhibitor.

  14. A Novel Strategy to Assemble the β-Diketo Acid Pharmacophore of HIV Integrase Inhibitors on Purine Nucleobase Scaffolds

    OpenAIRE

    Uchil, Vinod; Seo, Byung; Nair, Vasu

    2007-01-01

    Claisen condensation, the key step in constructing the pharmacophore of aryl β-diketo acids (DKA) as integrase inhibitors, fails in certain cases of highly electron-deficient heterocycles such as purines. A general synthetic strategy to assemble the DKA motif on the purine scaffold has been accomplished. The synthetic sequence entails a palladium-catalyzed cross-coupling, a C-acylation involving a tandem addition/elimination reaction and a novel ferric ion-catalyzed selective hydrolysis of an...

  15. Sargassum Wightii Extract as a Green Inhibitor for Corrosion of Brass in 0.1 N Phosphoric Acid Solution

    OpenAIRE

    R. Selva Kumar; Chandrasekaran, V.

    2015-01-01

    The effect of marine algae Sargassum wightii extract on corrosion inhibition of brass in phosphoric acid was investigated by weight-loss method, potentiodynamic polarization and electrochemical impedance spectroscopy studies. The inhibition efficiency is found to increase with increasing concentration of extract and decreases with rise in temperature. The inhibitive effect could be attributed to the phytochemical constituents present in the inhibitor containing N, S, O atoms. The activation e...

  16. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes

    OpenAIRE

    Grobler, Jay A.; Stillmock, Kara; Hu, Binghua; Witmer, Marc; Felock, Peter; Espeseth, Amy S.; Wolfe, Abigail; Egbertson, Melissa; Bourgeois, Michele; Melamed, Jeffrey; Wai, John S.; Young, Steve; Vacca, Joseph; Hazuda, Daria J.

    2002-01-01

    The process of integrating the reverse-transcribed HIV-1 DNA into the host chromosomal DNA is catalyzed by the virally encoded enzyme integrase (IN). Integration requires two metal-dependent reactions, 3′ end processing and strand transfer. Compounds that contain a diketo acid moiety have been shown to selectively inhibit the strand transfer reaction of IN in vitro and in infected cells and are effective as inhibitors of HIV-1 replication. To characterize the molecular basis of inhibition, we...

  17. Biological inhibitor abatement and ethanol fermentation of sugars from dilute acid-pretreated rice hulls

    Science.gov (United States)

    Fermentation inhibitors arise from lignin, hemicellulose, and degraded sugar during pretreatment of lignocellulosic biomass. Use of a microbe has been explored for abatement of pretreated biomass in which fermentation inhibitors, if left untreated, can complicate microbial conversion of biomass to f...

  18. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  19. Role of bile acids, prostaglandins and COX inhibitors in chronic esophagitis in a mouse model

    Institute of Scientific and Technical Information of China (English)

    C Poplawski; D Sosnowski; A Szaflarska-Poplawska; J Sarosiek; R McCallum; Z Bartuzi

    2006-01-01

    AIM: To develop a new experimental model of esophagitis that serves a complementary tool to clinical investigation in an insight into the mechanism of the damage to the esophagus mucosa by aggressive factors, and role of COX inhibitors in this process.METHODS: The study was conducted in 56 male mice.Animals were divided into seven groups: (1) perfused with HCl, (2) perfused with HCl and physiologic concentration of pepsin (HCl/P), (3) perfused with similar HCl/P solution enriched with conjugated bile acids (glycho- and tauro-sodium salts) designated esophageal infusion catheter under the general anesthesia, (4) perfused as in group 2 treated with indometacin, (5) perfused as in group 2 treated with NS-398, (6) perfused as in group 3 treated with indometacin, and (7) perfused as in group 3 treated with NS-398.The esophagus was divided into 3 parts: upper, middle and lower. The PGE2 concentration was measured in all parts of esophagus using RIA method. Esophagus of sacrificed animals was macroscopically evaluated using a low power dissecting microscope (20x). Specimeris, representing the most frequently seen changes were fixed,stained with H&E and assessed microscopically using the damage score, and inflammatory score.RESULTS: The macroscopic changes were significantly severer in HCl/P than those in HCl animals (77%) and in HCl/P/BA group (43%). In HCl/P NS-398 group we noticed significantly less changes than those in not treated group (42%) and in analogical group treated with indometacine (45%). In HCl/P/BA INDO group we observed significantly severer changes than that in not treated group (52%). We noticed less changes in HCl/P NS-398 than that in group with indometacine (46%). In HCl/P/BA NS-398 group we had less changes than that in indometacin group (34%). The microscopic changes observed in HCl/P/BA INDO group were severer than that in not treated group (48%). Esophagitis index in HCl group was significantly lower than in HCl/P and also HCl/P/BA group (32% and

  20. Impairment of liver regeneration by the histone deacetylase inhibitor valproic acid in mice

    Institute of Scientific and Technical Information of China (English)

    Qi KE; Rui-na YANG; Feng YE; Yu-jia WANG; Qiong WU; Li LI; Hong BU

    2012-01-01

    Background and objective:Liver regeneration is a complex process regulated by a group of genetic and epigenetic factors.A variety of genetic factors have been reported,whereas few investigations have focused on epigenetic regulation during liver regeneration.In the present study,valproic acid (VPA),a histone deacetylase (HDAC)inhibitor,was used to investigate the effect of HDAC on liver regeneration.Methods:VPA was administered via intraperitoneal injection to 2/3 partially hepatectomized mice to detect hepatocyte proliferation during liver regeneration.The mice were sacrificed,and their liver tissues were harvested at sequential time points from 0 to 168 h after treatment.DNA synthesis was detected via a BrdU assay,and cell proliferation was tested using Ki-67.The expressions of cyclin D1,cyclin E,cyclin dependent kinase 2 (CDK2),and CDK4 were detected by Western blot analysis.Chromatin immunoprecipitation (ChIP) assay was used to examine the recruitment of HDACs to the target promoter regions and the expression of the target gene was detected by Western blot.Results:Immunohistochemical analysis showed that cells positive for BrdU and Ki-67 decreased,and the peak of BrdU was delayed in the VPA-administered mice.Consistently,cyclin D1 expression was also delayed.We identified B-myc as a target gene of HDACs by complementary DNA (cDNA) microarray.The expression of B-myc increased in the VPA-administered mice after hepatectomy (PH).The ChIP assay confirmed the presence of HDACs at the B-myc promoter.Conclusions:HDAC activities are essential for liver regeneration,inhibiting HDAC activities delays liver regeneration and induces liver cell cycle arrest,thereby causing an anti-proliferative effect on liver regeneration.

  1. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    International Nuclear Information System (INIS)

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming

  2. Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress

    Energy Technology Data Exchange (ETDEWEB)

    Zhai, Yingying; Chen, Xi; Yu, Dehai [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Tao [Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Cui, Jiuwei; Wang, Guanjun [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Hu, Ji-Fan, E-mail: jifan@stanford.edu [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China); Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304 (United States); Li, Wei, E-mail: jdyylw@163.com [Stem Cell and Cancer Center, First Affiliated Hospital, Jilin University, Changchun, Jilin 130061 (China)

    2015-09-10

    Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC-inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. - Highlights: • Histone deacetylase inhibitor valproic acid enhances iPSC induction. • Valproic acid suppresses reprogramming-induced senescence stress. • Valproic acid downregulates the p16/p21 pathway in reprogramming. • This study demonstrates a new mechanistic role of valproic acid in enhancing reprogramming.

  3. Comparison of amino acid sequences of the trypsin inhibitors from taro (Colocasia esculenta), giant taro (Alocasia macrorrhiza) and giant swamp taro (Cyrtosperma chamissonis).

    Science.gov (United States)

    Peng, L; Bradbury, J H; Hammer, B C; Shaw, D C

    1993-09-01

    The amino acid sequences of the trypsin inhibitors from taro Colocasia esculenta var. esculenta and giant swamp taro Cyrtosperma chamissonis have been determined and are compared with the protein sequence of the trypsin/chymotrypsin inhibitor from giant taro Alocasia macrorrhiza. Both inhibitors display polymorphism and there is evidence of two components in the giant swamp taro. The positional identity between the proteins is highest at 73-75% for the comparison of the giant taro (GT) with the polymorphic forms of the taro (T) inhibitors and lowest at 56-58% for the pairs of taro and giant swamp taro (GST) proteins. The comparisons show that the inhibitors from T and GT are more related to each other than to GST, which supports their taxonomic classification into different tribes. Location of the P1 site for the trypsin inhibitors of aroids is different from that of other Kunitz-type inhibitors and could be at Leu56.

  4. Indian patients with nonalcoholic fatty liver disease presenting with raised transaminases are different at presentation

    Institute of Scientific and Technical Information of China (English)

    Ajay Duseja; Naveen Kaita; Ashim Das; Radha Krishan Dhiman; Yogesh Kumar Chawla; Reena Das; Sanjay Bhadada; Ravinder Sialy; Kiran Kumar Thumburu; Anil Bhansali

    2007-01-01

    @@ TO THE EDITOR We read with great interest the article, "Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians" by Madan et al in the recent issue of WJG. Twenty-eight (55%) out of 51 patients with nonalcoholic fatty liver disease (NAFLD) who presented with abnormal transaminases had histological evidence of nonalcoholic steatohepatitis (NASH).

  5. Selections of minimal conditions for a simple intensification and scale up of w-transaminase reactions

    DEFF Research Database (Denmark)

    Gundersen, Maria T.; Lloyd, Richard C; Woodley, John

    A step wise decision matrix is presented to quickly evaluate w - transaminase for a ‘simple scale up’ in the synthetic direction . Here a ‘simple scale up’ is defined as a system without specialized equipment or process development, thus a rapid implementation . The three step method consists...

  6. Disproportional exaggerated aspartate transaminase is a useful prognostic parameter in late leptospirosis

    Institute of Scientific and Technical Information of China (English)

    Ming-Ling Chang; Chih-Wei Yang; Jeng-Chang Chen; Yu-Pin Ho; Ming-Jeng Pan; Cheng-Hui Lin; Deng-Yn Lin

    2005-01-01

    AIM: To evaluate the hepatic dysfunction in leptospirosis is usually mild and resolved eventually. However,sequential follow-up of liver biochemical data remained lacking..METHODS: The biochemistry data and clinical symptoms of 11 sporadic patients were collected and analyzed, focusing on the impacts of leptospirosis upon liver biochemistry tests.RESULTS: The results disclosed that of the 11 cases, 5 or 45% died. The liver biochemistry data in the beginning of the disease course were only mildly elevated.Nevertheless, late exaggerated aspartate transaminase (AST)elevations were noted in three cases who finally died when compared with the typical course. Besides, significant higher AST/alanine transaminase (ALT) ratios (AARs) of the peak levels for transaminase were also noted in the cases who eventually succumbed. The mean±SD of AARs for the survival group and dead group were 5.65±2.27 (n = 5)and 1.86±0.64 (n = 6) respectively (P= 0.006). The ratios of the cases who finally died were all more than 3.0.Conversely, the survival group's ratios were less than 3.0.CONCLUSION: Serial follow-up of transaminase might provide evidence to predict some rare evolutions in leptospirosis. If AST elevated progressively without a concomitant change of ALT, it might indicate an acute disease course with ensuing death. Additionally, AAR is another prognostic parameter for leptospirosis. Once the value was higher than 3.0, a grave prognosis is inevitable.

  7. A Practical and Fast Method To Predict the Thermodynamic Preference of ω-Transaminase-Based Transformations

    DEFF Research Database (Denmark)

    Meier, Robert J.; Gundersen, Maria T.; Woodley, John;

    2015-01-01

    A simple, easy-to-use, and fast approach method is proposed and validated that can predict whether a transaminase reaction is thermodynamically unfavourable. This allowed us to de-select, in the present case, at least 50% of the reactions because they were thermodynamically unfavourable as confir...

  8. A Practical and Fast Method To Predict the Thermodynamic Preference of omega-Transaminase-Based Transformations

    DEFF Research Database (Denmark)

    Meier, Robert J.; Gundersen Deslauriers, Maria; Woodley, John;

    2015-01-01

    A simple, easy-to-use, and fast approach method is proposed and validated that can predict whether a transaminase reaction is thermodynamically unfavourable. This allowed us to de-select, in the present case, at least 50% of the reactions because they were thermodynamically unfavourable as confir...

  9. Cefalexin drug: A new and efficient corrosion inhibitor for mild steel in hydrochloric acid solution

    Energy Technology Data Exchange (ETDEWEB)

    Shukla, Sudhish Kumar [Department of Applied Chemistry, Institute of Technology, Banaras Hindu University, Varanasi 221 005 (India); Quraishi, M.A., E-mail: maquraishi.apc@itbhu.ac.in [Department of Applied Chemistry, Institute of Technology, Banaras Hindu University, Varanasi 221 005 (India)

    2010-03-15

    Corrosion inhibition of mild steel in 1N HCl by cefalexin has been studied by electrochemical and weight loss measurements. The inhibitor showed increase in inhibition efficiency with increase in inhibitor concentration up to optimum concentration 400 ppm. Potentiodynamic polarization suggests that it is a mixed type of inhibitor. Electrochemical impedance spectroscopy was used to investigate the mechanism of corrosion inhibition. Thermodynamic parameters were calculated to investigate mechanism of inhibition. AFM is used to investigate the surface morphology of the uninhibited and inhibited mild steel.

  10. Chemical Genetics Uncovers Novel Inhibitors of Lignification, Including p-Iodobenzoic Acid Targeting CINNAMATE-4-HYDROXYLASE1[OPEN

    Science.gov (United States)

    Van de Wouwer, Dorien; Decou, Raphaël; Audenaert, Dominique; Nguyen, Long

    2016-01-01

    Plant secondary-thickened cell walls are characterized by the presence of lignin, a recalcitrant and hydrophobic polymer that provides mechanical strength and ensures long-distance water transport. Exactly the recalcitrance and hydrophobicity of lignin put a burden on the industrial processing efficiency of lignocellulosic biomass. Both forward and reverse genetic strategies have been used intensively to unravel the molecular mechanism of lignin deposition. As an alternative strategy, we introduce here a forward chemical genetic approach to find candidate inhibitors of lignification. A high-throughput assay to assess lignification in Arabidopsis (Arabidopsis thaliana) seedlings was developed and used to screen a 10-k library of structurally diverse, synthetic molecules. Of the 73 compounds that reduced lignin deposition, 39 that had a major impact were retained and classified into five clusters based on the shift they induced in the phenolic profile of Arabidopsis seedlings. One representative compound of each cluster was selected for further lignin-specific assays, leading to the identification of an aromatic compound that is processed in the plant into two fragments, both having inhibitory activity against lignification. One fragment, p-iodobenzoic acid, was further characterized as a new inhibitor of CINNAMATE 4-HYDROXYLASE, a key enzyme of the phenylpropanoid pathway synthesizing the building blocks of the lignin polymer. As such, we provide proof of concept of this chemical biology approach to screen for inhibitors of lignification and present a broad array of putative inhibitors of lignin deposition for further characterization. PMID:27485881

  11. A new dioxime corrosion inhibitor for the protection and conservation of copper: synthesis, characterization and evaluation in acidic chloride solution

    Science.gov (United States)

    Abu-Baker, Ahmad N.; Al-Qudah, Mahmoud A.

    2016-08-01

    This study aimed to investigate a new dioxime compound as a corrosion inhibitor for copper. The compound (4,6-dihydroxy benzene-1,3-dicarbaldehyde dioxime) was synthesized and characterized by nuclear magnetic resonance spectroscopy. Electrochemical impedance spectroscopy and potentiodynamic polarization measurements were used to compare the dioxime compound with benzotriazole for their effectiveness as corrosion inhibitors for copper in 0.1 M HCl solution. Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) were used to investigate the bonding mechanisms and morphological changes of the two inhibitors on the copper surface. The electrochemical techniques showed that the new dioxime compound was more effective than benzotriazole in inhibiting copper corrosion in the acidic chloride medium. The FTIR and SEM results indicated that the dioxime compound was able to coordinate with copper ions and formed a protective film on the copper surface. It was concluded that the new dioxime compound proved effectiveness to be used as a corrosion inhibitor for the protection and conservation of copper.

  12. Discovery of a Potent, Selective, and Efficacious Class of Reversible α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Effective as Analgesicsa

    OpenAIRE

    Boger, Dale L.; Miyauchi, Hiroshi; Du, Wu; Hardouin, Christophe; Fecik, Robert A.; Cheng, Heng; Hwang, Inkyu; Hedrick, Michael P.; Leung, Donmienne; Acevedo, Orlando; Guimarães, Cristiano R. W.; Jorgensen, William L.; Cravatt, Benjamin F.

    2005-01-01

    Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routi...

  13. Detection of Reduced GABA Synthesis Following Inhibition of GABA Transaminase Using in Vivo Magnetic Resonance Signal of [13C]GABA C1

    OpenAIRE

    Yang, Jehoon; Johnson, Christopher; Shen, Jun

    2009-01-01

    Previous in vivo magnetic resonance spectroscopy (MRS) studies of gamma-aminobutyric acid (GABA) synthesis have relied on 13C label incorporation into GABA C2 from [1-13C] or [1,6-13C2]glucose. In this study, the [13C]GABA C1 signal at 182.3 ppm in the carboxylic/amide spectral region of localized in vivo 13C spectra was detected. GABA-transaminase of rat brain was inhibited by administration of gabaculine after pre-labeling of GABA C1 and its metabolic precursors with exogenous [2,5-13C2]glu...

  14. Anti-Tumor Effect in Human Lung Cancer by a Combination Treatment of Novel Histone Deacetylase Inhibitors: SL142 or SL325 and Retinoic Acids

    OpenAIRE

    Shaoteng Han; Takuya Fukazawa; Tomoki Yamatsuji; Junji Matsuoka; Hiroyuki Miyachi; Yutaka Maeda; Mary Durbin; Yoshio Naomoto

    2010-01-01

    Histone deacetylase (HDAC) inhibitors arrest cancer cell growth and cause apoptosis with low toxicity thereby constituting a promising treatment for cancer. In this study, we investigated the anti-tumor activity in lung cancer cells of the novel cyclic amide-bearing hydroxamic acid based HDAC inhibitors SL142 and SL325. In A549 and H441 lung cancer cells both SL142 and SL325 induced more cell growth inhibition and cell death than the hydroxamic acid-based HDAC inhibitor suberoylanilide hydrox...

  15. A Study of N,N-Diethylammonium O,O′-Di(p-methoxyphenyldithiophosphate as New Corrosion Inhibitor for Carbon Steel in Hydrochloric Acid Solution

    Directory of Open Access Journals (Sweden)

    Chuan Lai

    2016-01-01

    Full Text Available N,N-Diethylammonium O,O′-di(p-methoxyphenyldithiophosphate (EAPP as a new corrosion inhibitor was synthesized in the present work. The corrosion inhibition of EAPP in hydrochloric acid for carbon steel was evaluated by potentiodynamic polarization measurements, electrochemical impedance spectroscopy, weight loss measurements, and scanning electron microscopy. The results indicate that the EAPP is mixed type inhibitor, and the adsorption of EAPP on carbon steel surface obeys Langmuir isotherm. In addition, the inhibition efficiency increases with increasing the concentration of inhibitor and decreases with increasing the hydrochloric acid concentration, temperature, and storage time.

  16. Kinetics of Corrosion Inhibition of Aluminum in Acidic Media by Water-Soluble Natural Polymeric Pectates as Anionic Polyelectrolyte Inhibitors

    Directory of Open Access Journals (Sweden)

    Refat M. Hassan

    2013-06-01

    Full Text Available Corrosion inhibition of aluminum (Al in hydrochloric acid by anionic polyeletrolyte pectates (PEC as a water-soluble natural polymer polysaccharide has been studied using both gasometric and weight loss techniques. The results drawn from these two techniques are comparable and exhibit negligible differences. The inhibition efficiency was found to increase with increasing inhibitor concentration and decrease with increasing temperature. The inhibition action of PEC on Al metal surface was found to obey the Freundlich isotherm. Factors such as the concentration and geometrical structure of the inhibitor, concentration of the corrosive medium, and temperature affecting the corrosion rates were examined. The kinetic parameters were evaluated and a suitable corrosion mechanism consistent with the kinetic results is discussed in the paper.

  17. Baphia nitida Leaves Extract as a Green Corrosion Inhibitor for the Corrosion of Mild Steel in Acidic Media

    Directory of Open Access Journals (Sweden)

    V. O. Njoku

    2014-01-01

    Full Text Available The inhibiting effect of Baphia nitida (BN leaves extract on the corrosion of mild steel in 1 M H2SO4 and 2 M HCl was studied at different temperatures using gasometric and weight loss techniques. The results showed that the leaves extract is a good inhibitor for mild steel corrosion in both acid media and better performances were obtained in 2 M HCl solutions. Inhibition efficiency was found to increase with increasing inhibitor concentration and decreasing temperature. The addition of halides to the extract enhanced the inhibition efficiency due to synergistic effect which improved adsorption of cationic species present in the extract and was in the order KCl < KBr < KI suggesting possible role of radii of the halide ions. Thermodynamic parameters determined showed that the adsorption of BN on the metal surface is an exothermic and spontaneous process and that the adsorption was via a physisorption mechanism.

  18. Ellagic acid and polyhydroxylated urolithins are potent catalytic inhibitors of human topoisomerase II: an in vitro study.

    Science.gov (United States)

    Furlanetto, Valentina; Zagotto, Giuseppe; Pasquale, Riccardo; Moro, Stefano; Gatto, Barbara

    2012-09-12

    Ellagic acid (EA), a natural polyphenol abundant in fruits and common in our diet, is under intense investigation for its chemopreventive activity resulting from multiple effects. EA inhibits topoisomerase II, but the effects on the human enzyme of urolithins, its monolactone metabolites, are not known. Therefore, the action of several synthetic urolithins toward topoisomerases II was evaluated, showing that polyhydroxylated urolithins, EA, and EA-related compounds are potent inhibitors of the α and β isoforms of human topoisomerase II at submicromolar concentrations. Competition tests demonstrate a dose-dependent relationship between ATP and the inhibition of the enzyme. Docking experiments show that the active compounds bind the ATP pocket of the human enzyme, thus supporting the hypothesis that EA and polyhydroxylated urolithins act as ATP-competitive inhibitors of human topoisomerase II. PMID:22924519

  19. Outcomes in patients with nonerosive reflux disease treated with a proton pump inhibitor and alginic acid ± glycyrrhetinic acid and anthocyanosides

    Directory of Open Access Journals (Sweden)

    Di Pierro F

    2013-03-01

    Full Text Available Francesco Di Pierro,1 Mario Gatti,2 Giuliana Rapacioli,3 Leandro Ivaldi4 1Velleja Research, Milan, 2Gastroenterology Department, Giussano Hospital, Monza-Brianza, 3AIOR, Piacenza, 4Digestive Endoscopic Department, Ceva Hospital, Ceva, Cuneo, Italy Background: The purpose of this study was to compare the efficacy of alginic acid alone versus alginic acid combined with low doses of pure glycyrrhetinic acid and bilberry anthocyanosides as an addon to conventional proton pump inhibitor therapy in relieving symptoms associated with nonerosive reflux disease. Methods: This prospective, randomized, 8-week, open-label trial was conducted at two centers. Sixty-three patients with persistent symptoms of gastroesophageal reflux disease and normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A (n = 31 were treated with pantoprazole and a formula (Mirgeal® containing alginic acid and low doses of pure glycyrrhetinic acid + standardized Vaccinium myrtillus extract for 4 weeks, then crossed over to the multi-ingredient formula for a further 4 weeks. Patients in group B (n = 32 were treated pantoprazole and alginic acid alone twice daily, then crossed over to alginic acid twice daily for a further 4 weeks. Efficacy was assessed by medical evaluation of a symptom relief score, estimated using a visual analog scale (0–10. Side effects, tolerability, and compliance were also assessed. Results: Of the 63 patients enrolled in the study, 58 (29 in group A and 29 in group B completed the 8-week trial. The baseline characteristics were comparable between the two groups. During the study, significant differences were recorded in symptom scores for both groups. In group A, symptoms of chest pain, heartburn, and abdominal swelling were less serious than in group B. Treatment A was better tolerated, did not induce hypertension, and had fewer side effects than treatment B. No significant differences in compliance were found between the

  20. 2-aminohydroxamic acid derivatives as inhibitors of Bacillus cereus phosphatidylcholine preferred phospholipase C PC-PLC(Bc).

    Science.gov (United States)

    González-Bulnes, Patricia; González-Roura, Albert; Canals, Daniel; Delgado, Antonio; Casas, Josefina; Llebaria, Amadeu

    2010-12-15

    Phosphatidylcholine preferring phospholipase C (PC-PLC) is an important enzyme that plays a key role in a variety of cellular events and lipid homoeostases. Bacillus cereus phospholipase C (PC-PLC(Bc)) has antigenic similarity with the elusive mammalian PC-PLC, which has not thus far been isolated and purified. Therefore the discovery of inhibitors of PC-PLC(Bc) is of current interest. Here, we describe the synthesis and biological evaluation of a new type of compounds inhibiting PC-PLC(Bc). These compounds have been designed by evolution of previously described 2-aminohydroxamic acid PC-PLC(Bc) inhibitors that block the enzyme by coordination of the zinc active site atoms present in PC-PLC(Bc) [Gonzalez-Roura, A.; Navarro, I.; Delgado, A.; Llebaria, A.; Casas, J. Angew. Chem. Int. Ed.2004, 43, 862]. The new compounds maintain the zinc coordinating groups and possess an extra trimethylammonium function, linked to the hydroxyamide nitrogen by an alkyl chain, which is expected to mimic the trimethylammonium group of the phosphatidylcholine PC-PLC(Bc) substrates. Some of the compounds described inhibit the enzyme with IC(50)'s in the low micromolar range. Unexpectedly, the most potent inhibitors found are those that possess a trimethylammonium group but have chemically blocked the zinc coordinating functionalities. The results obtained suggest that PC-PLC(Bc) inhibition is not due to the interaction of compounds with the phospholipase catalytic zinc atoms, but rather results from the inhibitor cationic group recognition by the PC-PLC(Bc) amino acids involved in choline lipid binding.

  1. Two phenylpyrimidine derivatives as new corrosion inhibitors for cold rolled steel in hydrochloric acid solution

    International Nuclear Information System (INIS)

    Highlights: • 4-PPM and 5-PPM are new good inhibitors for steel in HCl solution. • Inhibition efficiency follows the order: 4-PPM > 5-PPM. • The adsorption of phenylpyrimidine inhibitor obeys Langmuir adsorption isotherm. • There is a correlation between quantum chemical parameters and inhibition action. • 4-PPM and 5-PPM molecules adsorb on Fe (0 0 1) surface in the nearly flat manner. - Abstract: The inhibition effect of two phenylpyrimidine derivatives of 4-phenylpyrimidine (4-PPM) and 5-phenylpyrimidine (5-PPM) on the corrosion of cold rolled steel (CRS) in HCl solution was studied by weight loss, polarization curves, electrochemical impedance spectroscopy (EIS) and scanning electron microscope (SEM) methods. Quantum chemical calculation and molecular dynamics (MD) were applied to theoretically determine the relationship between molecular structure and inhibition efficiency. The results show that two phenylpyrimidine derivatives are good inhibitors, and inhibition efficiency follows the order: 4-PPM > 5-PPM. The adsorption of each inhibitor on steel surface obeys Langmuir adsorption isotherm. Two phenylpyrimidine derivatives act as mixed-type inhibitors

  2. Chemically modified natural polysaccharide as green corrosion inhibitor for mild steel in acidic medium

    International Nuclear Information System (INIS)

    Highlights: ► Polyacrylamide grafted with Okra mucilage is a biodegradable co-polymer. ► It is an effective green corrosion inhibitor for mild steel in 0.5 M H2SO4. ► The inhibition efficiency is both concentration and time dependent. ► It acts as a predominantly cathodic inhibitor. ► Physically adsorbed polymer film on the metal surface restricts the corrosion. - Abstract: A new green polymeric material, polyacrylamide grafted with Okra mucilage, a natural grade polysaccharide, was tested as corrosion inhibitor for mild steel in 0.5 M H2SO4 using gravimetric and electrochemical techniques. The inhibition efficiency was found to increase with increasing inhibitor concentration up to maximum 96.6% for 100 ppm at 25 °C. The effects of immersion time (3–72 h) and temperature (25–65 °C) on the inhibition of corrosion have also been discussed. The adsorption of this inhibitor on the mild steel surface obeys a Langmuir adsorption isotherm. The scanning electron micrographs of the inhibited specimens show smoothening of the surface.

  3. Aminopyrimidine derivatives as inhibitors for corrosion of 1018 carbon steel in nitric acid solution

    Energy Technology Data Exchange (ETDEWEB)

    Abdallah, M. [Chemistry Department, Faculty of Science, Benha University, Benha (Egypt)]. E-mail: metwally552@hotmail.com; Helal, E.A. [Corrosion Department, Badr El-Din Petroleum company (Egypt); Fouda, A.S. [Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516 (Egypt)]. E-mail: asfouda@yahoo.com

    2006-07-15

    The effect of some aminopyrimidine derivatives on the corrosion of 1018 carbon steel in 0.05 M HNO{sub 3} solution was studied using weight loss and polarization techniques. The percentage inhibition efficiency was found to increase with increasing concentration of inhibitor and with decreasing temperature. The addition of KI to aminopyrimidine derivatives enhanced the inhibition efficiency due to synergistic effect. The inhibitors are adsorbed on the steel surface according to Temkin isotherm. Some thermodynamic functions were computed and discussed. It was found that the aminopyrimidine derivatives provide a good protection to steel against pitting corrosion in chloride containing solutions.

  4. Specificity for a CCR5 Inhibitor Is Conferred by a Single Amino Acid Residue: ROLE OF ILE198.

    Science.gov (United States)

    Lau, Gloria; Labrecque, Jean; Metz, Markus; Vaz, Roy; Fricker, Simon P

    2015-04-24

    The chemokine receptors CCR5 and CCR2b share 89% amino acid homology. CCR5 is a co-receptor for HIV and CCR5 antagonists have been investigated as inhibitors of HIV infection. We describe the use of two CCR5 antagonists, Schering-C (SCH-C), which is specific for CCR5, and TAK-779, a dual inhibitor of CCR5 and CCR2b, to probe the CCR5 inhibitor binding site using CCR5/CCR2b chimeric receptors. Compound inhibition in the different chimeras was assessed by inhibition of chemokine-induced calcium flux. SCH-C inhibited RANTES (regulated on activation, normal T cell expressed and secreted) (CCL5)-mediated calcium flux on CCR5 with an IC50 of 22.8 nM but was inactive against monocyte chemoattractant protein-1 (CCL2)-mediated calcium flux on CCR2b. However, SCH-C inhibited CCL2-induced calcium flux against a CCR5/CCR2b chimera consisting of transmembrane domains IV-VI of CCR5 with an IC50 of 55 nM. A sequence comparison of CCR5 and CCR2b identified a divergent amino acid sequence located at the junction of transmembrane domain V and second extracellular loop. Transfer of the CCR5 sequence KNFQTLKIV into CCR2b conferred SCH-C inhibition (IC50 of 122 nM) into the predominantly CCR2b chimera. Furthermore, a single substitution, R206I, conferred partial but significant inhibition (IC50 of 1023 nM) by SCH-C. These results show that a limited amino acid sequence is responsible for SCH-C specificity to CCR5, and we propose a model showing the interaction with CCR5 Ile(198).

  5. Pomegranate (Punica granatum Peel Extract as a Green Corrosion Inhibitor for Mild Steel in Hydrochloric Acid Solution

    Directory of Open Access Journals (Sweden)

    Habib Ashassi-Sorkhabi

    2015-01-01

    Full Text Available The inhibition effect of pomegranate peel extract (PPE on the corrosion of mild steel in hydrochloric acid (HCl solution was investigated. The polarization, mass loss, and electrochemical impendence techniques were used to evaluate the corrosion inhibition performance of the pomegranate peel extract. The results revealed that PPE acts as a corrosion inhibitor in HCl solution. The inhibition efficiency increased with the increase of extract concentration. The inhibition action was attributed to the adsorption of the chemical compounds present in the extract solution, on mild steel surface.

  6. Outcomes in patients with nonerosive reflux disease treated with a proton pump inhibitor and alginic acid ± glycyrrhetinic acid and anthocyanosides

    Science.gov (United States)

    Di Pierro, Francesco; Gatti, Mario; Rapacioli, Giuliana; Ivaldi, Leandro

    2013-01-01

    Background The purpose of this study was to compare the efficacy of alginic acid alone versus alginic acid combined with low doses of pure glycyrrhetinic acid and bilberry anthocyanosides as an addon to conventional proton pump inhibitor therapy in relieving symptoms associated with nonerosive reflux disease. Methods This prospective, randomized, 8-week, open-label trial was conducted at two centers. Sixty-three patients with persistent symptoms of gastroesophageal reflux disease and normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A (n = 31) were treated with pantoprazole and a formula (Mirgeal®) containing alginic acid and low doses of pure glycyrrhetinic acid + standardized Vaccinium myrtillus extract for 4 weeks, then crossed over to the multi-ingredient formula for a further 4 weeks. Patients in group B (n = 32) were treated pantoprazole and alginic acid alone twice daily, then crossed over to alginic acid twice daily for a further 4 weeks. Efficacy was assessed by medical evaluation of a symptom relief score, estimated using a visual analog scale (0–10). Side effects, tolerability, and compliance were also assessed. Results Of the 63 patients enrolled in the study, 58 (29 in group A and 29 in group B) completed the 8-week trial. The baseline characteristics were comparable between the two groups. During the study, significant differences were recorded in symptom scores for both groups. In group A, symptoms of chest pain, heartburn, and abdominal swelling were less serious than in group B. Treatment A was better tolerated, did not induce hypertension, and had fewer side effects than treatment B. No significant differences in compliance were found between the two groups. Conclusion Use of low doses of pure glycyrrhetinic acid + bilberry anthocyanosides, together with alginic acid as addon therapy, substantially improves symptoms in patients with nonerosive reflux disease without increasing side effects or worsening

  7. Pengaruh Obat Anti-Tuberkulosis terhadap Perubahan Enzim Transaminase Hati dalam Dua Bulan Pengobatan Tahun 2015

    OpenAIRE

    Jackson

    2016-01-01

    Since 1995, WHO recommends DOTS strategy to prevent TB in Indonesia. This strategy has high effectivity, but the cure rate is still low because of low compliance for regular treatment which one of the casues is drug side effect. Anti-TB Drug effects are various and one of them is hepatotoxicity which liver transaminase enzymes rise without clinical symptoms is a common episode after Anti-TB drug treatment so that BTS recommends liver function monitoring for two months. Therefore, the purpose ...

  8. Towards a standardized way of reporting physicochemical data and process metrics for transaminase reactions

    DEFF Research Database (Denmark)

    Tufvesson, Pär

    Transaminase catalyzed transformations have the potential of becoming a standard tool for the synthesis of optically pure chiral amines [1]. Many studies show the wide span of substrate acceptance and the excellent enantioselectivity that can be achieved [2]. However, many times critical informat......Transaminase catalyzed transformations have the potential of becoming a standard tool for the synthesis of optically pure chiral amines [1]. Many studies show the wide span of substrate acceptance and the excellent enantioselectivity that can be achieved [2]. However, many times critical...... information about the system and the reaction performance is lacking in the otherwise very useful scientific reports at laboratory scale. For instance, although K equilibrium is one of the key determining factors for the design and scale-up any transaminase process, it is very rarely reported [3]. In order...... to build a broader understanding of the correlation between the underlying physicochemical properties of the system (e.g. substrate volatility) and the process performance (e.g. gram of product per gram of biocatalyst), it would be highly beneficial if these data were reported, and ideally in a consistent...

  9. Cyclopiazonic acid, an inhibitor of calcium-dependent ATPases with antiviral activity against human respiratory syncytial virus.

    Science.gov (United States)

    Cui, Rui; Wang, Yizhuo; Wang, Liu; Li, Guiming; Lan, Ke; Altmeyer, Ralf; Zou, Gang

    2016-08-01

    Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants and young children worldwide, yet no vaccine or effective antiviral treatment is available. To search for new anti-RSV agents, we developed a cell-based assay that measures inhibition of RSV-induced cytopathic effect (CPE) and identified cyclopiazonic acid (CPA), an intracellular calcium ATPase inhibitor as a RSV inhibitor (EC50 values 4.13 μM) by screening of natural product library. CPA inhibited the replication of RSV strains belonging to both A and B subgroups and human parainfluenza virus type 3, but not Enterovirus 71. Mechanism of action study by time-of-addition assay and minigenome assay revealed that CPA acts at the step of virus genome replication and/or transcription. Moreover, two other calcium ATPase inhibitors (Thapsigargin and BHQ) and calcium ionophores (A23187 and ionomycin), but not calcium channel blockers (nifedipine, nimodipine, and tetrandrine), also had similar effect. These results indicate that an increase in intracellular calcium concentration is detrimental to RSV replication. Thus, our findings provide a new strategy for anti-RSV therapy via increasing intracellular calcium concentration. PMID:27210812

  10. The natural diyne-furan fatty acid EV-086 is an inhibitor of fungal delta-9 fatty acid desaturation with efficacy in a model of skin dermatophytosis.

    Science.gov (United States)

    Knechtle, Philipp; Diefenbacher, Melanie; Greve, Katrine B V; Brianza, Federico; Folly, Christophe; Heider, Harald; Lone, Museer A; Long, Lisa; Meyer, Jean-Philippe; Roussel, Patrick; Ghannoum, Mahmoud A; Schneiter, Roger; Sorensen, Alexandra S

    2014-01-01

    Human fungal infections represent a therapeutic challenge. Although effective strategies for treatment are available, resistance is spreading, and many therapies have unacceptable side effects. A clear need for novel antifungal targets and molecules is thus emerging. Here, we present the identification and characterization of the plant-derived diyne-furan fatty acid EV-086 as a novel antifungal compound. EV-086 has potent and broad-spectrum activity in vitro against Candida, Aspergillus, and Trichophyton spp., whereas activities against bacteria and human cell lines are very low. Chemical-genetic profiling of Saccharomyces cerevisiae deletion mutants identified lipid metabolic processes and organelle organization and biogenesis as targets of EV-086. Pathway modeling suggested that EV-086 inhibits delta-9 fatty acid desaturation, an essential process in S. cerevisiae, depending on the delta-9 fatty acid desaturase OLE1. Delta-9 unsaturated fatty acids-but not saturated fatty acids-antagonized the EV-086-mediated growth inhibition, and transcription of the OLE1 gene was strongly upregulated in the presence of EV-086. EV-086 increased the ratio of saturated to unsaturated free fatty acids and phosphatidylethanolamine fatty acyl chains, respectively. Furthermore, EV-086 was rapidly taken up into the lipid fraction of the cell and incorporated into phospholipids. Together, these findings demonstrate that EV-086 is an inhibitor of delta-9 fatty acid desaturation and that the mechanism of inhibition might involve an EV-086-phospholipid. Finally, EV-086 showed efficacy in a guinea pig skin dermatophytosis model of topical Trichophyton infection, which demonstrates that delta-9 fatty acid desaturation is a valid antifungal target, at least for dermatophytoses.

  11. Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors.

    Science.gov (United States)

    De Lucia, Daniela; Lucio, Oscar Méndez; Musio, Biagia; Bender, Andreas; Listing, Monika; Dennhardt, Sophie; Koeberle, Andreas; Garscha, Ulrike; Rizzo, Roberta; Manfredini, Stefano; Werz, Oliver; Ley, Steven V

    2015-08-28

    In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization.

  12. Design, synthesis and evaluation of semi-synthetic triazole-containing caffeic acid analogues as 5-lipoxygenase inhibitors.

    Science.gov (United States)

    De Lucia, Daniela; Lucio, Oscar Méndez; Musio, Biagia; Bender, Andreas; Listing, Monika; Dennhardt, Sophie; Koeberle, Andreas; Garscha, Ulrike; Rizzo, Roberta; Manfredini, Stefano; Werz, Oliver; Ley, Steven V

    2015-08-28

    In this work the synthesis, structure-activity relationship (SAR) and biological evaluation of a novel series of triazole-containing 5-lipoxygenase (5-LO) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent 5-LO inhibition with IC50 of 0.2 and 3.2 μm in cell-based and cell-free assays, respectively. Optimization of binding and functional potencies resulted in the identification of compound 13d, which showed an enhanced activity compared to the parent bioactive compound caffeic acid 5 and the clinically approved zileuton 3. Compounds 15 and 16 were identified as lead compounds in inhibiting 5-LO products formation in neutrophils. Their interference with other targets on the arachidonic acid pathway was also assessed. Cytotoxicity tests were performed to exclude a relationship between cytotoxicity and the increased activity observed after structure optimization. PMID:26197161

  13. Polymerized liposomes containing C-glycosides of sialic acid: Potent inhibitors of influenza virus in vitro infectivity

    Energy Technology Data Exchange (ETDEWEB)

    Spevak, W.; Bednarski, M.D.; Nagy, J.O.; Charych, D.H (Lawrence Berkeley Lab., CA (United States)); Schaefer, M.E.; Gilbert, J.H. (Glycomed, Inc., Alameda, CA (United States))

    1993-02-10

    The surface lectin of the influenza virus, hemagglutinin, binds to terminal [alpha]-glycosides of N-acetylneuraminic acid (NeuAc) on cell-surface glycoproteins and glycolipids. Viral binding to cells expression terminal NeuAc residues can be inhibited by [alpha]-O-glycosides of NeuAc (O-sialosides). Recently, dramatic enhancements in the inhibition of viral adhesion to erythrocytes have been achieved using synthetic polyvalent sialosides. In this communication, the authors report that polymerized liposomes containing [alpha]-C-glycosides of sialic acid are potent inhibitors of influenza virus in vitro infectivity. Their results also indicate that the capacity to inhibit hemagglutination does not necessarily reflect the capacity to inhibit in vitro infectivity. 14 refs., 1 tab.

  14. Design, synthesis and SAR studies of GABA uptake inhibitors derived from 2-substituted pyrrolidine-2-yl-acetic acids.

    Science.gov (United States)

    Steffan, Tobias; Renukappa-Gutke, Thejavathi; Höfner, Georg; Wanner, Klaus T

    2015-03-15

    In this paper, we disclose the design and synthesis of a series of 2-substituted pyrrolidine-2-yl-acetic acid as core structures and the N-arylalkyl derivatives thereof as potential GABA transport inhibitors. The 2-position in the side chain of pyrrolidine-2-yl-acetic acid derivatives was substituted with alkyl, hydroxy and amino groups to modulate the activity and selectivity to mGAT1 and mGAT4 proteins. SAR studies of the compounds performed for the four mouse GABA transporter proteins (mGAT1-mGAT4) implied significant potencies and subtype selectivities for 2-hydroxy-2-pyrrolidine-2-yl-acetic acid derivatives. The racemate rac-(u)-13c exhibited the highest potency (pIC50 5.67) at and selectivity for mGAT1 in GABA uptake assays. In fact, the potency of rac-(u)-13c at hGAT-1 (pIC50 6.14) was even higher than its potency at mGAT1. These uptake results for rac-(u)-13c are in line with the binding affinities to the aforesaid proteins mGAT1 (pKi 6.99) and hGAT-1 (pKi 7.18) determined by MS Binding Assay based on NO711 as marker quantified by LC-ESI-MS-MS analysis. Interestingly, the 2-hydroxy-2-pyrrolidine-2-yl-acetic acid rac-(u)-13d containing 2-{[tris(4-methoxyphenyl)]methoxy} ethyl group at the nitrogen atom of the pyrrolidine ring showed high potency at mGAT4 and a comparatively better selectivity for this protein (>15 against mGAT3) than the well known mGAT4 uptake inhibitor (S)-SNAP-5114.

  15. N-alkylated aminoacyl sulfamoyladenosines as potential inhibitors of aminoacylation reactions and microcin C analogues containing D-amino acids.

    Directory of Open Access Journals (Sweden)

    Gaston H Vondenhoff

    Full Text Available Microcin C analogues were recently envisaged as important compounds for the development of novel antibiotics. Two issues that may pose problems to these potential antibiotics are possible acquisition of resistance through acetylation and in vivo instability of the peptide chain. N-methylated aminoacyl sulfamoyladenosines were synthesized to investigate their potential as aminoacyl tRNA synthetase inhibitors and to establish whether these N-alkylated analogues would escape the natural inactivation mechanism via acetylation of the alpha amine. It was shown however, that these compounds are not able to effectively inhibit their respective aminoacyl tRNA synthetase. In addition, we showed that (D-aspartyl-sulfamoyladenosine (i.e. with a (D-configuration for the aspartyl moiety, is a potent inhibitor of aspartyl tRNA synthetase. However, we also showed that the inhibitory effect of (D- aspartyl-sulfamoyladenosine is relatively short-lasting. Microcin C analogues with (D-amino acids throughout from positions two to six proved inactive. They were shown to be resistant against metabolism by the different peptidases and therefore not able to release the active moiety. This observation could not be reversed by incorporation of (L-amino acids at position six, showing that none of the available peptidases exhibit endopeptidase activity.

  16. Complexes of Imidazole with Poly(ethylene glycol) as a Corrosion Inhibitor for Carbon Steel in Sulphuric Acid

    Science.gov (United States)

    Salimi, Saeed; Nasr-Esfahani, Mojtaba; Umoren, Saviour A.; Saebnoori, Ehsan

    2015-12-01

    The inhibiting action of polyethylene glycol and imidazole (PEG/IMZ)) complexes prepared by a simple deprotonation procedure on carbon steel corrosion in 0.5 mol/L sulphuric acid was evaluated using the weight loss, potentiodynamic polarization, and electrochemical impedance spectroscopy techniques complemented by surface analysis using scanning electron microscopy. The inhibiting effect of the PEG/IMZ complexes on carbon steel corrosion was compared with the non-complex forms. Results obtained show that PEG/IMZ complex is a very effective corrosion inhibitor of carbon steel in the acid environment. The inhibition efficiency increased with the increase in the temperature and also with increasing percentage of imidazole in the complex. Corrosion inhibition occurs by virtue of adsorption of PEG/IMZ complexes on the steel surface which was found to follow the Temkin adsorption isotherm model. The PEG/IMZ complexes function as a mixed-type inhibitor. Results from all the methods employed are in a reasonably good agreement.

  17. Expression in Pichia pastoris and characterization of APETx2, a specific inhibitor of acid sensing ion channel 3.

    Science.gov (United States)

    Anangi, Raveendra; Chen, Chih-Cheng; Lin, Yi-Wen; Cheng, Yuan-Ren; Cheng, Chun-Ho; Chen, Yi-Chun; Chu, Yuan-Ping; Chuang, Woei-Jer

    2010-12-01

    Acid sensing ion channels (ASICs) are family of proteins predominantly present in the central and peripheral nervous system. They are known to play important roles in the pathophysiology of pain and ischemic stroke. APETx2 is a potent and selective inhibitor of ASIC3-containing channels and was isolated from sea anemone Anthopleura elegantissima. To facilitate the study on the molecular determinants of ASIC3-ligand interactions, we expressed recombinant APETx2 in the Pichia pastoris (P. pastoris) expression system and purified it to homogeneity. Recombinant APETx2 produced in P. pastoris inhibited the acid-evoked ASIC3 current with the IC(50) value of 37.3 nM. The potency of recombinant toxin is similar to that of native APETx2. The sequential assignment and structure analysis of APETx2 were obtained by 2D and 3D (15)N-edited NMR spectra. Our NMR data suggests that APETx2 produced in P. pastoris retained its native fold. The results presented here provide the first direct evidence that highly disulfide bonded peptide inhibitor of ASIC3, APETx2, can be expressed in P. pastoris with correct fold and high yield. We also showed that the R17A mutant exhibited a decrease in activity, suggesting the feasibility of the use of this expression system to study the interactions between APETx2 and ASIC3. These evidences may serve as the basis for understanding the selectivity and activity of APETx2. PMID:20813121

  18. Organic compounds as corrosion inhibitors for mild steel in acidic media: correlation between inhibition efficiency and chemical structure

    Energy Technology Data Exchange (ETDEWEB)

    Elias, Elizandra C.S.; Chrisman, Erika C.A.N. [Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ (Brazil). Escola de Quimica

    2009-12-19

    The use of inhibitors for mild steels corrosion control which are in contact with aggressive environment is an accepted practice in acid treatment of oil-wells. Organic compounds have been studied to evaluate their corrosion inhibition potential. Film-forming corrosion inhibitors, commonly used to protect oil-field equipment, can be absorbed on the steel surface to give structurally ordered layers. Therefore, the electrons should act as an important role for this adsorption. Studies reveal that organic compounds show significant inhibition efficiency. For this purpose, their molecules should contain N, O and S heteroatoms in various functional groups, long hydrocarbon linear or branched radical and anion and cation active components. However, most of these compounds are not only expensive but also toxic to living beings. According to the 'Green Chemistry' rules, corrosion inhibitors based on organic compounds should be cheap, with low toxicity and have high inhibition efficiency. In this study, the effects of some organic compounds with different groups such as amide, ether, phenyldiamine, anime and aminophenol on the corrosion behavior of mild steel in acidic media have been investigated. The experimental data were obtained by gravimetric measurements. The results show that these compounds reveal a promising corrosion inhibition where phenyldiamine is the most efficient. The effect of molecular structure on the corrosion inhibition efficiency was investigated by semi-empirical quantum chemical calculations. The electronic properties such as highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO) energy levels, and LUMO-HOMO energy gap orbital density were calculated. The relations between the inhibition efficiency and some quantum parameters are discussed and correlations are proposed. The highest values for the HOMO densities were found in the vicinity nitrogen atom, indicating that it is the most probable adsorption center

  19. Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors.

    Science.gov (United States)

    Taddei, Maurizio; Cini, Elena; Giannotti, Luca; Giannini, Giuseppe; Battistuzzi, Gianfranco; Vignola, Davide; Vesci, Loredana; Cabri, Walter

    2014-01-01

    A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50=0.5μM against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far. PMID:24345446

  20. Electrochemical Study on Newly Synthesized Chlorocurcumin as an Inhibitor for Mild Steel Corrosion in Hydrochloric Acid

    Directory of Open Access Journals (Sweden)

    Ahmed A. Al-Amiery

    2013-11-01

    Full Text Available A new curcumin derivative, i.e., (1E,4Z,6E-5-chloro-1,7-bis(4-hydroxy-3-methoxyphenylhepta-1,4,6-trien-3-one (chlorocurcumin, was prepared starting with the natural compound curcumin. The newly synthesized compound was characterized by elemental analysis and spectral studies (IR, 1H-NMR and 13C-NMR. The corrosion inhibition of mild steel in 1 M HCl by chlorocurcumin has been studied using potentiodynamic polarization (PDP measurements and electrochemical impedance spectroscopy (EIS. The inhibition efficiency increases with the concentration of the inhibitor but decreases with increases in temperature. The potentiodynamic polarization reveals that chlorocurcumin is a mixed-type inhibitor. The kinetic parameters for mild steel corrosion were determined and discussed.

  1. N-methyl-2-(2-nitrobenzylidene) hydrazine carbothioamide-A new corrosion inhibitor for mild steel in 1 mol·L-1 hydrochloric acid

    Institute of Scientific and Technical Information of China (English)

    K Krishnaveni; K Sampath; J Ravichandran; C Jayabalakrishnan

    2015-01-01

    The corrosion inhibition of mild steel in 1 mol·L−1 hydrochloric acid by N-methyl-2-(2-nitrobenzylidene) hydrazine carbothioamide (MNBHC) was studied using weight loss and electrochemical studies. Results obtained indicate that the inhibitor is effective in hydrochloric acid medium and the efficiency decreases with increase in temperature. Added halide additives improve the efficiency of the inhibitor. The AC impedance studies reveal that the process of inhibition is through charge transfer. Polarization studies indicate the mixed nature of the in-hibitor. From the thermodynamic, spectral and surface analyses the nature of adsorption has been found out. The adsorption of the inhibitor on mild steel follows the Langmuir isotherm.

  2. Effect of inducers and inhibitors of glucuronidation on the biliary excretion and choleretic action of valproic acid in the rat.

    Science.gov (United States)

    Watkins, J B; Klaassen, C D

    1982-02-01

    Valproic acid (VPA) induces an immediate choleresis in the rat which may be attributable to the osmotic properties of VPA-glucuronic acid conjugates in bile. The influence of inducers and inhibitors of glucuronidation of VPA on the biliary excretion and choleretic effect of VPA was studied. Hepatic UDP-glucuronyltransferase activity toward VPA was determined in vitro. Pretreatment with phenobarbital (75 mg/kg/day for 4 days) enhanced VPA glucuronidation; borneol (750 mg/kg) decreased VPA conjugation; 3-methylcholanthrene (20 mg/kg/day for 4 days) and galactosamine (600 mg/kg) had no effect on glucuronidation of VPA in vitro. Hepatic UDP-glucuronic acid content was decreased by borneol and galactosamine administration and was enhanced by phenobarbital and 3-methylcholanthrene pretreatment. The enzyme inducers increased the plasma disappearance of VPA in vivo but did not augment its biliary excretion or choleretic effect. Borneol and galactosamine, which inhibited the conjugation and plasma disappearance of VPA, decreased its biliary excretion and inhibited the VPA-induced increase in bile flow. Thus, the bile flow rate after VPA administration is closely related to the excretion of VPA-glucuronic acid. These data support the conclusion that the choleretic effect of VPA is due to the osmotic activity of VPA conjugates in bile.

  3. Identification of Na+/K+-ATPase inhibitors in bovine plasma as fatty acids and hydrocarbons

    DEFF Research Database (Denmark)

    Tal, D M; Yanuck, M D; Van Hall, Gerrit;

    1989-01-01

    ouabain, and in addition it enhanced ouabain binding at high dilutions. These properties are indicative of nonspecific interactions with the Na+/K+-ATPase. The active fraction was identified by TLC, HPLC, NMR, GLC and GC-MS, to be a mixture of three unesterified fatty acids, mainly oleic acid (72...

  4. Analysis of docosahexaenoic acid biosynthesis in Crypthecodinium cohnii by 13C labelling and desaturase inhibitor experiments

    NARCIS (Netherlands)

    Swaaf, de M.E.; Rijk, de T.C.; Meer, van der P.; Eggink, G.; Sijtsma, L.

    2003-01-01

    The lipids of the heterotrophic microalga Crypthecodinium cohnii contain the omega-3 polyunsaturated fatty acid (PUFA) and docosahexaenoic acid (22:6) to a level of over 30&Eth;The pathway of 22:6 synthesis in C. cohnii is unknown. The ability of C. cohnii to use 13C-labelled externally supplied

  5. Glycyrrhetinic acid and its derivatives as inhibitors of poly(ADP-ribosepolymerases 1 and 2, apurinic/apyrimidinic endonuclease 1 and DNA polymerase β

    Directory of Open Access Journals (Sweden)

    Salakhutdinov N. F.

    2012-06-01

    Full Text Available Aim. For strengthening the efficiency of monofunctional alkylating antineoplastic drugs it is important to lower the capacity of base excision repair (BER system which corrects the majority of DNA damages caused by these reagents. The objective was to create inhibitors of the key BER enzymes (PARP1, PARP2, DNA polymerase β, and APE1 by the directed modification of glycyrrhetinic acid (GA. Methods. Amides of GA were produced from the GA acetate by formation of the corresponding acyl chloride, amidation with the appropriate amine and subsequent deacylation. Small library of 2-cyano substituted derivatives of GA methyl esters was obtained by the structural modification of GA framework and carboxylic acid group. The inhibitory capacity of the compounds was estimated by comparison of the enzyme activities in specific tests in the presence of compounds versus their absence. Results. None of tested compounds inhibits PARP1 significantly. Unmodified GA and its morpholinic derivative were shown to be weak inhibitors of PARP2. The derivatives of GA containing keto-group in 11 triterpene framework were shown to be moderate inhibitors of pol β. Compound 3, containing 12-oxo-9(11-en moiety in the ring C, was shown to be a single inhibitor of APE1 among all compounds studied. Conclusions. The class of GA derivatives, selective pol β inhibitors, was found out. The selective inhibitor of APE1 and weak selective inhibitor of PARP2 were also revealed.

  6. Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells.

    Directory of Open Access Journals (Sweden)

    Jaspreet Singh

    Full Text Available In X-ALD, mutation/deletion of ALD gene (ABCD1 and the resultant very long chain fatty acid (VLCFA derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD. The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs (1 and 3 in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL and cell survival (phospho-Erk1/2 proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC inhibitor suberoylanilide hydroxamic acid (SAHA corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.

  7. Ionic derivatives of betulinic acid as novel HIV-1 protease inhibitors.

    Science.gov (United States)

    Zhao, Hua; Holmes, Shaletha S; Baker, Gary A; Challa, Suresh; Bose, Himangshu S; Song, Zhiyan

    2012-10-01

    Betulinic acid is a natural product possessing abundant and favourable biological activity, including anti-cancer, anti-malarial, anti-inflammatory and anti-HIV properties, while causing minimal toxicity to unaffected cells. The full biological potency of betulinic acid cannot be fully unlocked, however, for a number of reasons, a primary one being its limited solubility in aqueous and biologically pertinent organic media. Aiming to improve the water solubility of betulinic acid without disrupting its structurally related bioactivity, we have prepared different ionic derivatives of betulinic acid. Inhibition bioassays on HIV-1 protease-catalysed peptide hydrolysis indicate significantly improved performance resulting from converting the betulinic acid to organic salt form. Indeed, for one particular cholinium-based derivative, its water solubility is improved more than 100 times and the half maximal inhibitory concentration (IC(50)) value (22 μg mL(-1)) was one-third that of wide-type betulinic acid (60 μg mL(-1)). These encouraging results advise that additional studies of ionic betulinic acid derivatives as a therapeutic solution against HIV-1 infection are warranted.

  8. Punica granatum leave extract as green corrosion inhibitor for mild steel in Hydrochloric acid

    OpenAIRE

    Abboud Y.; Chagraoui A.; Tanane O.; El Bouari A.; Hannache H.

    2013-01-01

    Leave of Punica granatum extract (LPGE) as green inhibitor for the corrosion of mild steel in 1M HCl solution was studied using weight-loss and potentiodynamic polarization measurements. The results obtained revealed that LPGE has fairly good inhibiting properties for mild steel corrosion in 1M HCl solution, with efficiency of around 94 % at a concentration of 1 g/l. The inhibition was of a mixed anodic–cathodic nature. The film which is formed over the metal surface was analysed by FT-IR spe...

  9. New benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents

    DEFF Research Database (Denmark)

    Thanh Tung, Truong; Oanh, Dao Thi Kim; Dung, Phan Thi Phuong;

    2013-01-01

    Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza(®) (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing...... research to find novel small molecules to target these important enzymes, we synthesized a series of benzothiazole-containing analogues of SAHA and found several compounds with very potent anticancer cytotoxicity. In this study, three more compounds of this type, including N(1)-(6-chlorobenzo[d]thiazol-2...

  10. Inhibitor of fatty acid synthase induced apoptosis in human colonic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Pei Lin Huang; Zhen Sheng Dai; Yue Lin Jin; Shi Neng Zhu; Shi Lun Lu

    2000-01-01

    @@INTRODUCTION The treatment of human epithelial malignancies is limited by drug resistance and toxic and side effects,which results in the failure in the treatment of majority of advanced cancer victims. To seek for a new, and specific antineoplastic therapy will provide hope for tumor treatment. Although disordered intermediary metabolism in cancer cells has been known for many years, much of the work focused on abnormal glucose catabolism. At the same time, little attention has been paid to fatty acid synthasis in tumor tissues, dispite of the significance of fatty acid synthase (FAS) in some clinical human ovarian[1], breast[2], colorectal[3],and prostatic cancers[4,5]. Tumor cells which express high levels of fatty acid synthesizing enzymes use endogeneously synthesized fatty acids for membrance biosynthesis and appear to export large amounts of lipid. In contrast, normal cells preferentially utilize diary lipid.

  11. Prescribing pattern of proton pump inhibitors in the management of acid peptic disorders, focus on ilaprazole

    Directory of Open Access Journals (Sweden)

    Mayur M. Mayabhate

    2016-06-01

    Conclusions: This survey highlights the lack of 24 hour acid control in APDs with use of conventional PPIs leading to variety of symptoms, especially at night, seriously hampering the sleep quality. Ilaprazole displays important advantages in the clinical settings, with regard to better probability of extending the inhibition of acid secretion over 24 hours as compared to conventional PPIs. [Int J Basic Clin Pharmacol 2016; 5(3.000: 1104-1107

  12. Liarozole, an Inhibitor of Retinoic Acid Metabolism, Retarded Atherogenesis in LDLR-/- Mice

    OpenAIRE

    Zolberg Relevy, Noa; Harari, Ayelet; Kamari, Yehuda; Harats, Dror; Shaish, Aviv

    2015-01-01

    Liarozole is a Retinoic Acid Metabolism Blocking Agent (RAMBA). As retinoic acid (RA) and its precursor, beta-carotene (BC), have been shown to inhibit atherosclerosis development in mouse models, in the present study we investigated whether liarozole can mimic the anti-atherogenic effect of RA. We demonstrate, by using the LDL receptor-knockout mouse model fed a high-fat diet, that liarozole significantly reduces by 50% the aortic sinus atherosclerotic lesion area.    

  13. High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zhi-wei; Vignaud, Caroline; Jaafar, Adil; Lévy, Bernard; Guéritte, Françoise; Guénard, Daniel; Lederer, Florence; Mathews, F. Scott (CNRS-UMR); (WU-MED)

    2012-05-24

    Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value. These enzymes are the only human members of the family of FMN-dependent L-2-hydroxy acid-oxidizing enzymes, with yeast flavocytochrome b{sub 2} (Fcb2) among its well studied members. We screened a chemical library for inhibitors, using in parallel rat LCHAO, human GOX and the Fcb2 flavodehydrogenase domain (FDH). Among the hits was an inhibitor, CCPST, with an IC{sub 50} in the micromolar range for all three enzymes. We report here the crystal structure of a complex between this compound and LCHAO at 1.3 {angstrom} resolution. In comparison with a lower resolution structure of this enzyme, binding of the inhibitor induces a conformational change in part of the TIM barrel loop 4, as well as protonation of the active site histidine. The CCPST interactions are compared with those it forms with human GOX and those formed by two other inhibitors with human GOX and spinach GOX. These compounds differ from CCPST in having the sulfur replaced with a nitrogen in the five-membered ring as well as different hydrophobic substituents. The possible reason for the {approx}100-fold difference in affinity between these two series of inhibitors is discussed. The present results indicate that specificity is an issue in the quest for therapeutic inhibitors of either LCHAO or GOX, but they may give leads for this quest.

  14. Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid

    Institute of Scientific and Technical Information of China (English)

    Yan-Ting Jian; Guo-Feng Mai; Ji-De Wang; Ya-Li Zhang; Rong-Cheng Luo; Yong-Xin Fang

    2005-01-01

    AIM: To ascertain the molecule mechanism of nuclear factor-κB (NF-κB) inhibitor curcumin preventive and therapeutic effects in rats' colitis induced by trinitrobenzene sulfonic acid (TNBS).METHODS: Sixty rats with TNBS-induced colitis weretreated with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine (SASP).Thirty negative control rats and thirty model rats were treated with general diet. Changes of body weight together with histological scores were evaluated. Survival rates were also evaluated. Cell nuclear NF-κB activity in colonic mucosa was evaluated by using electrophoretic mobility shift assay. Cytoplasmic IκB protein in colonic mucosa was detected by using Western Blot analysis.Cytokine messenger expression in colonic tissue was assessed by using semiquantitative reverse-transcription polymerase chain reaction.RESULTS: Treatment with curcumin could prevent and treat both wasting and histopathologic signs of rats with TNBS-induced intestinal inflammation. In accordance with these findings, NF-κB activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of cytoplasmic IκB protein in colonic mucosa were blocked by curcumin treatment. Proinfiammatory cytokine messenger RNA expression in colonic mucosa was also suppressed.CONCLUSION: This study shows that NF-κB inhibitor curcumin could prevent and improve experimental colitis in murine model with inflammatory bowel disease (IBD).The findings suggest that NF-κB inhibitor curcumin could be a potential target for the patients with IBD.

  15. Investigations and design of pyridine-2-carboxylic acid thiazol-2-ylamide analogs as methionine aminopeptidase inhibitors using 3D-QSAR and molecular docking

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian

    2014-01-01

    -dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of pyridine-2-carboxylic acid thiazol-2-ylamide-based MetAP inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The models were...... complexes, four new pyridine-2-carboxylic acid thiazol-2-ylamide analogs were designed. These analogs exhibit significantly better predicted activity than the reported molecules. The present work has implications for the development of novel antibiotics as potent MetAP inhibitors....

  16. Aryl-acetic and cinnamic acids as lipoxygenase inhibitors with antioxidant, anti-inflammatory, and anticancer activity.

    Science.gov (United States)

    Hadjipavlou-Litina, Dimitra; Pontiki, Eleni

    2015-01-01

    Cinnamic acids have been identified as interesting compounds with cytotoxic, anti-inflammatory, and antioxidant properties. Lipoxygenase pathway, catalyzing the first two steps of the transformation of arachidonic acid into leukotrienes is implicated in several processes such as cell differentiation, inflammation and carcinogenesis. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer, and blood vessel disorders. Till now, asthma consists of the only pathological case in which improvement has been shown by lipoxygenase LO inhibitors. Thus, the research has been directed towards the development of drugs that interfere with the formation of leukotrienes. In order to explore the anti-inflammatory and cytotoxic effects of antioxidant acrylic/cinnamic acids a series of derivatives bearing the appropriate moieties have been synthesized via the Knoevenagel condensation and evaluated for their biological activities. The compounds have shown important antioxidant activity, anti-inflammatory activity and very good inhibition of soybean lipoxygenase while some of them were tested for their anticancer activity.

  17. 2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity.

    Directory of Open Access Journals (Sweden)

    Lei Wang

    Full Text Available We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-ylpiperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d were active HDAC inhibitors, the meta substituted analogues (8a-d were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1-1.0 μM over HDAC1 (IC50 = 0.9-6 μM and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity.

  18. 2-Benzazolyl-4-Piperazin-1-Ylsulfonylbenzenecarbohydroxamic Acids as Novel Selective Histone Deacetylase-6 Inhibitors with Antiproliferative Activity

    Science.gov (United States)

    Wang, Lei; Kofler, Marina; Brosch, Gerald; Melesina, Jelena; Sippl, Wolfgang; Martinez, Elisabeth D.; Easmon, Johnny

    2015-01-01

    We have screened our compound collection in an established cell based assay that measures the derepression of an epigenetically silenced transgene, the locus derepression assay. The screen led to the identification of 4-[4-(1-methylbenzimidazol-2-yl)piperazin-1-yl]sulfonylbenzenecarbohydroxamic acid (9b) as an active which was found to inhibit HDAC1. In initial structure activity relationships study, the 1-methylbenzimidazole ring was replaced by the isosteric heterocycles benzimidazole, benzoxazole, and benzothiazole and the position of the hydroxamic acid substituent on the phenyl ring was varied. Whereas compounds bearing a para substituted hydroxamic acid (9a-d) were active HDAC inhibitors, the meta substituted analogues (8a-d) were appreciably inactive. Compounds 9a-d selectively inhibited HDAC6 (IC50 = 0.1–1.0μM) over HDAC1 (IC50 = 0.9–6μM) and moreover, also selectively inhibited the growth of lung cancer cells vs. patient matched normal cells. The compounds induce a cell cycle arrest in the S-phase while induction of apoptosis is neglible as compared to controls. Molecular modeling studies uncovered that the MM-GBSA energy for interaction of 9a-d with HDAC6 was higher than for HDAC1 providing structural rationale for the HDAC6 selectivity. PMID:26698121

  19. Immobilization of Escherichia coli containing ω‐transaminase activity in LentiKats®

    DEFF Research Database (Denmark)

    Cárdenas‐Fernández, Max; Lima Afonso Neto, Watson; López, Carmen;

    2012-01-01

    Whole Escherichia coli cells overexpressing ω‐transaminase (ω‐TA) and immobilized cells entrapped in LentiKats® were used as biocatalysts in the asymmetric synthesis of the aromatic chiral amines 1‐phenylethylamine (PEA) and 3‐amino‐1‐phenylbutane (APB). Whole cells were permeabilized...... whole cell biocatalysis, the reaction with IPA was one order of magnitude faster than with Ala. No reaction was detected when permeabilized E. coli cells containing ω‐TA were employed using Ala as the amino donor. Additionally, the synthesis of APB from 4‐phenyl‐2‐butanone and IPA was studied. Whole...

  20. A Rapid Selection Procedure for Simple Commercial Implementation of omega-Transaminase Reactions

    DEFF Research Database (Denmark)

    Gundersen Deslauriers, Maria; Tufvesson, Pär; Rackham, Emma J.;

    2016-01-01

    equipment. The procedure may be used when investment in intensive process development cannot be justified or when rapid execution is paramount, for applications such as small singular batches. The three step evaluation procedure consists of: (1) thermodynamic assessment, (2) biocatalyst activity screening......A stepwise selection procedure is presented to quickly evaluate whether a given omega-transaminase reaction is suitable for a so-called "simple" scale-up for fast industrial implementation. Here "simple" is defined as a system without the need for extensive process development or specialized...

  1. Studies on the Corrosion Inhibitor of Zinc in Hydrolfuoric Acid Solution%氢氟酸介质中锌缓蚀剂的研制

    Institute of Scientific and Technical Information of China (English)

    林冬; 焦庆祝; 赵斌; 贺淼; 张涵; 赵丽; 张爽; 王佳

    2015-01-01

    本文采用正交实验方法对有机盐类、无机盐类和季铵盐类化合物进行复配得到一种氢氟酸介质中金属锌的优良缓蚀剂。利用失重法和电化学极化曲线法对该缓蚀剂进行了评价,并研究了金属腐蚀速率随缓蚀剂浓度,酸度,温度,时间等变化趋势。实验结果表明,该复合缓蚀剂用量在0.5%,温度小于50℃,酸度小于7%时具有良好的缓蚀效果,该缓蚀剂为阴极型缓蚀剂。%A composite corrosion inhibitor of zinc in hydrofluoric acid solution was developed by orthogonal test with the compound of organic salt, inorganic salt and quaternary ammonium salt. The corrosion inhibitor was evaluated by weight-loss method and electrochemical method. The change of zinc corrosion rate with concentration of corrosion inhibitor, hydrofluoric acid acidity, temperature and reaction time was investigated. It was shown by the results that the corrosion inhibitor has an excellent corrosion inhibition when the quantity of the corrosion inhibitor is more than 0.5%, the temperature is below 50℃and the concentration of hydrofluoric acid is under 7%. The composite corrosion inhibitor is a kind of electrochemical cathode type inhibitor.

  2. Populus nigra (Salicaceae) absolute rich in phenolic acids, phenylpropanoïds and flavonoids as a new potent tyrosinase inhibitor.

    Science.gov (United States)

    Maack, A; Pegard, A

    2016-06-01

    The purpose of this study was to evaluate the tyrosinase inhibitory capacity of Populus nigra buds absolute (PBA) and compare it to kojic acid (KA), controversial reference tyrosinase inhibitor. Populus nigra buds were extracted with hexane and ethanol to obtain PBA. The inhibitory effect of this absolute was first tested on the mushroom Agaricus bisporus tyrosinase. Then the depigmenting potential of PBA was tested on B16F10 murine melanocytes by assaying the activity of tyrosinase and melanin content. Consecutively, a microscopic analysis of intracellular melanin granules was performed. Finally, melanised reconstructed human epidermis (RHE) were used to assess the lightening potential activity of this PBA on human skin. Results show that PBA inhibits A. bisporus tyrosinase (IC50=77±8ppm) and inhibits melanocytes B16F10 tyrosinase (IC50=27±1ppm). PBA decreases intracellular melanin levels, with 50% loss at 39±9ppm. Finally, PBA at 1000ppm lightens RHE and decreases their melanin content of 20%. PBA is a strong inhibitor of tyrosinase and reduces melanogenesis in melanocytes B16F10. Thus, PBA has potential applications in skin-lightening cosmetics. PMID:27091790

  3. Lysophosphatidylcholines containing polyunsaturated fatty acids were found as Na+,K+-ATPase inhibitors in acutely volume-expanded hog

    International Nuclear Information System (INIS)

    Na+,K+-ATPase inhibitors activities against the specific binding of ouabain to Na+,K+-ATPase and 86Rb uptake into hog erythrocytes have been purified from the plasma of acutely saline-infused hog. The purifications were performed by a combination of Amberlite XAD-2 adsorption chromatography and four steps of high-performance liquid chromatography with four different types of columns. Fast atom bombardment (FAB) mass and proton NMR spectrometric studies identified the purified substances as γ-arachidoyl- [LPCA(γ), 34%], β-arachidoyl- [LPCA(β), 4%], γ-linoleoyl- (LPCL, 33%), and γ-oleoyl- (LPCO, 25%) lysophosphatidylcholine, expressed in molar ratio in the plasma. Small amounts of γ-docosapentaenoyl-, γ-eicosatrienoyl-, and γpalmitoyllysophosphatidylcholine were also detected by both FAB mass and 1H NMR spectrometric studies. The inhibition of Na+,K+-ATPase activity due to these compounds was always more sensitive than that of both ouabain-binding and 86Rb uptake activities. The ouabain-displacing activity in plasma due to these compounds increased with time during saline infusion. The maximal plasma level was approximately 10 times higher than that in the preinfusion plasma sample. Although these results suggest that γ-acyl-LPC's with long-chain polyunsaturated fatty acids are not simple competitive inhibitors to Na+,K+-ATPase, these compounds could be implicated in the pathogenesis of the circulation abnormality through the modulation of membrane enzyme

  4. sym-Trisubstituted 1,3,5-Triazine Derivatives as Promising Organic Corrosion Inhibitors for Steel in Acidic Solution.

    Science.gov (United States)

    El-Faham, Ayman; Dahlous, Kholood A; Al Othman, Zeid A; Al-Lohedan, Hamad A; El-Mahdy, Gamal A

    2016-03-31

    Triazine derivatives, namely, 2,4,6-tris(quinolin-8-yloxy)-1,3,5-triazine (T3Q), N²,N⁴,N⁶-tris(pyridin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine (T3AMPy) and 2,2',2''-[(1,3,5-triazine-2,4,6-triyl)tris(azanediyl)] tris(ethan-1-ol) (T3EA) were synthesized and their inhibition of steel corrosion in hydrochloric acid solution was investigated using electrochemical techniques. The corrosion protection of the prepared compounds increased with increasing concentration and reached up to 98% at 250 ppm. The adsorption of T3Q, T3AMPy, and T3EA on the steel surface was in accordance with the Langmuir adsorption isotherm. The electrochemical results revealed that T3Q, T3AMPy and T3EA act as excellent organic inhibitors and can labeled as mixed type inhibitors. The efficiencies of the tested compounds were affected by the nature of the side chain present in the triazine ring, where T3EA gave the least inhibition while T3Q and T3AMPy gave higher and almost the same inhibition effects. The inhibition efficiencies obtained from the different electrochemical techniques were in good agreement.

  5. Tetrabromocinnamic acid (TBCA) and related compounds represent a new class of specific protein kinase CK2 inhibitors.

    Science.gov (United States)

    Pagano, Mario A; Poletto, Giorgia; Di Maira, Giovanni; Cozza, Giorgio; Ruzzene, Maria; Sarno, Stefania; Bain, Jenny; Elliott, Matthew; Moro, Stefano; Zagotto, Giuseppe; Meggio, Flavio; Pinna, Lorenzo A

    2007-01-01

    Abnormally high constitutive activity of protein kinase CK2, levels of which are elevated in a variety of tumours, is suspected to underlie its pathogenic potential. The most widely employed CK2 inhibitor is 4,5,6,7-tetrabromobenzotriazole (TBB), which exhibits a comparable efficacy toward another kinase, DYRK1 a. Here we describe the development of a new class of CK2 inhibitors, conceptually derived from TBB, which have lost their potency toward DYRK1 a. In particular, tetrabromocinnamic acid (TBCA) inhibits CK2 five times more efficiently than TBB (IC50 values 0.11 and 0.56 microM, respectively), without having any comparable effect on DYRK1 a (IC50 24.5 microM) or on a panel of 28 protein kinases. The usefulness of TBCA for cellular studies has been validated by showing that it reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis. Collectively taken, the reported data support the view that suitably derivatized tetrabromobenzene molecules may provide powerful reagents for dissecting the cellular functions of CK2 and counteracting its pathogenic potentials. PMID:17133643

  6. Benevolent behavior ofKleinia grandifloraleaf extract as a green corrosion inhibitor for mild steel in sulfuric acid solution

    Institute of Scientific and Technical Information of China (English)

    Muthukrishnan Pitchaipillai; Karthik Raj; Jeyaprabha Balasubramanian; Prakash Periakaruppan

    2014-01-01

    The ethanolic extract ofKleinia grandifloraleaves was characterized and tested for its potential anticorrosion properties on mild steel in 1 M H2SO4 medium using mass-loss analysis, potentiodynamic polarization measurements, electrochemical impedance spectroscopy, Fourier-transform infrared spectroscopy, scanning electron microscopy, UV–visible spectroscopy, and X-ray diffraction analysis. The effect of temperature on the corrosion behavior of mild steel was studied in the range of 308 to 328 K. The inhibition efficiency was observed to increase with increasing concentration of the extract. Polarization curves revealed that theKleinia grandiflora leaf extract is a mixed inhibitor. Impedance diagrams revealed that an increase ofKleinia grandiflora leaf extract concentration increased the charge transfer resistance and decreased the double-layer capacitance. The adsorption process obeys Langmuir’s model, with a standard free energy of adsorption (∆Gads) of−18.62 kJ/mol. The obtained results indicate that theKleinia grandiflora leaf extract can serve as an effective inhibitor for the corrosion of mild steel in a sulfuric acid medium.

  7. Benevolent behavior of Kleinia grandiflora leaf extract as a green corrosion inhibitor for mild steel in sulfuric acid solution

    Science.gov (United States)

    Pitchaipillai, Muthukrishnan; Raj, Karthik; Balasubramanian, Jeyaprabha; Periakaruppan, Prakash

    2014-11-01

    The ethanolic extract of Kleinia grandiflora leaves was characterized and tested for its potential anticorrosion properties on mild steel in 1 M H2SO4 medium using mass-loss analysis, potentiodynamic polarization measurements, electrochemical impedance spectroscopy, Fourier-transform infrared spectroscopy, scanning electron microscopy, UV-visible spectroscopy, and X-ray diffraction analysis. The effect of temperature on the corrosion behavior of mild steel was studied in the range of 308 to 328 K. The inhibition efficiency was observed to increase with increasing concentration of the extract. Polarization curves revealed that the Kleinia grandiflora leaf extract is a mixed inhibitor. Impedance diagrams revealed that an increase of Kleinia grandiflora leaf extract concentration increased the charge transfer resistance and decreased the double-layer capacitance. The adsorption process obeys Langmuir's model, with a standard free energy of adsorption (Δ G ads) of -18.62 kJ/mol. The obtained results indicate that the Kleinia grandiflora leaf extract can serve as an effective inhibitor for the corrosion of mild steel in a sulfuric acid medium.

  8. Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase.

    Science.gov (United States)

    Winkler, Marisa L; Rodkey, Elizabeth A; Taracila, Magdalena A; Drawz, Sarah M; Bethel, Christopher R; Papp-Wallace, Krisztina M; Smith, Kerri M; Xu, Yan; Dwulit-Smith, Jeffrey R; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; van den Akker, Focco; Bonomo, Robert A

    2013-02-14

    Inhibitor resistant (IR) class A β-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV β-lactamase, from Klebsiella pneumoniae , results in resistance to ampicillin/clavulanate. After site-saturation mutagenesis of Lys-234 in SHV, microbiological and biochemical characterization of the resulting β-lactamases revealed that only -Arg conferred resistance to ampicillin/clavulanate. X-ray crystallography revealed two conformations of Arg-234 and Ser-130 in SHV K234R. The movement of Ser-130 is the principal cause of the observed clavulanate resistance. A panel of boronic acid inhibitors was designed and tested against SHV-1 and SHV K234R. A chiral ampicillin analogue was discovered to have a 2.4 ± 0.2 nM K(i) for SHV K234R; the chiral ampicillin analogue formed a more complex hydrogen-bonding network in SHV K234R vs SHV-1. Consideration of the spatial position of Ser-130 and Lys-234 and this hydrogen-bonding network will be important in the design of novel antibiotics targeting IR β-lactamases.

  9. Tryptamine as a green iron corrosion inhibitor in 0.5 M deaerated sulphuric acid

    International Nuclear Information System (INIS)

    The inhibition effects of tryptamine (TA) on the corrosion behaviour of ARMCO iron in 0.5 M deaerated H2SO4 (in the 25-55 deg. C temperature range) was studied in both short and long time tests (1, 24 and 72 h) by means of potentiodynamic curves (PCM) and electrochemical impedance spectroscopy (EIS). TA was found to be an effective ARMCO iron inhibitor, even at 55 deg. C and 72 h, but only at 10 mM. At this concentration the inhibition percentages (IP%), calculated by PCM and EIS, ranged from 90% to 99% and did not diminish over time and as the temperature increased. TA adsorption followed Bockris-Swinkels' isotherm (x=1). The thermodynamic data indicated that, in the more concentrated solutions, TA also chemisorbed on the iron surface

  10. Proton pump inhibitors in acid-related diseases. Issues in diagnosis, treatment and outcome

    OpenAIRE

    Jonasson, Christian

    2013-01-01

    Acid-related disease (ARD) is a term used to describe a range of conditions in which acid is involved in the generation of symptoms and/or complications. Two of the most common ARDs are gastro-esophageal reflux disease (GERD) and peptic ulcer disease (PUD). PPIs are today regarded as the gold standard in the treatment of both symptoms and mucosal injury in patients with GERD as well as for prevention and acute treatment of PUD. Since the PPIs were introduced in the late 1980-ie...

  11. Anti-tumor effect in human lung cancer by a combination treatment of novel histone deacetylase inhibitors: SL142 or SL325 and retinoic acids.

    Directory of Open Access Journals (Sweden)

    Shaoteng Han

    Full Text Available Histone deacetylase (HDAC inhibitors arrest cancer cell growth and cause apoptosis with low toxicity thereby constituting a promising treatment for cancer. In this study, we investigated the anti-tumor activity in lung cancer cells of the novel cyclic amide-bearing hydroxamic acid based HDAC inhibitors SL142 and SL325. In A549 and H441 lung cancer cells both SL142 and SL325 induced more cell growth inhibition and cell death than the hydroxamic acid-based HDAC inhibitor suberoylanilide hydroxamic acid (SAHA. Moreover, the combination treatment using retinoid drugs ATRA or 9-cis RA along with SL142 or SL325 significantly induced more apoptosis and suppressed colony formation than the single use of either. The expression of the retinoic acid receptors RARα, RARβ, RXRα and RXRβ were unchanged with the treatment. However a luciferase reporter construct (pGL4. RARE 7x containing seven tandem repeats of the retinoic acid responsible element (RARE generated significant transcriptional activity after the combination treatment of retinoic acids and SL142 or SL325 in H441 lung cancer cells. Moreover, apoptosis-promoting Bax expression and caspase-3 activity was increased after the combination treatment. These results suggest that the combination treatment of SL142 or SL325 with retinoic acids exerts significant anti-tumor activity and is a promising therapeutic candidate to treat human lung cancer.

  12. [Calcium suppletion for patients who use gastric acid inhibitors: calcium citrate or calcium carbonate?].

    NARCIS (Netherlands)

    Jonge, H.J. de; Gans, R.O.; Huls, G.A.

    2012-01-01

    Various calcium supplements are available for patients who have an indication for calcium suppletion. American guidelines and UpToDate recommend prescribing calcium citrate to patients who use antacids The rationale for this advice is that water-insoluble calcium carbonate needs acid for adequate ab

  13. Inhibitors of lactic acid fermentation in Spanish-style green olive brines of the Manzanilla variety.

    Science.gov (United States)

    Medina, Eduardo; Romero, Concepción; de Castro, Antonio; Brenes, Manuel; García, Aranzazu

    2008-10-15

    Frequently, a delay or lack of lactic acid fermentation occurs during the processing of Spanish-style green olives, in particular of the Manzanilla variety. Many variables can affect the progress of fermentation such as temperature, nutrients, salt concentration, antimicrobials in brines, and others. In this study, it was demonstrated that an inappropriate alkaline treatment (low NaOH strength and insufficient alkali penetration) allowed for the presence of several antimicrobial compounds in brines, which inhibited the growth of Lactobacillus pentosus. These substances were the dialdehydic form of decarboxymethyl elenolic acid either free or linked to hydroxytyrosol and an isomer of oleoside 11-methyl ester. Olive brines, from olives treated with a NaOH solution of low concentration up to 1/2 the distance to the pit, contained these antimicrobials, and no lactic acid fermentation took place in them. By contrast, a more intense alkaline treatment (2/3 lye depth penetration) gave rise to an abundant growth of lactic acid bacteria without any antimicrobial in brines. Therefore, the precise cause of stuck fermentation in Manzanilla olive brines was demonstrated for the first time and this finding will contribute to better understand the table olive fermentation process. PMID:26047282

  14. Semisynthetic and Natural Garcinoic Acid Isoforms as New mPGES-1 Inhibitors.

    Science.gov (United States)

    Alsabil, Khaled; Suor-Cherer, Sorphon; Koeberle, Andreas; Viault, Guillaume; Lavaud, Alexis; Temml, Veronika; Waltenberger, Birgit; Schuster, Daniela; Litaudon, Marc; Lorkowski, Stefan; de Vaumas, René; Helesbeux, Jean-Jacques; Guilet, David; Stuppner, Hermann; Werz, Oliver; Seraphin, Denis; Richomme, Pascal

    2016-07-01

    Over the last twenty years, tocotrienol analogues raised great interest because of their higher level and larger domain of biological activities when compared with tocopherols. Amongst the most promising therapeutic application, anti-inflammatory potency has been evaluated through the inhibition of various mediators of inflammation. Here, we worked on the isolation of two natural isoforms of garcinoic acid (i.e., δ and γ) from two different sources, respectively, Garcinia kola seeds and Garcinia amplexicaulis bark. We also developed semisynthetic strategies to access the other two non-natural α- and β-garcinoic acid isoforms. In the next stage of our work, microsomal prostaglandin E2 synthase was defined as a target to evaluate the anti-inflammatory potential of the four garcinoic acid isomers. Both dimethylated isoforms, β- and γ-garcinoic acid, exhibited the lowest IC50, 2.8 µM and 2.0 µM, respectively. These results showed that the affinity of tocotrienol analogues to microsomal prostaglandin E2 synthase-1 most probably contributes to the anti-inflammatory potential of this class of derivatives. PMID:27286327

  15. Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

    Directory of Open Access Journals (Sweden)

    Mitesh Patel

    2014-04-01

    Full Text Available Poor systemic concentrations of lopinavir (LPV following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp and multidrug resistance-associated proteins (MRPs and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1 and MRP2 (MDCK-MRP2 transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2.

  16. Benzoxazolone Carboxamides: Potent and Systemically Active Inhibitors of Intracellular Acid Ceramidase

    DEFF Research Database (Denmark)

    Pizzirani, Daniela*; Bach, Anders*; Realini, Natalia;

    2015-01-01

    The ceramides are a family of bioactive lipid-derived messengers involved in the control of cellular senescence, inflammation, and apoptosis. Ceramide hydrolysis by acid ceramidase (AC) stops the biological activity of these substances and influences survival and function of normal and neoplastic...

  17. The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

    Science.gov (United States)

    Bredy, Timothy W.; Barad, Mark

    2008-01-01

    Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

  18. The occurrence of abscisic acid in inhibitors B1 and C from immature fruit of Ceratonia siliqua L. (carob) and in commercial carob syrup.

    Science.gov (United States)

    Most, B H; Gaskin, P; Macmillan, J

    1970-03-01

    The presence of abscisic acid in the inhibitors B1 and C from immature carob fruit, whole and minus seed, has been established by thin-layer and gas chromatography and by combined gas chromatography-mass spectrometry. Abscisic acid has been identified in commercial carob syrup by the same means. Most, if not all, of the growth inhibitory activity in these fractions is accounted for as abscisic acid by quantitative gas chromatography as the methyl ester. Trimethylsilylation of abscisic acid with bis (trimethylsilyl) acetamide in pyridine gives two isomeric tris(trimethylsilyl) derivatives.

  19. Termoativação da transaminase glutâmico oxaloacética

    Directory of Open Access Journals (Sweden)

    Hélion Póvoa Júnior

    1973-01-01

    Full Text Available Estudou-se a atividade da transaminase glutâmico oxaloacética (TGO em diferentes tecidos (fígado, músculo, rim, pulmão, baço e soro sanguíneo de ratos e de soro humano. verificou-se que a atividade da enzima proveniente de qualquer um destes tecidos é aumentada cerca de tr~es vezes quando a incubação se faz a 60ºC, ao invés de 37ºC. São feitas considerações acerca da importância deste fato.Glutamic Oxalacetic transaminase is thermoativated. Its optimum of catalytical activity is at 60ºC. At this temperature, colour is approximately three times more intense than at 37ºC, temperature usually utilized for determination of enzyme activity. This phenomenon is observed in human blood serum and several rat tissues (liver, heart, striated muscle, spleen, lung, kidney and blood serum.

  20. 4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP).

    Science.gov (United States)

    Banoglu, Erden; Çelikoğlu, Erşan; Völker, Susanna; Olgaç, Abdurrahman; Gerstmeier, Jana; Garscha, Ulrike; Çalışkan, Burcu; Schubert, Ulrich S; Carotti, Andrea; Macchiarulo, Antonio; Werz, Oliver

    2016-05-01

    In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 μM, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 ≥ 8 μM). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis. PMID:26922224

  1. Design and Synthesis of Bis-amide and Hydrazide-containing Derivatives of Malonic Acid as Potential HIV-1 Integrase Inhibitors

    Directory of Open Access Journals (Sweden)

    Nouri Neamati

    2008-10-01

    Full Text Available HIV-1 integrase (IN is an attractive and validated target for the development of novel therapeutics against AIDS. In the search for new IN inhibitors, we designed and synthesized three series of bis-amide and hydrazide-containing derivatives of malonic acid. We performed a docking study to investigate the potential interactions of the title compounds with essential amino acids on the IN active site.

  2. Structure-based rational design of peptide hydroxamic acid inhibitors to target tumor necrosis factor-α converting enzyme as potential therapeutics for hepatitis.

    Science.gov (United States)

    Wu, Dan; Gu, Qiuhong; Zhao, Ning; Xia, Fei; Li, Zhiwei

    2015-12-01

    The human tumor necrosis factor-α converting enzyme (TACE) has recently been raised as a new and promising therapeutic target of hepatitis and other inflammatory diseases. Here, we reported a successful application of the solved crystal structure of TACE complex with a peptide-like ligand INN for rational design of novel peptide hydroxamic acid inhibitors with high potency and selectivity to target and inhibit TACE. First, the intermolecular interactions between TACE catalytic domain and INN were characterized through an integrated bioinformatics approach, with which the key substructures of INN that dominate ligand binding were identified. Subsequently, the INN molecular structure was simplified to a chemical sketch of peptide hydroxamic acid compound, which can be regarded as a linear tripeptide capped by a N-terminal carboxybenzyl group (chemically protective group) and a C-terminal hydroxamate moiety (coordinated to the Zn(2+) at TACE active site). Based on the sketch, a virtual combinatorial library containing 180 peptide hydroxamic acids was generated, from which seven samples were identified as promising candidates by using a knowledge-based protein-peptide affinity predictor and were then tested in vitro with a standard TACE activity assay protocol. Consequently, three designed peptide hydroxamic acids, i.e. Cbz-Pro-Ile-Gln-hydroxamic acid, Cbz-Leu-Ile-Val-hydroxamic acid and Cbz-Phe-Val-Met-hydroxamic acid, exhibited moderate or high inhibitory activity against TACE, with inhibition constants Ki of 36 ± 5, 510 ± 46 and 320 ± 26 nM, respectively. We also examined the structural basis and non-bonded profile of TACE interaction with a designed peptide hydroxamic acid inhibitor, and found that the inhibitor ligand is tightly buried in the active pocket of TACE, forming a number of hydrogen bonds, hydrophobic forces and van der Waals contacts at the interaction interface, conferring both stability and specificity for TACE-inhibitor complex

  3. Identification and Optimization of Anthranilic Acid Based Inhibitors of Replication Protein A.

    Science.gov (United States)

    Patrone, James D; Pelz, Nicholas F; Bates, Brittney S; Souza-Fagundes, Elaine M; Vangamudi, Bhavatarini; Camper, Demarco V; Kuznetsov, Alexey G; Browning, Carrie F; Feldkamp, Michael D; Frank, Andreas O; Gilston, Benjamin A; Olejniczak, Edward T; Rossanese, Olivia W; Waterson, Alex G; Chazin, Walter J; Fesik, Stephen W

    2016-04-19

    Replication protein A (RPA) is an essential single-stranded DNA (ssDNA)-binding protein that initiates the DNA damage response pathway through protein-protein interactions (PPIs) mediated by its 70N domain. The identification and use of chemical probes that can specifically disrupt these interactions is important for validating RPA as a cancer target. A high-throughput screen (HTS) to identify new chemical entities was conducted, and 90 hit compounds were identified. From these initial hits, an anthranilic acid based series was optimized by using a structure-guided iterative medicinal chemistry approach to yield a cell-penetrant compound that binds to RPA70N with an affinity of 812 nm. This compound, 2-(3- (N-(3,4-dichlorophenyl)sulfamoyl)-4-methylbenzamido)benzoic acid (20 c), is capable of inhibiting PPIs mediated by this domain. PMID:26748787

  4. Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors

    OpenAIRE

    Kumar, Satish; Namkung, Wan; A S Verkman; Sharma, Pawan K

    2012-01-01

    Transmembrane protein 16A (TMEM16A) channels are recently discovered membrane proteins that functions as a calcium activated chloride channel (CaCC). CaCCs are major regulators of various physiological processes, such as sensory transduction, epithelial secretion, smooth muscle contraction and oocyte fertilization. Thirty novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids (B01–B30) were synthesized and evaluated for their TMEM16A inhibitory activity by using short circuit curre...

  5. Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction

    DEFF Research Database (Denmark)

    Persson, Tobias; Yde, Christina W.; Rasmussen, Jakob Ewald;

    2007-01-01

    Densely functionalised pyrazole carboxamides and carboxylic acids were synthesised in an expedient manner through saponification and transamidation, respectively, of ester-functionalised pyrazoles. This synthetic protocol allowed for three diversifying steps in which appendages on the pyrazole...... potential biological activity, MCF-7 human breast cancer cells were incubated with the most promising derivatives. Two analogues caused changes in MCF-7 cell growth, one of them through cell cycle arrest demonstrated by cell cycle analysis....

  6. Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase.

    Science.gov (United States)

    Pinto, Andrea; Tamborini, Lucia; Pennacchietti, Eugenia; Coluccia, Antonio; Silvestri, Romano; Cullia, Gregorio; De Micheli, Carlo; Conti, Paola; De Biase, Daniela

    2016-01-01

    The γ-aminobutyrate (GABA)-degradative enzyme GABA aminotransferase (GABA-AT) is regarded as an attractive target to control GABA levels in the central nervous system: this has important implications in the treatment of several neurological disorders and drug dependencies. We have investigated the ability of newly synthesized compounds to act as GABA-AT inhibitors. These compounds have a unique bicyclic structure: the carbocyclic ring bears the GABA skeleton, while the fused 3-Br-isoxazoline ring contains an electrophilic warhead susceptible of nucleophilic attack by an active site residue of the target enzyme. Out of the four compounds tested, only the one named (+)-3 was found to significantly inhibit mammalian GABA-AT in vitro. Docking studies, performed on the available structures of GABA-AT, support the experimental findings: out of the four tested compounds, only (+)-3 suitably orients the electrophilic 3-Br-isoxazoline warhead towards the active site nucleophilic residue Lys329, thereby explaining the irreversible inhibition of GABA-AT observed experimentally. PMID:25807299

  7. Anthranilimide-based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes: 1. Identification of 1-amino-1-cycloalkyl carboxylic acid headgroups

    Energy Technology Data Exchange (ETDEWEB)

    Sparks, Steven M.; Banker, Pierette; Bickett, David M.; Carter, H. Luke; Clancy, Daphne C.; Dickerson, Scott H.; Dwornik, Kate A.; Garrido, Dulce M.; Golden, Pamela L.; Nolte, Robert T.; Peat, Andrew J.; Sheckler, Lauren R.; Tavares, Francis X.; Thomson, Stephen A.; Wang, Liping; Weiel, James E.; (GSKNC)

    2009-05-15

    Optimization of the amino acid residue within a series of anthranilimide-based glycogen phosphorylase inhibitors is described. These studies culminated in the identification of anthranilimides 16 and 22 which displayed potent in vitro inhibition of GPa in addition to reduced inhibition of CYP2C9 and excellent pharmacokinetic properties.

  8. Post-translational regulation of acid invertase activity by vacuolar invertase inhibitor affects resistance to cold-induced sweetening of potato tubers.

    Science.gov (United States)

    McKenzie, Marian J; Chen, Ronan K Y; Harris, John C; Ashworth, Matthew J; Brummell, David A

    2013-01-01

    Cold-induced sweetening (CIS) is a serious post-harvest problem for potato tubers, which need to be stored cold to prevent sprouting and pathogenesis in order to maintain supply throughout the year. During storage at cold temperatures (below 10 °C), many cultivars accumulate free reducing sugars derived from a breakdown of starch to sucrose that is ultimately cleaved by acid invertase to produce glucose and fructose. When affected tubers are processed by frying or roasting, these reducing sugars react with free asparagine by the Maillard reaction, resulting in unacceptably dark-coloured and bitter-tasting product and generating the probable carcinogen acrylamide as a by-product. We have previously identified a vacuolar invertase inhibitor (INH2) whose expression correlates both with low acid invertase activity and with resistance to CIS. Here we show that, during cold storage, overexpression of the INH2 vacuolar invertase inhibitor gene in CIS-susceptible potato tubers reduced acid invertase activity, the accumulation of reducing sugars and the generation of acrylamide in subsequent fry tests. Conversely, suppression of vacuolar invertase inhibitor expression in a CIS-resistant line increased susceptibility to CIS. The results show that post-translational regulation of acid invertase by the vacuolar invertase inhibitor is an important component of resistance to CIS. PMID:22734927

  9. Lipid phosphate phosphatases regulate lysophosphatidic acid production and signaling in platelets: studies using chemical inhibitors of lipid phosphate phosphatase activity.

    Science.gov (United States)

    Smyth, Susan S; Sciorra, Vicki A; Sigal, Yury J; Pamuklar, Zehra; Wang, Zuncai; Xu, Yong; Prestwich, Glenn D; Morris, Andrew J

    2003-10-31

    Blood platelets play an essential role in ischemic heart disease and stroke contributing to acute thrombotic events by release of potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator produced by platelets and found in the blood and atherosclerotic plaques. LPA receptors on platelets, leukocytes, endothelial cells, and smooth muscle cells regulate growth, differentiation, survival, motility, and contractile activity. Definition of the opposing pathways of synthesis and degradation that control extracellular LPA levels is critical to understanding how LPA bioactivity is regulated. We show that intact platelets and platelet membranes actively dephosphorylate LPA and identify the major enzyme responsible as lipid phosphate phosphatase 1 (LPP1). Localization of LPP1 to the platelet surface is increased by exposure to LPA. A novel receptor-inactive sn-3-substituted difluoromethylenephosphonate analog of phosphatidic acid that is a potent competitive inhibitor of LPP1 activity potentiates platelet aggregation and shape change responses to LPA and amplifies LPA production by agonist-stimulated platelets. Our results identify LPP1 as a pivotal regulator of LPA signaling in the cardiovascular system. These findings are consistent with genetic and cell biological evidence implicating LPPs as negative regulators of lysophospholipid signaling and suggest that the mechanisms involve both attenuation of lysophospholipid actions at cell surface receptors and opposition of lysophospholipid production. PMID:12909631

  10. Preparation and Evaluation of Aromatic Amine-Epoxidized Sunflower Free Fatty Acid Adducts As Corrosion Inhibitors in Curable Varnishes

    International Nuclear Information System (INIS)

    Five aromatic amines [o-, m- and p- Toluidine (o-T, m-T and p-T), p- anizidine (p-A) and p- chloroaniline (p-ClA)] were reacted with epoxidized sunflower free fatty acid (ESFA) under severe conditions of inert atmosphere and high temperature. The produced adducts were characterized physically, chemically and by IR spectroscopic analysis. Acid value and oxiran content of the prepared adducts were determined to confirm the participation of carboxylic groups and epoxy groups respectively in the reaction of ESFA with aromatic amines. The prepared adducts of (o-T-ESFA, m-T-ESFA, p-T-ESFA, p-A-ESFA and p-ClA-ESFA) were evaluated as corrosion inhibitors of mild steel in epoxy acrylate oligomer formulations curable by electron beam irradiation. Different concentrations of the prepared aromatic adducts were added in varnish formulations. Physical and mechanical measurements were carried out, in addition to corrosion resistance tests and weight loss of coated steel panels. The efficiency of adducts in varnishes formulation were determined, in which it was found that, the varnish formulations containing the prepared aromatic amine adducts could protect steel from corrosion. Superior corrosion inhibition efficiency was found for the varnish formula containing 0.6% p-A-ESFA adduct. The corrosion inhibition efficiency of the prepared aromatic amine in epoxy acrylate oligomer varnishes follows the order: p-A-ESFA > p-T-ESFA > m-T-ESFA > o-T-ESFA > p-ClA-ESFA

  11. The pharmacology and therapeutic potential of small molecule inhibitors of acid-sensing ion channels in stroke intervention

    Institute of Scientific and Technical Information of China (English)

    Tian-dong LENG; Zhi-gang XIONG

    2013-01-01

    In the nervous system,a decrease in extracellular pH is a common feature of various physiological and pathological processes,including synaptic transmission,cerebral ischemia,epilepsy,brain trauma,and tissue inflammation.Acid-sensing ion channels (ASICs) are proton-gated cation channels that are distributed throughout the central and peripheral nervous systems.Following the recent identification of ASICs as critical acid-sensing extracellular proton receptors,growing evidence has suggested that the activation of ASICs plays important roles in physiological processes such as nociception,mechanosensation,synaptic plasticity,learning and memory.However,the over-activation of ASICs is also linked to adverse outcomes for certain pathological processes,such as brain ischemia and multiple sclerosis.Based on the well-demonstrated role of ASlC1a activation in acidosis-mediated brain injury,small molecule inhibitors of ASIC1a may represent novel therapeutic agents for the treatment of neurological disorders,such as stroke.

  12. Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

    Directory of Open Access Journals (Sweden)

    Yingzi eHe

    2014-11-01

    Full Text Available In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, nonmammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well suited for studying hair cell development and regeneration. Histone deacetylase (HDAC activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA or valproic acid (VPA increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line.

  13. Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.

    Science.gov (United States)

    Li, Xing-Cong; Joshi, Alpana S; ElSohly, Hala N; Khan, Shabana I; Jacob, Melissa R; Zhang, Zhizheng; Khan, Ikhlas A; Ferreira, Daneel; Walker, Larry A; Broedel, Sheldon E; Raulli, Robert E; Cihlar, Ronald L

    2002-12-01

    Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined. PMID:12502337

  14. Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaofei; Zhu, Yanshuang [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); He, Huabin [Department of Orthopedics, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Lou, Lianqing; Ye, Weiwei; Chen, Yongxin [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China); Wang, Jinghe, E-mail: Xiaofeili2000@163.com [Department of Infectious Diseases, Yiwu Central Hospita, 519 Nan men Street, Yiwu, Jinhua, Zhejing 322000 (China)

    2013-06-28

    Highlights: •Novel combination therapy using aspirin and valproic acid (VPA). •Combination of aspirin and VPA elicits synergistic cytotoxic effects. •Combination of aspirin and VPA significantly reduces the drug dosage required alone. •Combination of aspirin and VPA significantly inhibit tumor growth. •Lower dose of aspirin in combination therapy will minimize side effects of aspirin. -- Abstract: Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines’ significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis.

  15. SERUM LIPID PROFILE AND TRANSAMINASES LEVELS IN HIV PATIENTS ON HAART WITH ADIPOSE TISSUE ALTERATIONS

    Directory of Open Access Journals (Sweden)

    Vijay

    2016-02-01

    Full Text Available BACKGROUND HIV patients receiving highly active Anti-Retroviral Therapy (HAART usually suffer from side effects like hepatitis, neurological problems, abnormal fat distribution etc. Among these, the most physical, mental and cosmetically disturbing side effect is adipose tissue alterations (ATA, also called as lipodystrophy, which is abnormal fat deposition (Lipohypertrophy and/or fat atrophy (Lipoatrophy. AIM Several studies have shown dyslipidemia in patients on HAART, but there are very few studies on the lipid profile changes in patients on ART with ATA. Hence a study was conducted to assess the serum lipid profile and transaminases activity in patients on ART with ATA and also to evaluate whether lipid profile parameters can predict ATA changes in HIV patients on HAART. METHOD Randomly selected HIV positive patients, who were attending ART centre, were included in the study. Twenty five of these patients in whom HAART was yet to be started were considered as Control group, 25 patients on HAART for more than 12 months but without ATA as ART group and 23 patients on HAART with ATA as ATA group. Lipid profile and serum transaminases in all the groups were assayed by standard methods. RESULTS Serum cholesterol and LDL were significantly increased in ART group and ATA group when compared to control group, but there was no significant difference in lipid profile parameters between ART group and ATA group. Serum AST and ALT levels were significantly increased (p<0.02 in ATA group when compared to ART group. Buffalo hump was seen only in females in our study. Lipoatrophy (facial and limbs and central obesity was seen in males. CONCLUSION There was no significant change in lipid profile parameters in ATA group when compared with ART group. Hence lipid profile parameters are not good predictors of ATA changes in HIV patients on HAART. Significant increase in transaminase levels suggests increased hepatotoxity in ATA patients due to HAART drugs. There

  16. Glycyrrhetinic acid as inhibitor or amplifier of permeability transition in rat heart mitochondria.

    Science.gov (United States)

    Battaglia, Valentina; Brunati, Anna Maria; Fiore, Cristina; Rossi, Carlo Alberto; Salvi, Mauro; Tibaldi, Elena; Palermo, Mario; Armanini, Decio; Toninello, Antonio

    2008-01-01

    Glycyrrhetinic acid (GE), a hydrolysis product of glycyrrhizic acid, one of the main constituents of licorice root, is able, depending on its concentration, to prevent or to induce the mitochondrial permeability transition (MPT) (a phenomenon related to oxidative stress) in rat heart mitochondria (RHM). In RHM, below a threshold concentration of 7.5 microM, GE prevents oxidative stress and MPT induced by supraphysiological Ca2+ concentrations. Above this concentration, GE induces oxidative stress by interacting with a Fe-S centre of Complex I, thus producing ROS, and amplifies the opening of the transition pore, once again induced by Ca2+. GE also inhibits Ca2+ transport in RHM, thereby preventing the oxidative stress induced by the cation. However, the reduced amount of Ca2+ transported in the matrix is sufficient to predispose adenine nucleotide translocase for pore opening. Comparisons between observed results and the effects of GE in rat liver mitochondria (RLM), in which the drug induces only MPT without exhibiting any protective effect, confirm that it interacts in a different way with RHM, suggesting tissue specificity for its action. The concentration dependence of the opposite effects of GE, in RHM but not RLM, is most probably due to the existence of a different, more complex, pathway by means of which GE reaches its target. It follows that high GE concentrations are necessary to stimulate the oxidative stress capable of inducing MPT, because of the above effect, which prevents the interaction of low concentrations of GE with the Fe-S centre. The reported results also explain the mechanism of apoptosis induction by GE in cardiomyocytes. PMID:17980701

  17. Eugenol: a dual inhibitor of platelet-activating factor and arachidonic acid metabolism.

    Science.gov (United States)

    Saeed, S A; Simjee, R U; Shamim, G; Gilani, A H

    1995-07-01

    Eugenol is an active principal and responsible for several pharmacological activities of clove oil. We studied the effects of eugenol on human platelet aggregation, arachidonic acid (AA) and platelet-activating factor (PAF) metabolism and in vivo effects on AA and PAF-induced shock in rabbits. Eugenol strongly inhibited PAF-induced platelet aggregation with lesser effect against AA and collegen. The IC(50) values were against AA: 31 ± 0.5; collagen: 64 ± 0.7 and PAF 7 ± 0.2 μM (n=9) respectively. In addition, eugenol stimulated PAF-acetylhydrolase activity suggesting that inhibition of PAF could be due to its inactivation to lyso-PAF. Pretreatment of rabbits with eugenol (50-100 mg/kg) prevented the lethal effects of intravenous PAF (11 μgg/kg) or AA (2 mg/kg) in a dose-dependent fashion. The protective effects of eugenol in the rabbits, however, were more pronounced against PAF-induced mortality (100% protection). In addition, eugenol also inhibited AA metabolism via cyclooxygenase and lipoxygenase pathways in human platelets. Both the production of thromboxane-A(2) and 12-hydroxy-eicosatetraenoic acid was inhibited by eugenol in a concentration-related manner (30-120 μM). In vivo, eugenol (50-100 mg/kg; i.p.) inhibited carrageenan-induced rat paw oedema (P < 0.001). In this test, eugenol was 5 times more potent than aspirin. These results provide evidence that eugenol acts as a dual antagonist of AA and PAF. PMID:23196096

  18. Mutants of GABA transaminase (POP2 suppress the severe phenotype of succinic semialdehyde dehydrogenase (ssadh mutants in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Frank Ludewig

    Full Text Available BACKGROUND: The gamma-aminubutyrate (GABA shunt bypasses two steps of the tricarboxylic acid cycle, and is present in both prokaryotes and eukaryotes. In plants, the pathway is composed of the calcium/calmodulin-regulated cytosolic enzyme glutamate decarboxylase (GAD, the mitochondrial enzymes GABA transaminase (GABA-T; POP2 and succinic semialdehyde dehydrogenase (SSADH. We have previously shown that compromising the function of the GABA-shunt, by disrupting the SSADH gene of Arabidopsis, causes enhanced accumulation of reactive oxygen intermediates (ROIs and cell death in response to light and heat stress. However, to date, genetic investigations of the relationships between enzymes of the GABA shunt have not been reported. PRINCIPAL FINDINGS: To elucidate the role of succinic semialdehyde (SSA, gamma-hydroxybutyrate (GHB and GABA in the accumulation of ROIs, we combined two genetic approaches to suppress the severe phenotype of ssadh mutants. Analysis of double pop2 ssadh mutants revealed that pop2 is epistatic to ssadh. Moreover, we isolated EMS-generated mutants suppressing the phenotype of ssadh revealing two new pop2 alleles. By measuring thermoluminescence at high temperature, the peroxide contents of ssadh and pop2 mutants were evaluated, showing that only ssadh plants accumulate peroxides. In addition, pop2 ssadh seedlings are more sensitive to exogenous SSA or GHB relative to wild type, because GHB and/or SSA accumulate in these plants. SIGNIFICANCE: We conclude that the lack of supply of succinate and NADH to the TCA cycle is not responsible for the oxidative stress and growth retardations of ssadh mutants. Rather, we suggest that the accumulation of SSA, GHB, or both, produced downstream of the GABA-T transamination step, is toxic to the plants, resulting in high ROI levels and impaired development.

  19. A preclinical study on the rescue of normal tissue by nicotinic acid in high-dose treatment with APO866, a specific nicotinamide phosphoribosyltransferase inhibitor

    DEFF Research Database (Denmark)

    Olesen, Uffe Høgh; Thougaard, Annemette V; Jensen, Peter Buhl;

    2010-01-01

    B(3)). We examined the toxicity profile of APO866 in B6D2F1 mice and the effect of oral administration of nicotinic acid on tissue toxicity. Nicotinic acid (50 mg/kg) protects mice from death and severe toxicity from an APO866 dose (60 mg/kg) four times the monotherapy maximum tolerated dose (15 mg......Inhibitor of nicotinamide phosphoribosyltransferase APO866 is a promising cancer drug currently in phase II clinical trials in oncology. Here, we present a strategy for increasing the therapeutic potential of APO866 through the rescue of normal tissues by coadministration of nicotinic acid (Vitamin...

  20. A case study on robust optimal experimental design for model calibration of ω-Transaminase

    DEFF Research Database (Denmark)

    Daele, Timothy, Van; Van Hauwermeiren, Daan; Ringborg, Rolf Hoffmeyer;

    Proper calibration of models describing enzyme kinetics can be quite challenging. This is especially the case for more complex models like transaminase models (Shin and Kim, 1998). The latter fitted model parameters, but the confidence on the parameter estimation was not derived. Hence...... and measurement errors. Since the latter was not provided, a conservative standard deviation of 5% was assumed. The confidence analysis yielded that only two (Vr and Kac) out of five parameters were reliable estimates, which means that model predictions and decisions based on them are highly uncertain. The reason...... behind this problem is practical identifiability, which can be related to both the model structure and/or the information content of the data.The available data are 25 experiments performed by Shin and Kim, set up in a 5x5 factorial design (2 substrates with 5 concentration levels each) across...

  1. Kunitz trypsin Inhibitor and phytic acid levels in conventional and genetically modified soybean seeds from Londrina and Ponta Grossa, South Brazil

    OpenAIRE

    Olívio F. Galão; Mercedes C. Carrão-Panizzi; José Marcos G. Mandarino; Rodrigo Santos Leite; Thiago Claus; Jesuí Vergílio Visentainer

    2014-01-01

    Differences in the levels of antinutritional components - Kunitz trypsin inhibitor and phytic acid - were determined for conventional and genetically modified soybean cultivated in Londrina and Ponta Grossa, South Brazil. Trypsin inhibitor levels in the conventional cultivars of Londrina and Ponta Grossa varied from 14.56 mg g-1 (BRS 267) to 20.40 mg g-1 (BRS 261) and from 13.51 mg g-1 (BRS 232) to 19.65 mg g-1 (BRS 268), respectively, whereas in the genetically modified (GM) cultivars, they ...

  2. Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET

    International Nuclear Information System (INIS)

    The fatty acids, n-butyric acid (BA), 4-phenylbutyric acid (PBA) and valproic acid (VPA, 2-propylpentanoic acid) have been used for many years in the treatment of a variety of CNS and peripheral organ diseases including cancer. New information that these drugs alter epigenetic processes through their inhibition of histone deacetylases (HDACs) has renewed interest in their biodistribution and pharmacokinetics and the relationship of these properties to their therapeutic and side effect profiles. In order to determine the pharmacokinetics and biodistribution of these drugs in primates, we synthesized their carbon-11 labeled analogues and performed dynamic positron emission tomography (PET) in six female baboons over 90 min. The carbon-11 labeled carboxylic acids were prepared by using 11CO2 and the appropriate Grignard reagents. [11C]BA was metabolized rapidly (only 20% of the total carbon-11 in plasma was parent compound at 5 min post injection) whereas for VPA and PBA 98% and 85% of the radioactivity were the unmetabolized compound at 30 min after their administration respectively. The brain uptake of all three carboxylic acids was very low ( VPA > PBA), which is consistent with the need for very high doses for therapeutic efficacy. Most of the radioactivity was excreted through the kidneys and accumulated in the bladder. However, the organ biodistribution between the drugs differed. [11C]BA showed relatively high uptake in spleen and pancreas whereas [11C]PBA showed high uptake in liver and heart. Notably, [11C]VPA showed exceptionally high heart uptake possibly due to its involvement in lipid metabolism. The unique biodistribution of each of these drugs may be of relevance in understanding their therapeutic and side effect profile including their teratogenic effects

  3. Statistical analysis of a corrosion inhibitor family on three steel surfaces (duplex, super-13 and carbon) in hydrochloric acid solutions

    International Nuclear Information System (INIS)

    Previous studies have addressed the experimental and theoretical investigation of the inhibition corrosion efficiencies (ICE) of single metal surfaces. Along this line we carried out calculations concerning to 23 compounds on three different single-steel surfaces, duplex, super-13 and the carbon steel in hydrochloric acid (15% w/v) solutions. The overall experiment is composed of 69 results of weight loss ICEs at 60 deg. C for amines, alcohols, thiourea and its derivatives acting as corrosion inhibitors for three steel surfaces. In these studies ICEs were correlated with group and quantum AM1 descriptors through the use of three different statistical methodologies based on calibration and validation of regular and modified OLS and PLS (partial least squares) methods. All calculations have shown better results using weight isoesteric Langmuir adsorption function (WILA function), ln(θM/(1-θ)) or ln Kads, calculated from the weight loss data as the response function. The function -log(i) has been used, as well, on all comparisons. Variables describing the metal were added to the previous set of group and quantum IC variables and several models have been designed to fit the three-steel problem. Simple products of metal and IC variables with 250 (25 x 10) products were tested as model I. Selection of the best variable set was carried out for the calibration and validation procedures and these calculations indicated very few descriptors in common, i.e. each particular selection (calibration or validation) finds its own optimal descriptor set. The overall results showed excellent correlations with R2 values between 0.80 and 0.96 and a Q2 values from 0.75 to 0.93. We are unaware of any similar QSPR study on the steels here studied, and neither the study of such massive amount of data concerning molecular inhibitors on three different steel surfaces. Our best result for the second-order cross-validation descriptor selection employs 29 variables, Y29. The results

  4. Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids.

    Science.gov (United States)

    Jiang, Jianfei; Bakan, Ahmet; Kapralov, Alexandr A; Silva, K Ishara; Huang, Zhentai; Amoscato, Andrew A; Peterson, James; Garapati, Venkata Krishna; Saxena, Sunil; Bayir, Hülya; Atkinson, Jeffrey; Bahar, Ivet; Kagan, Valerian E

    2014-06-01

    Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency. PMID:24631490

  5. Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis.

    Science.gov (United States)

    Jimenez, Laura; Wang, Jindong; Morrison, Monique A; Whatcott, Clifford; Soh, Katherine K; Warner, Steven; Bearss, David; Jette, Cicely A; Stewart, Rodney A

    2016-04-01

    The epithelial-to-mesenchymal transition (EMT) is a highly conserved morphogenetic program essential for embryogenesis, regeneration and cancer metastasis. In cancer cells, EMT also triggers cellular reprogramming and chemoresistance, which underlie disease relapse and decreased survival. Hence, identifying compounds that block EMT is essential to prevent or eradicate disseminated tumor cells. Here, we establish a whole-animal-based EMT reporter in zebrafish for rapid drug screening, calledTg(snai1b:GFP), which labels epithelial cells undergoing EMT to producesox10-positive neural crest (NC) cells. Time-lapse and lineage analysis ofTg(snai1b:GFP)embryos reveal that cranial NC cells delaminate from two regions: an early population delaminates adjacent to the neural plate, whereas a later population delaminates from within the dorsal neural tube. TreatingTg(snai1b:GFP)embryos with candidate small-molecule EMT-inhibiting compounds identified TP-0903, a multi-kinase inhibitor that blocked cranial NC cell delamination in both the lateral and medial populations. RNA sequencing (RNA-Seq) analysis and chemical rescue experiments show that TP-0903 acts through stimulating retinoic acid (RA) biosynthesis and RA-dependent transcription. These studies identify TP-0903 as a new therapeutic for activating RAin vivoand raise the possibility that RA-dependent inhibition of EMT contributes to its prior success in eliminating disseminated cancer cells.

  6. Phenotypic chemical screening using a zebrafish neural crest EMT reporter identifies retinoic acid as an inhibitor of epithelial morphogenesis

    Directory of Open Access Journals (Sweden)

    Laura Jimenez

    2016-04-01

    Full Text Available The epithelial-to-mesenchymal transition (EMT is a highly conserved morphogenetic program essential for embryogenesis, regeneration and cancer metastasis. In cancer cells, EMT also triggers cellular reprogramming and chemoresistance, which underlie disease relapse and decreased survival. Hence, identifying compounds that block EMT is essential to prevent or eradicate disseminated tumor cells. Here, we establish a whole-animal-based EMT reporter in zebrafish for rapid drug screening, called Tg(snai1b:GFP, which labels epithelial cells undergoing EMT to produce sox10-positive neural crest (NC cells. Time-lapse and lineage analysis of Tg(snai1b:GFP embryos reveal that cranial NC cells delaminate from two regions: an early population delaminates adjacent to the neural plate, whereas a later population delaminates from within the dorsal neural tube. Treating Tg(snai1b:GFP embryos with candidate small-molecule EMT-inhibiting compounds identified TP-0903, a multi-kinase inhibitor that blocked cranial NC cell delamination in both the lateral and medial populations. RNA sequencing (RNA-Seq analysis and chemical rescue experiments show that TP-0903 acts through stimulating retinoic acid (RA biosynthesis and RA-dependent transcription. These studies identify TP-0903 as a new therapeutic for activating RA in vivo and raise the possibility that RA-dependent inhibition of EMT contributes to its prior success in eliminating disseminated cancer cells.

  7. Hydrazino-methoxy-1,3,5-triazine Derivatives’ Excellent Corrosion Organic Inhibitors of Steel in Acidic Chloride Solution

    Directory of Open Access Journals (Sweden)

    Ayman El-Faham

    2016-06-01

    Full Text Available The corrosion inhibition performance of 2-hydrazino-4,6-dimethoxy-1,3,5-tirazine (DMeHT, 2,4-dihydrazino-6-methoxy-1,3,5-triaizine (DHMeT, and 2,4,6-tridydrazino-1,3,5-triaizne (TH3 on steel corrosion in acidic media was examined using electrochemical techniques. The results showed 2,4-Ddihydrazino-6-methoxy-1,3,5-triaizine (DHMeT gave the best corrosion protection performance among the other hydrazino derivatives even at a low concentration of 25 ppm (95%. The number of hydrazino groups play an important role in the corrosion inhibition, where the two hydrazine groups increased the electrostatic interactions between the protonated tested compounds, the negatively charged steel surface resulted from the adsorption of the chloride anions, and the presence of the methoxy group made the compound more reliable for formation of film protection on the surface of steel through the lone pair of oxygen atoms. Electrochemical Impedance Spectroscopy (EIS measurements suggested that the corrosion process of steel in presence of the hydrazino-s-triazine derivatives (TH3, DMeHT and DHMeT were being controlled by the charge transfer reaction. Polarization curves indicated that the examined TH3, DMeHT and DHMeT behaved as mixed type inhibitors.

  8. Hydrazino-methoxy-1,3,5-triazine Derivatives' Excellent Corrosion Organic Inhibitors of Steel in Acidic Chloride Solution.

    Science.gov (United States)

    El-Faham, Ayman; Osman, Sameh M; Al-Lohedan, Hamad A; El-Mahdy, Gamal A

    2016-06-01

    The corrosion inhibition performance of 2-hydrazino-4,6-dimethoxy-1,3,5-tirazine (DMeHT), 2,4-dihydrazino-6-methoxy-1,3,5-triaizine (DHMeT), and 2,4,6-tridydrazino-1,3,5-triaizne (TH₃) on steel corrosion in acidic media was examined using electrochemical techniques. The results showed 2,4-Ddihydrazino-6-methoxy-1,3,5-triaizine (DHMeT) gave the best corrosion protection performance among the other hydrazino derivatives even at a low concentration of 25 ppm (95%). The number of hydrazino groups play an important role in the corrosion inhibition, where the two hydrazine groups increased the electrostatic interactions between the protonated tested compounds, the negatively charged steel surface resulted from the adsorption of the chloride anions, and the presence of the methoxy group made the compound more reliable for formation of film protection on the surface of steel through the lone pair of oxygen atoms. Electrochemical Impedance Spectroscopy (EIS) measurements suggested that the corrosion process of steel in presence of the hydrazino-s-triazine derivatives (TH₃, DMeHT and DHMeT) were being controlled by the charge transfer reaction. Polarization curves indicated that the examined TH₃, DMeHT and DHMeT behaved as mixed type inhibitors.

  9. Interaction of acid ceramidase inhibitor LCL521 with tumor response to photodynamic therapy and photodynamic therapy-generated vaccine.

    Science.gov (United States)

    Korbelik, Mladen; Banáth, Judit; Zhang, Wei; Saw, Kyi Min; Szulc, Zdzislaw M; Bielawska, Alicja; Separovic, Duska

    2016-09-15

    Acid ceramidase has been identified as a promising target for cancer therapy. One of its most effective inhibitors, LCL521, was examined as adjuvant to photodynamic therapy (PDT) using mouse squamous cell carcinoma SCCVII model of head and neck cancer. Lethal effects of PDT, assessed by colony forming ability of in vitro treated SCCVII cells, were greatly enhanced when combined with 10 µM LCL521 treatment particularly when preceding PDT. When PDT-treated SCCVII cells are used to vaccinate SCCVII tumor-bearing mice (PDT vaccine protocol), adjuvant LCL521 treatment (75 mg/kg) resulted in a marked retardation of tumor growth. This effect can be attributed to the capacity of LCL521 to effectively restrict the activity of two main immunoregulatory cell populations (Tregs and myeloid-derived suppressor cells, MDSCs) that are known to hinder the efficacy of PDT vaccines. The therapeutic benefit with adjuvant LCL521 was also achieved with SCCVII tumors treated with standard PDT when using immunocompetent mice but not with immunodeficient hosts. The interaction of LCL521 with PDT-based antitumor mechanisms is dominated by immune system contribution that includes overriding the effects of immunoregulatory cells, but could also include a tacit contribution from boosting direct tumor cell kill. PMID:27136745

  10. Flavianate, an amino acid precipitant, is a competitive inhibitor of trypsin at pH 3.0

    Directory of Open Access Journals (Sweden)

    J.M. Schneedorf

    1998-09-01

    Full Text Available Textile dyes bind to proteins leading to selective co-precipitation of a complex involving one protein molecule and more than one dye molecule of opposite charge in acid solutions, in a process of reversible denaturation that can be utilized for protein fractionation. In order to understand what occurs before the co-precipitation, a kinetic study using bovine ß-trypsin and sodium flavianate was carried out based on reaction progress curve techniques. The experiments were carried out using a-CBZ-L-Lys-p-nitrophenyl ester as substrate which was added to 50 mM sodium citrate buffer, pH 3.0, containing varying concentrations of ß-trypsin and dye. The reaction was recorded spectrophotometrically at 340 nm for 30 min, and the families of curves obtained were analyzed simultaneously by fitting integrated Michaelis-Menten equations. The dye used behaved as a competitive inhibitor of trypsin at pH 3.0, with Ki = 99 µM; kinetic parameters for the substrate hydrolysis were: Km = 32 µM, and kcat = 0.38/min. The competitive character of the inhibition suggests a specific binding of the first dye molecule to His-57, the only positively charged residue at the active site of the enzyme.

  11. Hydrazino-methoxy-1,3,5-triazine Derivatives' Excellent Corrosion Organic Inhibitors of Steel in Acidic Chloride Solution.

    Science.gov (United States)

    El-Faham, Ayman; Osman, Sameh M; Al-Lohedan, Hamad A; El-Mahdy, Gamal A

    2016-01-01

    The corrosion inhibition performance of 2-hydrazino-4,6-dimethoxy-1,3,5-tirazine (DMeHT), 2,4-dihydrazino-6-methoxy-1,3,5-triaizine (DHMeT), and 2,4,6-tridydrazino-1,3,5-triaizne (TH₃) on steel corrosion in acidic media was examined using electrochemical techniques. The results showed 2,4-Ddihydrazino-6-methoxy-1,3,5-triaizine (DHMeT) gave the best corrosion protection performance among the other hydrazino derivatives even at a low concentration of 25 ppm (95%). The number of hydrazino groups play an important role in the corrosion inhibition, where the two hydrazine groups increased the electrostatic interactions between the protonated tested compounds, the negatively charged steel surface resulted from the adsorption of the chloride anions, and the presence of the methoxy group made the compound more reliable for formation of film protection on the surface of steel through the lone pair of oxygen atoms. Electrochemical Impedance Spectroscopy (EIS) measurements suggested that the corrosion process of steel in presence of the hydrazino-s-triazine derivatives (TH₃, DMeHT and DHMeT) were being controlled by the charge transfer reaction. Polarization curves indicated that the examined TH₃, DMeHT and DHMeT behaved as mixed type inhibitors. PMID:27258241

  12. pKa modulation of the acid/base catalyst within GH32 and GH68: a role in substrate/inhibitor specificity?

    Directory of Open Access Journals (Sweden)

    Shuguang Yuan

    Full Text Available Glycoside hydrolases of families 32 (GH32 and 68 (GH68 belong to clan GH-J, containing hydrolytic enzymes (sucrose/fructans as donor substrates and fructosyltransferases (sucrose/fructans as donor and acceptor substrates. In GH32 members, some of the sugar substrates can also function as inhibitors, this regulatory aspect further adding to the complexity in enzyme functionalities within this family. Although 3D structural information becomes increasingly available within this clan and huge progress has been made on structure-function relationships, it is not clear why some sugars bind as inhibitors without being catalyzed. Conserved aspartate and glutamate residues are well known to act as nucleophile and acid/bases within this clan. Based on the available 3D structures of enzymes and enzyme-ligand complexes as well as docking simulations, we calculated the pKa of the acid-base before and after substrate binding. The obtained results strongly suggest that most GH-J members show an acid-base catalyst that is not sufficiently protonated before ligand entrance, while the acid-base can be fully protonated when a substrate, but not an inhibitor, enters the catalytic pocket. This provides a new mechanistic insight aiming at understanding the complex substrate and inhibitor specificities observed within the GH-J clan. Moreover, besides the effect of substrate entrance on its own, we strongly suggest that a highly conserved arginine residue (in the RDP motif rather than the previously proposed Tyr motif (not conserved provides the proton to increase the pKa of the acid-base catalyst.

  13. Regional selectivity of a gamma-aminobutyric acid-induced (/sup 3/H)acetylcholine release sensitive to inhibitors of gamma-aminobutyric acid uptake

    Energy Technology Data Exchange (ETDEWEB)

    Bonanno, G.; Raiteri, M.

    1987-05-01

    The effects of gamma-aminobutyric acid (GABA) on the release of (/sup 3/H)acetylcholine ((/sup 3/H)ACh) were studied in synaptosomes prepared from rat hippocampus, cerebral cortex, hypothalamus, and striatum and prelabelled with (/sup 3/H)choline. When synaptosomes were exposed in superfusion to exogenous GABA (0.01-0.3 mM) the basal release of newly synthesized (/sup 3/H)ACh was increased in a concentration-dependent way in hippocampus, cortex, and hypothalamus nerve endings. In contrast, the release of (/sup 3/H)ACh was not significantly affected by GABA in striatal synaptosomes. The effect of GABA was not antagonized significantly by bicuculline or picrotoxin. Muscimol caused only a slight not significant increase of (/sup 3/H)ACh release when tested at 0.3 mM whereas, at this concentration, (-)-baclofen was totally inactive. The GABA-induced release of (/sup 3/H)ACh was counteracted by SKF 89976A, SKF 100561, and SKF 100330A, three strong and selective GABA uptake inhibitors. The data suggest that, in selective areas of the rat brain, GABA causes release of (/sup 3/H)ACh following penetration into cholinergic nerve terminals through a GABA transport system.

  14. Corrosion inhibition of mild steel in acidic solution by Tagetes erecta (Marigold flower) extract as a green inhibitor

    International Nuclear Information System (INIS)

    Highlights: • Tagetes erecta extract is a green corrosion inhibitor for mild steel in 0.5 M H2SO4. • Inhibition efficiency increases with concentration but decreases with temperature. • It acts as a mixed inhibitor. • It inhibits the corrosion through the physical adsorption of Lutein. - Abstract: The extract of Tagetes erecta (Marigold flower) [TEE] has been evaluated as a corrosion inhibitor for mild steel in 0.5 M H2SO4 solution by means of gravimetric, potentiodynamic polarization and electrochemical impedance spectroscopic measurements. Tafel polarization studies reveal that TEE acts as an efficient mixed inhibitor. The adsorption of the inhibitor on the mild steel (MS) surface follows the Langmuir adsorption isotherm, indicating monolayer adsorption. The activation parameters governing adsorption show that the inhibitor is physically adsorbed. The results of quantum chemical calculation indicate high feasibility of adsorption of molecular and protonated Lutein, a major component of TEE

  15. A novel highly potent autotaxin/ENPP2 inhibitor produces prolonged decreases in plasma lysophosphatidic acid formation in vivo and regulates urethral tension.

    Directory of Open Access Journals (Sweden)

    Hiroshi Saga

    Full Text Available Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2, is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation. The IC50 values of ONO-8540506 for lysophospholipase D activity were 6.4-19 nM for recombinant autotaxin/ENPP2 proteins and 4.7-11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration. Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.

  16. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Saleha B Vuyyuri

    Full Text Available Ascorbic acid (AA exhibits significant anticancer activity at pharmacologic doses achievable by parenteral administration that have minimal effects on normal cells. Thus, AA has potential uses as a chemotherapeutic agent alone or in combination with other therapeutics that specifically target cancer-cell metabolism. We compared the effects of AA and combinations of AA with the glycolysis inhibitor 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3-PO on the viability of three non-small cell lung cancer (NSCLC cell lines to the effects on an immortalized lung epithelial cell line. AA concentrations of 0.5 to 5 mM caused a complete loss of viability in all NSCLC lines compared to a <10% loss of viability in the lung epithelial cell line. Combinations of AA and 3-PO synergistically enhanced cell death in all NSCLC cell lines at concentrations well below the IC50 concentrations for each compound alone. A synergistic interaction was not observed in combination treatments of lung epithelial cells and combination treatments that caused a complete loss of viability in NSCLC cells had modest effects on normal lung cell viability and reactive oxygen species (ROS levels. Combination treatments induced dramatically higher ROS levels compared to treatment with AA and 3-PO alone in NSCLC cells and combination-induced cell death was inhibited by addition of catalase to the medium. Analyses of DNA fragmentation, poly (ADP-ribose polymerase cleavage, annexin V-binding, and caspase activity demonstrated that AA-induced cell death is caused via the activation of apoptosis and that the combination treatments caused a synergistic induction of apoptosis. These results demonstrate the effectiveness of AA against NSCLC cells and that combinations of AA with 3-PO synergistically induce apoptosis via a ROS-dependent mechanism. These results support further evaluation of pharmacologic concentrations of AA as an adjuvant treatment for NSCLC and that combination of AA with

  17. 3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties.

    Science.gov (United States)

    Papakyriakou, Athanasios; Zervoudi, Efthalia; Tsoukalidou, Sofia; Mauvais, Francois-Xavier; Sfyroera, Georgia; Mastellos, Dimitrios C; van Endert, Peter; Theodorakis, Emmanuel A; Vourloumis, Dionisios; Stratikos, Efstratios

    2015-02-12

    Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses. PMID:25635706

  18. Characterization of the acidic and basic limbs of a bell-shaped pH profile in the inhibitory activity of bromelain inhibitor VI.

    Science.gov (United States)

    Hatano, Ken-ichi; Sawano, Yoriko; Miyakawa, Takuya; Tanokura, Masaru

    2006-03-01

    Bromelain inhibitor VI (BI-VI) is a cysteine proteinase inhibitor from pineapple stem and a unique two-chain inhibitor composed of two distinct domains. BI-VI's inhibitory activity toward the target enzyme bromelain is maximal at pH 4 and shows a bell-shaped pH profile with pKa values of about 2.5 and 5.3. This pH profile is quite different from that of bromelain, which is optimally active around pH 7. In the present article, to characterize the acidic limb, we first expressed the recombinant inhibitors designed to lose two putative hydrogen bonds of Ser7(NH)-Asp28(beta-CO2H) and Lys38(NH)-Asp51(beta-CO2H) and confirmed the existence of the hydrogen bonds by two-dimensional nuclear magnetic resonance (NMR). Moreover, it was revealed that these hydrogen bonds are not the essential electrostatic factor and some ionizable groups would be responsible for the acidic limb in the pH-inhibition profile. On the other hand, to characterize the basic limb, we examined the pH-dependent inhibition using the cysteine proteinase papain, some of whose properties differ from those of bromelain, and compared the data with the corresponding data for bromelain. The result suggests that the basic limb would be affected by some electrostatic factors, probably some carboxyl groups in the target proteinase.

  19. 10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of DYRK1A.

    Science.gov (United States)

    Falke, Hannes; Chaikuad, Apirat; Becker, Anja; Loaëc, Nadège; Lozach, Olivier; Abu Jhaisha, Samira; Becker, Walter; Jones, Peter G; Preu, Lutz; Baumann, Knut; Knapp, Stefan; Meijer, Laurent; Kunick, Conrad

    2015-04-01

    The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PMID:25730262

  20. Effects of inhibitors of protein synthesis and intracellular transport on the gamma-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, Gert Helge; Meier, E;

    1990-01-01

    The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological differenti......The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological...... of membranes for [3H]GABA binding assays. In some experiments the functional activity of the newly induced low-affinity GABA receptors was assessed by investigation of the ability of GABA to inhibit neurotransmitter release from the neurons. These experiments were performed to differentiate between...

  1. Discovery of a New Class of Sortase A Transpeptidase Inhibitors to Tackle Gram-Positive Pathogens: 2-(2-Phenylhydrazinylidenealkanoic Acids and Related Derivatives

    Directory of Open Access Journals (Sweden)

    Benedetta Maggio

    2016-02-01

    Full Text Available 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-phenylhydrazinylidenebutanoate 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-(3,4dichlorophenylhydrazinylidenebutanoic 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.

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

    Science.gov (United States)

    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

  3. Inhibition mechanism analysis & research of the poly aspartic acid corrosion inhibitor%聚天冬氨酸缓蚀剂缓蚀机理分析研究

    Institute of Scientific and Technical Information of China (English)

    王娴

    2012-01-01

    文中介绍了聚天冬氨酸缓蚀剂缓蚀机理,并对聚天冬氨酸缓蚀剂机理的研究现状以及发展趋势进行了综述。%It was introduced inhibition mechanism of the poly aspartic acid corrosion inhibitor. Mean- while, it was summarizeed the research progress of the inhibition meehanismf the poly aspartic acid cor- rosion inhibitor and the development trend of the poly aspartic acid corrosion inhibitor in this article.

  4. Glycyrrhetinic acid and its derivatives as inhibitors of poly(ADP-ribose)polymerases 1 and 2, apurinic/apyrimidinic endonuclease 1 and DNA polymerase β

    OpenAIRE

    Salakhutdinov N. F.; Schreiber V.; Khodyreva S. N.; Ilina E. S.; Kutuzov M. M.; Sukhanova M. V.; Salomatina O. V.; Zakharenko A. L.; Lavrik O. I.

    2012-01-01

    Aim. For strengthening the efficiency of monofunctional alkylating antineoplastic drugs it is important to lower the capacity of base excision repair (BER) system which corrects the majority of DNA damages caused by these reagents. The objective was to create inhibitors of the key BER enzymes (PARP1, PARP2, DNA polymerase β, and APE1) by the directed modification of glycyrrhetinic acid (GA). Methods. Amides of GA were produced from the GA acetate by formation of the corresponding acyl chlorid...

  5. Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine

    OpenAIRE

    Brunkhorst, R.; Friedlaender, F.; Ferreirós, N.; Schwalm, S.; Koch, A.; Grammatikos, G.; Toennes, S.; Foerch, C; Pfeilschifter, J.; Pfeilschifter, W.

    2015-01-01

    Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown ther...

  6. Effect of lignocellulose-derived inhibitors on the growth and D-lactic acid production of Sporolactobacillus inulinus YBS1-5.

    Science.gov (United States)

    Bai, Zhongzhong; Gao, Zhen; He, Bingfang; Wu, Bin

    2015-10-01

    The impact of lignocellulose-derived inhibitors on the cell growth and D-lactic production of Sporolactobacillus inulinus YBS1-5 was investigated. At high concentrations, both furans and phenolics, such as furfural, HMF, syringaldehyde and vanillin, affected cell growth and D-lactic acid production and syringaldehyde exhibited the highest. Further experiments showed that only vanillin caused cellular membrane damage. Based on the Biolog approach, in vivo studies on intact S. inulinus cells indicated that phenolics had a stronger inhibitory effect than furan derivatives on the metabolic activity of the concerned substrates related with the key enzymes of D-lactic acid fermentation. The direct in vitro inhibitory effect of the model compounds on the four key enzymes displayed similar patterns. Syringaldehyde was the strongest inhibitor. In general, comparison with published results for other microorganisms indicated that strain YBS1-5 was a robust microorganism against inhibitors of lignocellulose hydrolysate. Notably, in concentrated corn stover hydrolysate, S. inulinus YBS1-5 produced 70.7 g/L D-lactic acid, which was 87.7 % of the yield from the control experiment. However, the fermentation time was prolonged 36 h. In order to improve fermentation rate, a detoxification technology or more robust mutant to phenolics especially syringaldehyde should be developed. PMID:26216317

  7. Isolation of 4,5-O-Dicaffeoylquinic Acid as a Pigmentation Inhibitor Occurring in Artemisia capillaris Thunberg and Its Validation In Vivo

    Directory of Open Access Journals (Sweden)

    Nadia Tabassum

    2016-01-01

    Full Text Available There is a continual need to develop novel and effective melanogenesis inhibitors for the prevention of hyperpigmentation disorders. The plant Artemisia capillaris Thunberg (Oriental Wormwood was screened for antipigmentation activity using murine cultured cells (B16-F10 malignant melanocytes. Activity-based fractionation using HPLC and NMR analyses identified the compound 4,5-O-dicaffeoylquinic acid as an active component in this plant. 4,5-O-Dicaffeoylquinic acid significantly reduced melanin synthesis and tyrosinase activity in a dose-dependent manner in the melanocytes. In addition, 4,5-O-dicaffeoylquinic acid treatment reduced the expression of tyrosinase-related protein-1. Significantly, we could validate the antipigmentation activity of this compound in vivo, using a zebrafish model. Moreover, 4,5-O-dicaffeoylquinic acid did not show toxicity in this animal model. Our discovery of 4,5-O-dicaffeoylquinic acid as an inhibitor of pigmentation that is active in vivo shows that this compound can be developed as an active component for formulations to treat pigmentation disorders.

  8. Isolation of 4,5-O-Dicaffeoylquinic Acid as a Pigmentation Inhibitor Occurring in Artemisia capillaris Thunberg and Its Validation In Vivo.

    Science.gov (United States)

    Tabassum, Nadia; Lee, Ji-Hyung; Yim, Soon-Ho; Batkhuu, Galzad Javzan; Jung, Da-Woon; Williams, Darren R

    2016-01-01

    There is a continual need to develop novel and effective melanogenesis inhibitors for the prevention of hyperpigmentation disorders. The plant Artemisia capillaris Thunberg (Oriental Wormwood) was screened for antipigmentation activity using murine cultured cells (B16-F10 malignant melanocytes). Activity-based fractionation using HPLC and NMR analyses identified the compound 4,5-O-dicaffeoylquinic acid as an active component in this plant. 4,5-O-Dicaffeoylquinic acid significantly reduced melanin synthesis and tyrosinase activity in a dose-dependent manner in the melanocytes. In addition, 4,5-O-dicaffeoylquinic acid treatment reduced the expression of tyrosinase-related protein-1. Significantly, we could validate the antipigmentation activity of this compound in vivo, using a zebrafish model. Moreover, 4,5-O-dicaffeoylquinic acid did not show toxicity in this animal model. Our discovery of 4,5-O-dicaffeoylquinic acid as an inhibitor of pigmentation that is active in vivo shows that this compound can be developed as an active component for formulations to treat pigmentation disorders. PMID:27528883

  9. A new insight into resource recovery of excess sewage sludge: feasibility of extracting mixed amino acids as an environment-friendly corrosion inhibitor for industrial pickling.

    Science.gov (United States)

    Su, Wen; Tang, Bing; Fu, Fenglian; Huang, Shaosong; Zhao, Shiyuan; Bin, Liying; Ding, Jiewei; Chen, Cuiqun

    2014-08-30

    The work mainly presented a laboratory-scale investigation on an effective process to extract a value-added product from municipal excess sludge. The functional groups in the hydrolysate were characterized with Fourier transform infrared spectrum, and the contained amino acids were measured by means of an automatic amino acid analyzer. The corrosion-inhibition characteristics of the hydrolysate were determined with weight-loss measurement, electrochemical polarization and scanning electron microscopy. Results indicated that the hydrolysate contained 15 kinds of amino acid, and their adsorption on the surface could effectively inhibit the corrosion reaction of the steel from the acid medium. Polarization curves indicated that the obtained hydrolysate was a mixed-type inhibitor, but mainly restricted metal dissolution on the anode. The adsorption accorded well with the Langmuir adsorption isotherm, involved an increase in entropy, and was a spontaneous, exothermic process. PMID:25036999

  10. Characterization of inhibitory effects of the potential therapeutic inhibitors, benzoic acid and pyridine derivatives, on the monophenolase and diphenolase activities of tyrosinase

    Directory of Open Access Journals (Sweden)

    Nematollah Gheibi

    2015-02-01

    Full Text Available Objective(s:Involvement of tyrosinase in the synthesis of melanin and cell signaling pathway has made it an attractive target in the search for therapeutic inhibitors for treatment of different skin hyperpigmentation disorders and melanoma cancers. Materials and Methods: In the present study, we conducted a comprehensive kinetic analysis to understand the mechanisms of inhibition imposed by 2-amino benzoic acid, 4-amino benzoic acid, nicotinic acid, and picolinic acid on the monophenolase and diphenolase activities of the mushroom tyrosinase, and then MTT assay was exploited to evaluate their toxicity on the melanoma cells. Results: Kinetic analysis revealed that nicotinic acid and picolinic acid competitively restricted the monophenolase activity with inhibition constants (Ki of 1.21 mM and 1.97 mM and the diphenolase activity with Kis of 2.4 mM and 2.93 mM, respectively. 2-aminobenzoic acid and 4-aminobenzoic acid inhibited the monophenolase activity in a non-competitive fashion with Kis of 5.15 µM and 3.8 µM and the diphenolase activity with Kis of 4.72 µM and 20 µM, respectively. Conclusion: Our cell-based data revealed that only the pyridine derivatives imposed cytotoxicity in melanoma cells. Importantly, the concentrations of the inhibitors leading to 50% decrease in the cell density (IC50 werecomparable to those causing 50% drop in the enzyme activity, implying that the observed cytotoxicity is highly likely due to the tyrosinase inhibition. Moreover, our cell-based data exhibited that the pyridine derivatives acted as anti-proliferative agents, perhaps inducing cytotoxicity in the melanoma cells through inhibition of the tyrosinase activities.

  11. Magnetic catechol-chitosan with bioinspired adhesive surface: preparation and immobilization of ω-transaminase.

    Directory of Open Access Journals (Sweden)

    Kefeng Ni

    Full Text Available The magnetic chitosan nanocomposites have been studied intensively and been used practically in various biomedical and biological applications including enzyme immobilization. However, the loading capacity and the remained activity of immobilized enzyme based on existing approaches are not satisfied. Simpler and more effective immobilization strategies are needed. Here we report a simple catechol modified protocol for preparing a novel catechol-chitosan (CCS-iron oxide nanoparticles (IONPs composites carrying adhesive moieties with strong surface affinity. The ω-transaminase (ω-TA was immobilized onto this magnetic composite via nucleophilic reactions between catechol and ω-TA. Under optimal conditions, 87.5% of the available ω-TA was immobilized on the composite, yielding an enzyme loading capacity as high as 681.7 mg/g. Furthermore, the valuation of enzyme activity showed that ω-TA immobilized on CCS-IONPs displayed enhanced pH and thermal stability compared to free enzyme. Importantly, the immobilized ω-TA retained more than 50% of its initial activity after 15 repeated reaction cycles using magnetic separation and 61.5% of its initial activity after storage at 4°C in phosphate buffered saline (PBS for 15 days. The results suggested that such adhesive magnetic composites may provide an improved platform technology for bio-macromolecules immobilized.

  12. Experimental and theoretical evaluation of two pyridinecarboxaldehyde thiosemicarbazone compounds as corrosion inhibitors for mild steel in hydrochloric acid solution

    International Nuclear Information System (INIS)

    Highlights: •The studied inhibitors contain both pyridine ring and Schiff’s base structure. •The inhibitors show good inhibitive properties for mild steel in HCl. •The inhibitors adsorb on mild steel surface both physically and chemically. •The PZC measurements show the mild steel surface was positively charged. -- Abstract: The inhibition effect of two Schiff’s base derivatives on the corrosion of mild steel in 1.0 M HCl solution was studied by electrochemical techniques, SEM and theoretical calculation methods. The experimental results show that the inhibition efficiency of 2-pyridinecarboxaldehyde thiosemicarbazone (2-PCT) is higher than that of 4-pyridinecarboxaldehyde thiosemicarbazone (4-PCT), and both the two compounds are good inhibitors for mild steel in 1.0 M HCl. Potentiodynamic polarization curves show that the two inhibitors act as mixed type inhibitors. The adsorption of inhibitors obeys the Langmuir adsorption isotherm, and the thermodynamic parameters (Ea, Kads, ΔGads0) were calculated and discussed. The mechanism of inhibition was determined by PZC measurements and theoretical calculation methods

  13. Experimental and theoretical studies on some amino acids and their potential activity as inhibitors for the corrosion of mild steel, part 2

    Directory of Open Access Journals (Sweden)

    Nnabuk O. Eddy

    2011-01-01

    Full Text Available Substituent constants and quantum chemical parameters were calculated from PM6, PM3, AM1, RM1 and MNDO. Hamiltonians were used to predict the corrosion inhibition potential of nine amino acids grouped under three skeletons. Skeleton I consisted of cysteine (CYS, serine (SER and amino butyric acid (ABU. Those in skeleton II included threonine (THR, alanine (ALA and valine (VAL while those in skeleton III are aromatic amino acids, which included phenylalanine (PHE, tryptophan (TRP and tyrosine (TYR. Trends obtained from substituent constants were not entirely useful in predicting the corrosion inhibition potentials of the studied amino acids. However, the results obtained from quantum chemical parameters indicated that the trends for the variation of corrosion inhibition potentials of the studied amino acids in skeletons I, II and III are CYS > SER > ABU, THR > ALA > VAL and TRP > TYR > PHE, respectively. Highest values of inhibition efficiency were obtained for inhibitors in skeleton III and are attributed to the presence of aromatic ring in the molecule while the corrosion inhibition potential of inhibitors in skeletons I and II are attributed to the presence of –SH and –OH functional groups, respectively. Analysis of data obtained from relative nucleophilicity/electrophilicity, condensed Fukui and softness functions indicated that the sites for electrophilic attacks for the amino acids in skeletons I and II are in the amine bonds but for those in skeleton III the sites were in their respective phenyl ring. The author proposed that quantum chemical parameters may be used to predict the corrosion inhibition potentials of amino acids.

  14. Effects of the protonation state in the interaction of an HIV-1 reverse transcriptase (RT) amino acid, Lys101, and a non nucleoside RT inhibitor, GW420867X.

    Science.gov (United States)

    Galembeck, Sérgio E; Bickelhaupt, F Matthias; Fonseca Guerra, Célia; Galembeck, Eduardo

    2014-07-01

    Interactions between an inhibitor and amino acids from a binding pocket could help not only to understand the nature of these interactions, but also to support the design of new inhibitors. In this paper, we explore the key interaction between a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI), GW420867X, and HIV-1 RT amino acid Lys101 (K101), by quantum mechanical methods. The neutral, protonated, and zwitterionic complexes of GW420867X-K101 were studied. The interaction energies were determined by SCS-MP2/def2-cc-pVQZ, and the electron density was analyzed by natural bond orbital (NBO), atoms in molecules (AIM) and reduced gradient analysis. A large increase in the interaction was observed with the tautomerization of neutral or neutral protonated species. The monomers interact by two medium-strength hydrogen bonds, one partially covalent and another noncovalent. There are some van der Waals intramolecular interactions that are topologically unstable. The nature of the intermolecular interactions was also analyzed using quantitative molecular orbital (MO) theory in combination with an energy decomposition analysis (EDA) based on dispersion-corrected density functional theory (DFT) at BLYP-D/TZ2P. PMID:24965933

  15. Radiation-induced enzyme efflux from rat heart: sedentary animals. [Gamma radiation, lactate dehydrogenase, creative kinase, glutamate oxaloacetate transaminase

    Energy Technology Data Exchange (ETDEWEB)

    MacWilliam, L.D.; Bhakthan, N.M.G.

    1976-01-01

    Serum levels of lactate dehydrogenase, creatine kinase, and glutamate oxaloacetate transaminase show initial elevations within 12 hr of exposure to 2,000 rads of ..gamma..-radiation to the thoracic region of rats. Significant decreases in heart muscle homogenate levels of these enzymes parallel initial elevations in the serum and may suggest that enhanced leakage of enzymes is a consequence of radiation injury to heart muscle. Insignificant alterations in mitochondrial glutamate oxaloacetate transaminase levels after exposure indicate that in vivo injury to the mitochondria from therapeutic levels of ..gamma..-radiation is questionable. The results support the contention that ionizing radiation instigates alterations in the dynamic permeability of membranes, allowing leakage of biologically active material out of the injured cell.

  16. A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Krauze, Andra V. [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States); Myrehaug, Sten D. [Department of Radiation Oncology, Lakeridge Health Durham Regional Cancer Centre, Oshawa, Ontario (Canada); Chang, Michael G.; Holdford, Diane J. [Massey Cancer Center Virginia Commonwealth University, Richmond, Virginia (United States); Smith, Sharon; Shih, Joanna; Tofilon, Philip J. [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States); Fine, Howard A. [New York University Langone Medical Center, New York, New York (United States); Camphausen, Kevin, E-mail: camphauk@mail.nih.gov [Radiation Oncology Branch, National Cancer Institute/National Institutes of Health, Bethesda, Maryland (United States)

    2015-08-01

    Purpose: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. Methods and Materials: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). Results: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. Conclusions: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

  17. Histone deacetylase inhibitor, 2-propylpentanoic acid, increases the chemosensitivity and radiosensitivity of human glioma cell lines in vitro

    Institute of Scientific and Technical Information of China (English)

    SHAO Cui-jie; WU Ming-wei; CHEN Fu-rong; LI Cong; XIA Yun-fei; CHEN Zhong-ping

    2012-01-01

    Background Treatment for malignant glioma generally consists of cytoreductive surgery followed by radiotherapy and chemotherapy.In this study,we intended to investigate the effects of 2-propylpentanoic acid (VPA),a histone deacetylase inhibitor,on chemosensitivity and radiosensitivity in human glioma cell lines.Methods Human glioma cell lines,T98-G,and SF295,were treated with temozolomide (TMZ) or irradiation (IR),with or without VPA (1.0 mmol/L).Then,cytotoxicity and clonogenic survival assay was performed.Cell cycle stage,apoptosis,and autophagy were also detected using flow cytometry and dansyl monocadaverin (MDC) incorporation assay.One-way analysis of variance (ANOVA) and t-test were used to analyze the differences among variant groups.Results Mild cytotoxicity of VPA was revealed in both cell lines,T98-G and SF295,with the 50% inhibiting concentration (IC50) value of (3.85±0.58) mmol/L and (2.15±0.38) mmol/L,respectively; while the IC50 value of TMZ was (0.20±0.09) mmol/L for T98-G and (0.08±0.02) mmol/L for SF295.Moreover,if combined with VPA (1.0 mmol/L) for 96hours,the sensitivity of glioma cells to TMZ was significant increased (P <0.05).The surviving fractions at 2 Gy (SF2) of T98-G and SF295 cells exposed to IR alone were 0.52 and 0.58.However,when VPA was combined with IR,the SF2 of T98-G and SF295 dropped to 0.39 (P=0.047) and 0.49 (P=-0.049),respectively.Treatment with VPA plus TMZ or IR also resulted in a significant decrease in the proportion of cells in the G2 phase and increased apoptotic rates as well as autophagy in T98-G and SF295 cell lines (P <0.01).Conclusion VPA may enhance the activities of TMZ and IR on glioma cells possibly through cell cycle block and promote autophagy,and thus could be a potential sensitizer of glioma treatment.

  18. Profile of hemogram and transaminases in dengue-suspected patients at a first-aid health unit

    Directory of Open Access Journals (Sweden)

    Érica Maria da Silva

    2015-04-01

    Full Text Available Current retrospective analysis describes the laboratorial profile of patients hypothetically diagnosed with dengue at a First-Aid Health Unit in Recife, Pernambuco State, Brazil. Results of hemograms were assessed by counting platelets and transaminase dosages, in the first half of 2012. Further, 394 patients (252 females or 64% and 142 males or 34% were listed, mostly during March and April. Hemograms with platelet counting was undertaken with 210 patients (53.3% and hemogram plus transaminases dosages with 184 patients (46.7%. Thrombocytopenia, neutropenia and atypical lymphocytes occurred in both genders. Hematocrits were highest in males and transaminases were more altered in females. Patients attended at the health unit with clinical symptoms of classical dengue had a laboratory profile of non-specific exams which is a feature of infection by the dengue virus. Diagnosis could not be confirmed and the need of a fast test in the health unit services was mandatory. The above avoids dengue cases not being notified and treated or overestimated.

  19. Inhibitors from Carob (Ceratonia siliqua L.): II. Effect on Growth Induced by Indoleacetic Acid or Gibberellins A(1), A(4), A(5), and A(7).

    Science.gov (United States)

    Corcoran, M R

    1970-10-01

    Two inhibitory fractions (B(1) and C) from extracts of immature fruit of carob were tested for their ability to inhibit the action of indoleacetic acid (IAA) in three bioassays. There was no reduction of IAA-induced reactions in the Avena curvature test, abscission of debladed coleus petioles, or growth of cucumber hypocotyls. The highest ratio of inhibitor to IAA was 10,000 times greater than the ratio necessary to inhibit by 50% the growth caused by an equivalent amount of gibberellin A(3) in pea seedlings. At the highest concentration used, fraction C alone caused curvature of Avena coleoptiles. The inhibitory fractions appeared to enhance the effect of IAA in the cucumber test.Concentrated whole extract and fractions B(1) and C were tested for reduction of growth caused by gibberellins A(1), A(4), A(5), A(7), and a neutral gibberellin-like substance from beans in the dwarf-5 maize bioassay. Each gibberellin was inhibited and required the same amount of inhibitor for a 50% reduction of the induced growth. The inhibiting effect could be completely overcome by increasing the amount of gibberellin while maintaining the same concentration of inhibitor. Fractions B(1) and C were also tested with gibberellins A(2) and A(4) in the cucumber hypocotyl test. Both inhibitory fractions reduced growth but were more effective against gibberellin A(3) than gibberellin A(4) in the assay. The ability to reduce gibberellin-induced growth and not reduce IAA-induced growth indicates that the inhibitors from carob have a greater specificity of action than that previously reported for any inhibitor.

  20. A randomised feasibility study of EPA and Cox-2 inhibitor (Celebrex versus EPA, Cox-2 inhibitor (Celebrex, Resistance Training followed by ingestion of essential amino acids high in leucine in NSCLC cachectic patients - ACCeRT Study

    Directory of Open Access Journals (Sweden)

    Rogers Elaine S

    2011-11-01

    Full Text Available Abstract Background Cancer cachexia is a syndrome of progressive weight loss. Non-small cell lung cancer patients experience a high incidence of cachexia of 61%. Research into methods to combat cancer cachexia in various tumour sites has recently progressed to the combination of agents. The combination of the anti-cachectic agent Eicosapentaenoic acid (EPA and the cyclo-oxygenase-2 (COX-2 inhibitor celecoxib has been tested in a small study with some benefit. The use of progressive resistance training (PRT followed by the oral ingestion of essential amino acids (EAA, have shown to be anabolic on skeletal muscle and acceptable in older adults and other cancer groups. The aim of this feasibility study is to evaluate whether a multi-targeted approach encompassing a resistance training and nutritional supplementation element is acceptable for lung cancer patients experiencing cancer cachexia. Methods/Design Auckland's Cancer Cachexia evaluating Resistance Training (ACCeRT is an open label, prospective, randomised controlled feasibility study with two parallel arms. All patients will be treated with EPA and the COX-2 inhibitor celecoxib on an outpatient basis at the study site. In the experimental group patients will participate in PRT twice a week, followed by the ingestion of essential amino acids high in leucine. A total of 21 patients are planned to be enrolled. Patients will be randomised using 1:2 ratio with 7 patients enrolled into the control arm, and 14 patients into the treatment arm. The primary endpoint is the acceptability of the above multi-targeted approach, determined by an acceptability questionnaire. Discussion To our knowledge ACCeRT offers for the first time the opportunity to investigate the effect of stimulating the anabolic skeletal muscle pathway with the use of PRT along with EAA alongside the combination of EPA and celecoxib in this population. Trial registration Netherlands Trial Register (NTR: ACTRN12611000870954

  1. Characterisation of (R-2-(2-Fluorobiphenyl-4-yl-N-(3-Methylpyridin-2-ylPropanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor.

    Directory of Open Access Journals (Sweden)

    Sandra Gouveia-Figueira

    Full Text Available Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH and substrate selective cyclooxygenase (COX-2 inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl-N-(3-methylpyridin-2-ylpropanamide (Flu-AM1. These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known.COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon γ- stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manner, with IC50 values in the absence of a preincubation phase of: (R-Flu-AM1, COX-1 (arachidonic acid 6 μM; COX-2 (arachidonic acid 20 μM; COX-2 (2-AG 1 μM; (S-Flu-AM1, COX-1 (arachidonic acid 3 μM; COX-2 (arachidonic acid 10 μM; COX-2 (2-AG 0.7 μM. The compounds showed no enantiomeric selectivity in their FAAH inhibitory properties. (R-Flu-AM1 (10 μM greatly inhibited the production of prostaglandin D2 and E2 in both unstimulated and lipopolysaccharide + interferon γ- stimulated RAW 264.7 macrophage cells. Levels of 2-AG were not affected either by (R-Flu-AM1 or by 10 μM flurbiprofen, either alone or in combination with the FAAH inhibitor URB597 (1 μM.Both enantiomers of Flu-AM1 are more potent inhibitors of 2-AG compared to arachidonic acid oxygenation by COX-2. Inhibition of COX in lipopolysaccharide + interferon γ- stimulated RAW 264.7 cells is insufficient to affect 2-AG levels despite the large induction of COX-2 produced by this treatment.

  2. A new insight into resource recovery of excess sewage sludge: Feasibility of extracting mixed amino acids as an environment-friendly corrosion inhibitor for industrial pickling

    Energy Technology Data Exchange (ETDEWEB)

    Su, Wen; Tang, Bing, E-mail: renytang@163.com; Fu, Fenglian; Huang, Shaosong; Zhao, Shiyuan; Bin, Liying; Ding, Jiewei; Chen, Cuiqun

    2014-08-30

    Graphical abstract: - Highlights: • A value-added product was extracted from the municipal excess sludge. • The effective components contained in the product were mixed amino acids. • The product could provide a reliable protection to the steel from the acid medium. • A new insight into the resource recovery of excess sewage sludge was provided. - Abstract: The work mainly presented a laboratory-scale investigation on an effective process to extract a value-added product from municipal excess sludge. The functional groups in the hydrolysate were characterized with Fourier transform infrared spectrum, and the contained amino acids were measured by means of an automatic amino acid analyzer. The corrosion-inhibition characteristics of the hydrolysate were determined with weight-loss measurement, electrochemical polarization and scanning electron microscopy. Results indicated that the hydrolysate contained 15 kinds of amino acid, and their adsorption on the surface could effectively inhibit the corrosion reaction of the steel from the acid medium. Polarization curves indicated that the obtained hydrolysate was a mixed-type inhibitor, but mainly restricted metal dissolution on the anode. The adsorption accorded well with the Langmuir adsorption isotherm, involved an increase in entropy, and was a spontaneous, exothermic process.

  3. A new insight into resource recovery of excess sewage sludge: Feasibility of extracting mixed amino acids as an environment-friendly corrosion inhibitor for industrial pickling

    International Nuclear Information System (INIS)

    Graphical abstract: - Highlights: • A value-added product was extracted from the municipal excess sludge. • The effective components contained in the product were mixed amino acids. • The product could provide a reliable protection to the steel from the acid medium. • A new insight into the resource recovery of excess sewage sludge was provided. - Abstract: The work mainly presented a laboratory-scale investigation on an effective process to extract a value-added product from municipal excess sludge. The functional groups in the hydrolysate were characterized with Fourier transform infrared spectrum, and the contained amino acids were measured by means of an automatic amino acid analyzer. The corrosion-inhibition characteristics of the hydrolysate were determined with weight-loss measurement, electrochemical polarization and scanning electron microscopy. Results indicated that the hydrolysate contained 15 kinds of amino acid, and their adsorption on the surface could effectively inhibit the corrosion reaction of the steel from the acid medium. Polarization curves indicated that the obtained hydrolysate was a mixed-type inhibitor, but mainly restricted metal dissolution on the anode. The adsorption accorded well with the Langmuir adsorption isotherm, involved an increase in entropy, and was a spontaneous, exothermic process

  4. Design, synthesis, and evaluation of 2 beta-alkenyl penam sulfone acids as inhibitors of beta-lactamases.

    Science.gov (United States)

    Richter, H G; Angehrn, P; Hubschwerlen, C; Kania, M; Page, M G; Specklin, J L; Winkler, F K

    1996-09-13

    A general method for synthesis of 2 beta-alkenyl penam sulfones has been developed. The new compounds inhibited most of the common types of beta-lactamase. The level of activity depended very strongly on the nature of the substituent in the 2 beta-alkenyl group. The inhibited species formed with the beta-lactamase from Citrobacter freundii 1205 was sufficiently stable for X-ray crystallographic studies. These, together with UV absorption spectroscopy and studies of chemical degradation, suggested a novel reaction mechanism for the new inhibitors that might account for their broad spectrum of action. The (Z)-2 beta-acrylonitrile penam sulfone Ro 48-1220 was the most active inhibitor from this class of compound. The inhibitor enhanced the action of, for example, ceftriaxone against a broad selection of organisms producing beta-lactamases. The organisms included strains of Enterobacteriaceae that produce cephalosporinases, which is an exceptional activity for penam sulfones.

  5. Performance evaluation of pectin as ecofriendly corrosion inhibitor for X60 pipeline steel in acid medium: experimental and theoretical approaches.

    Science.gov (United States)

    Umoren, Saviour A; Obot, Ime B; Madhankumar, A; Gasem, Zuhair M

    2015-06-25

    The corrosion inhibition effect of pectin (a biopolymer) for X60 pipeline steel in HCl medium was investigated using weight loss, electrochemical, water contact angle measurements, and scanning electron microscopy techniques. The results obtained show that pectin acts as a good corrosion inhibitor for X60 steel. Inhibition efficiency increased with increase in pectin concentration and temperature. Potentiodynamic polarization results reveal that pectin could be classified as a mixed-type corrosion inhibitor with predominant control of the cathodic reaction. The effective corrosion inhibition potential of pectin could be related to the adsorption of pectin molecules at the metal/solution interface which is found to accord with the Langmuir adsorption isotherm model and a protective film formation. Quantum chemical calculations provided insights into the active sites and reactivity parameters governing pectin activity as a good corrosion inhibitor for X60 steel.

  6. Isolation of linoleic and alpha-linolenic acids as COX-1 and -2 inhibitors in rose hip

    DEFF Research Database (Denmark)

    Jäger, Anna; Petersen, K N; Thomasen, G.;

    2008-01-01

    /2 activity-guided. The bioassay-guided fractionation led to the isolation of linoleic acid (the IC50 for COX-1 was 85 microm and 0.6 microM for COX-2) and alpha-linolenic acid (the IC50 for COX-1 was 52 microM and 12 microM for COX-2). The COX-2/COX-1 ratio was 0.007 for linoleic acid and 0.2 for alpha......-linolenic acid. Linoleic acid and alpha-linolenic acid contribute to the COX-1 and -2 inhibitory activity of rose hip....

  7. Aminooxy-naphthylpropionic acid and its derivatives are inhibitors of auxin biosynthesis targeting l-tryptophan aminotransferase: structure-activity relationships.

    Science.gov (United States)

    Narukawa-Nara, Megumi; Nakamura, Ayako; Kikuzato, Ko; Kakei, Yusuke; Sato, Akiko; Mitani, Yuka; Yamasaki-Kokudo, Yumiko; Ishii, Takahiro; Hayashi, Ken-Ichiro; Asami, Tadao; Ogura, Takehiko; Yoshida, Shigeo; Fujioka, Shozo; Kamakura, Takashi; Kawatsu, Tsutomu; Tachikawa, Masanori; Soeno, Kazuo; Shimada, Yukihisa

    2016-08-01

    We previously reported l-α-aminooxy-phenylpropionic acid (AOPP) to be an inhibitor of auxin biosynthesis, but its precise molecular target was not identified. In this study we found that AOPP targets TRYPTOPHAN AMINOTRANSFERASE of ARABIDOPSIS 1 (TAA1). We then synthesized 14 novel compounds derived from AOPP to study the structure-activity relationships of TAA1 inhibitors in vitro. The aminooxy and carboxy groups of the compounds were essential for inhibition of TAA1 in vitro. Docking simulation analysis revealed that the inhibitory activity of the compounds was correlated with their binding energy with TAA1. These active compounds reduced the endogenous indole-3-acetic acid (IAA) content upon application to Arabidopsis seedlings. Among the compounds, we selected 2-(aminooxy)-3-(naphthalen-2-yl)propanoic acid (KOK1169/AONP) and analyzed its activities in vitro and in vivo. Arabidopsis seedlings treated with KOK1169 showed typical auxin-deficient phenotypes, which were reversed by exogenous IAA. In vitro and in vivo experiments indicated that KOK1169 is more specific for TAA1 than other enzymes, such as phenylalanine ammonia-lyase. We further tested 41 novel compounds with aminooxy and carboxy groups to which we added protection groups to increase their calculated hydrophobicity. Most of these compounds decreased the endogenous auxin level to a greater degree than the original compounds, and resulted in a maximum reduction of about 90% in the endogenous IAA level in Arabidopsis seedlings. We conclude that the newly developed compounds constitute a class of inhibitors of TAA1. We designated them 'pyruvamine'. PMID:27147230

  8. Continuation of medically necessary platelet aggregation inhibitors - acetylsalicylic acid and clopidogrel - during surgery for spinal degenerative disorders: Results in 100 patients

    Directory of Open Access Journals (Sweden)

    Reza Akhavan-Sigari

    2014-01-01

    Full Text Available Background: Patients undergoing spinal surgery while under anticoagulation therapy are at risk of developing bleeding complications, even though lower incidences have been reported for joint arthroplasty surgery. There is a gap in the medical literature examining the incidence of postoperative spinal bleeding in patients who were under anticoagulation medication at the time of surgery. Methods: We prospectively followed a consecutive cohort of 100 patients (58 male, 42 female undergoing spinal surgery. The average patient age was 48.7 years and the minimum follow up time was 12 months. Diagnosis was lumbar spinal stenosis in 20, herniated lumbar discs in 63, degenerative cervical disc disease in 3, and cervical disc herniation in 14 cases. In our study, platelet aggregation inhibitors (clopidogrel and/or acetylsalicylic acid were given for the treatment of cardiovascular and cerebrovascular thrombotic events, to reduce risk of stroke in patients who have had transient ischemia of the brain or acute coronary syndrome, and as secondary prevention of atherosclerotic events (fatal or nonfatal myocardial infarction (MI. A cessation of anticoagulants (acetylsalicylic acid or clopidogrel in our patients in the peri- and postoperative period was contraindicated. Results: Sixty-three patients were on both clopidogrel and acetylsalicylic acid and 37 on acetylsalicylic acid only. None of the patients suffered any postoperative bleeding complication. Three patients suffered postoperative wound dehiscence and one patient had an infection that required reoperation. Conclusion: The question of whether preoperative platelet aggregation inhibitors must be stopped before elective spinal surgery has never been answered in the literature. In our prospective series, we have found no increase in the risk of postoperative spinal bleeding with the use of clopidogrel or acetylsalicylic acid. This finding suggests that spine surgery can be done without stopping

  9. Impact of nitrification inhibitor with organic manure and urea on nitrogen dynamics and N2O emission in acid sulphate soil

    OpenAIRE

    Shordar Mohamed Shamsuzzaman; Mohamed Musa Hanafi Hanafi; Abd Wahid Samsuri; Soud Mohd Halimi; Masuda Begum; Jantan Nur Maisarah

    2016-01-01

    ABSTRACT The accurate prediction of N transformation is an important requisite for optimizing N use efficiency in cropping systems. An incubation study was conducted to verify the impacts of nitrification inhibitor (NI) with organic manure (OM) and urea on N dynamics and N2O emission in acid sulphate soil. The conducted experiment was two-level factorial with 4 N sources (N1 = 100% of N from urea, N2 = 75% of N from urea + 25% N from rice straw, N3 = 75% of N from urea + 25% of N from cow dun...

  10. Myrsinoic A acid and its derivative: in vitro inhibitors of photosynthesis; Acido myrsinoico A e derivado: inibidores da fotossintese in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Burger, Marcela Carmen de M.; Oliveira, Gracielle S. de; Menezes, Antonio Carlos S. [Universidade Estadual de Goias, Anapolis, GO (Brazil). Unidade Universitaria de Ciencias Exatas e Tecnologicas; Vieira, Paulo Cezar; Silva, Maria Fatima das G.F. da [Universidade Federal de Sao Carlos (UFSCar), SP (Brazil). Dept. de Quimica; Veiga, Thiago A.M., E-mail: tveiga@unifesp.br [Universidade Federal de Sao Paulo (UNIFESP), SP (Brazil). Inst. de Ciencias Ambientais, Quimicas e Farmaceuticas. Dept. de Ciencias Exatas e da Terra

    2012-07-01

    Myrsinoic A acid, isolated from Myrsine cuneifolia and its hydrogenated derivative had their effect on photosynthesis tested. The compounds inhibited the electron flow (basal, phosphorylating and uncoupled) from water to methyl viologen; therefore, they act as Hill reaction inhibitors in spinach thylakoids. They inhibited partial reactions of PSII electron flow from water to 2,5-dichloro-1,4-benzoquinone, from water to sodium silicomolybdate, and partially electron flow from diphenylcarbazide to 2,6-dichloroindophenol. Their inhibition sites were at the donor and acceptor sides of PSII, between P{sub 680} and Q{sub A}. Chlorophyll {alpha} fluorescence measurements confirmed the behavior of the compounds (pool of quinones). (author)

  11. Thermodynamic characterization of metal dissolution and inhibitor adsorption processes in the low carbon steel/mimosa tannin/sulfuric acid system

    Science.gov (United States)

    Martinez, Sanja; Stern, Ivica

    2002-10-01

    The corrosion rates in the presence of mimosa tannin as a low carbon steel corrosion inhibitor in sulfuric acid media, were measured by the weight loss method, in the range of temperatures from 20 to 60 °C. The Temkin, Frumkin and Freundlich isotherms were tested for their fit to the experimental data. The free energies and enthalpies for the adsorption process and the apparent activation energies, enthalpies and entropies of the dissolution process were determined. The fundamental thermodynamic functions were used to glean important information about the mimosa tannin inhibitory behavior. The results were explained in terms of chemical thermodynamics.

  12. Structural analysis and mutant growth properties reveal distinctive enzymatic and cellular roles for the three major L-alanine transaminases of Escherichia coli.

    Science.gov (United States)

    Peña-Soler, Esther; Fernandez, Francisco J; López-Estepa, Miguel; Garces, Fernando; Richardson, Andrew J; Quintana, Juan F; Rudd, Kenneth E; Coll, Miquel; Vega, M Cristina

    2014-01-01

    In order to maintain proper cellular function, the metabolism of the bacterial microbiota presents several mechanisms oriented to keep a correctly balanced amino acid pool. Central components of these mechanisms are enzymes with alanine transaminase activity, pyridoxal 5'-phosphate-dependent enzymes that interconvert alanine and pyruvate, thereby allowing the precise control of alanine and glutamate concentrations, two of the most abundant amino acids in the cellular amino acid pool. Here we report the 2.11-Å crystal structure of full-length AlaA from the model organism Escherichia coli, a major bacterial alanine aminotransferase, and compare its overall structure and active site composition with detailed atomic models of two other bacterial enzymes capable of catalyzing this reaction in vivo, AlaC and valine-pyruvate aminotransferase (AvtA). Apart from a narrow entry channel to the active site, a feature of this new crystal structure is the role of an active site loop that closes in upon binding of substrate-mimicking molecules, and which has only been previously reported in a plant enzyme. Comparison of the available structures indicates that beyond superficial differences, alanine aminotransferases of diverse phylogenetic origins share a universal reaction mechanism that depends on an array of highly conserved amino acid residues and is similarly regulated by various unrelated motifs. Despite this unifying mechanism and regulation, growth competition experiments demonstrate that AlaA, AlaC and AvtA are not freely exchangeable in vivo, suggesting that their functional repertoire is not completely redundant thus providing an explanation for their independent evolutionary conservation.

  13. A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Hermit, M B; Nielsen, B;

    2000-01-01

    We have studied the pharmacological effects of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and the enantiomers of (RS)-2-amino-3-(3-hydroxy-1,2, 5-thiadiazol-4-yl)propionic acid (TDPA) on cloned human excitatory amino acid transporter subtypes 1, 2 and 3 (EAAT1-3) expres...

  14. Field evaluation of a prototype paper-based point-of-care fingerstick transaminase test.

    Directory of Open Access Journals (Sweden)

    Nira R Pollock

    Full Text Available Monitoring for drug-induced liver injury (DILI via serial transaminase measurements in patients on potentially hepatotoxic medications (e.g., for HIV and tuberculosis is routine in resource-rich nations, but often unavailable in resource-limited settings. Towards enabling universal access to affordable point-of-care (POC screening for DILI, we have performed the first field evaluation of a paper-based, microfluidic fingerstick test for rapid, semi-quantitative, visual measurement of blood alanine aminotransferase (ALT. Our objectives were to assess operational feasibility, inter-operator variability, lot variability, device failure rate, and accuracy, to inform device modification for further field testing. The paper-based ALT test was performed at POC on fingerstick samples from 600 outpatients receiving HIV treatment in Vietnam. Results, read independently by two clinic nurses, were compared with gold-standard automated (Roche Cobas results from venipuncture samples obtained in parallel. Two device lots were used sequentially. We demonstrated high inter-operator agreement, with 96.3% (95% C.I., 94.3-97.7% agreement in placing visual results into clinically-defined "bins" (5x upper limit of normal, >90% agreement in validity determination, and intraclass correlation coefficient of 0.89 (95% C.I., 0.87-0.91. Lot variability was observed in % invalids due to hemolysis (21.1% for Lot 1, 1.6% for Lot 2 and correlated with lots of incorporated plasma separation membranes. Invalid rates <1% were observed for all other device controls. Overall bin placement accuracy for the two readers was 84% (84.3%/83.6%. Our findings of extremely high inter-operator agreement for visual reading-obtained in a target clinical environment, as performed by local practitioners-indicate that the device operation and reading process is feasible and reproducible. Bin placement accuracy and lot-to-lot variability data identified specific targets for device optimization and

  15. β-Secretase inhibitor increases amyloid-β precursor protein level in rat brain cortical primary neurons induced by okadaic acid

    Institute of Scientific and Technical Information of China (English)

    YU Chun-Jiang; WANG Wei-zhi; LIU Wei

    2008-01-01

    Background Senile plaques and neurofibrillary tangles (NFTs) represent two of the major histopathological hallmarks of Alzheimer's disease (AD). The plaques are primarily composed of aggregated amyloid β (Aβ) peptides. The processing of amyloid-β precursor protein (AβPP) in okadaic acid (OA)-induced tau phosphorylation primary neurons was studied.Methods Primary cultures of rat brain cortical neurons were treated with OA and β-secretase inhibitor. Neurons' viability was measured. AβPP processing was examined by immunocytochemistry and Western blotting with specific antibodies against the AβPP-N-terminus (NT) and AβPP-C-terminus (CT).Results Ten nrnol/L OA had a time-dependent suppression effect on primary neurons' viability. The suppression effect was alleviated markedly by pretreatment with β-secretase inhibitor. After OA treatment, both AβPP and β-C-terminal fragment (βCTF) were significantly increased in neurons. AβPP level was increased further in neurons pretreated with β-secretase inhibitor.Conclusions In OA-induced tau phosphorylation cell model, inhibition of β-secretase may protect neurons from death induced by OA. Because of increased accumulation of AβPP in neurons after OA treatment, more AβPP turns to be cleaved by β-secretase, producing neurotoxic βCTF. As a potential effective therapeutic target, β-secretase is worth investigating further.

  16. Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

    Energy Technology Data Exchange (ETDEWEB)

    Tabackman, Alexa A.; Frankson, Rochelle; Marsan, Eric S.; Perry, Kay; Cole, Kathryn E. (Ithaca); (Cornell)

    2016-10-17

    Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.

  17. Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor.

    Science.gov (United States)

    Adeniji, Adegoke; Uddin, Md Jashim; Zang, Tianzhu; Tamae, Daniel; Wangtrakuldee, Phumvadee; Marnett, Lawrence J; Penning, Trevor M

    2016-08-25

    Type 5 17β-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Δ(4)-androstene-3,17-dione and 5α-androstane-3,17-dione to testosterone (T) and 5α-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R-profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease.

  18. Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Toshihisa Ishikawa

    2011-09-01

    Full Text Available Photodynamic diagnosis (PDD is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP-binding cassette (ABC transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new approach of quantitative structure-activity relationship (QSAR analysis to design potent ABCG2-inhibitors.

  19. A structural insight into the P1S1 binding mode of diaminoethylphosphonic and phosphinic acids, selective inhibitors of alanine aminopeptidases.

    Science.gov (United States)

    Węglarz-Tomczak, Ewelina; Berlicki, Łukasz; Pawełczak, Małgorzata; Nocek, Bogusław; Joachimiak, Andrzej; Mucha, Artur

    2016-07-19

    N'-substituted 1,2-diaminoethylphosphonic acids and 1,2-diaminoethylphosphinic dipeptides were explored to unveil the structural context of the unexpected selectivity of these inhibitors of M1 alanine aminopeptidases (APNs) versus M17 leucine aminopeptidase (LAP). The diaminophosphonic acids were obtained via aziridines in an improved synthetic procedure that was further expanded for the phosphinic pseudodipeptide system. The inhibitory activity, measured for three M1 and one M17 metalloaminopeptidases of different sources (bacterial, human and porcine), revealed several potent compounds (e.g., Ki = 65 nM of 1u for HsAPN). Two structures of an M1 representative (APN from Neisseria meningitidis) in complex with N-benzyl-1,2-diaminoethylphosphonic acid and N-cyclohexyl-1,2-diaminoethylphosphonic acid were determined by the X-ray crystallography. The analysis of these structures and the models of the phosphonic acid complexes of the human ortholog provided an insight into the role of the additional amino group and the hydrophobic substituents of the ligands within the S1 active site region. PMID:27100031

  20. Kunitz trypsin Inhibitor and phytic acid levels in conventional and genetically modified soybean seeds from Londrina and Ponta Grossa, South Brazil

    Directory of Open Access Journals (Sweden)

    Olívio F. Galão

    2014-09-01

    Full Text Available Differences in the levels of antinutritional components - Kunitz trypsin inhibitor and phytic acid - were determined for conventional and genetically modified soybean cultivated in Londrina and Ponta Grossa, South Brazil. Trypsin inhibitor levels in the conventional cultivars of Londrina and Ponta Grossa varied from 14.56 mg g-1 (BRS 267 to 20.40 mg g-1 (BRS 261 and from 13.51 mg g-1 (BRS 232 to 19.65 mg g-1 (BRS 268, respectively, whereas in the genetically modified (GM cultivars, they were found to be 14.16 mg g-1 (BRS 242 RR to 18.21 mg g-1 (BRS 255 RR for Londrina, and 13.68 mg g-1 (BRS 244 RR to 18.73 mg g-1 (BRS 256 RR for Ponta Grossa. Average levels of phytic acid in the Londrina’s conventional and GM samples were estimated as 2.05 and 1.78 mg g-1, respectively, and in the Ponta Grossa conventional and GM samples, the respective average values were lower, 1.60 and 1.51 mg g-1.

  1. Berberine as an Environmental-Friendly Inhibitor for Hot-Dip Coated Steels in Diluted Hydrochloric Acid

    Institute of Scientific and Technical Information of China (English)

    Hong Ju; Yulin Ju; Yan Li

    2012-01-01

    The inhibition effect of an excellent environmental-friendly corrosion inhibitor--berberine on hot-dip coated steels in the diluted HCI has been investigated by using quantum chemistry analysis, mass-loss tests, elec- trochemical measurements and scanning electron microscopy (SEM) observation. Calculation results show that berberine has a nearly planar structure with a number of active centers. The value of Mulliken charge, and the distribution of the highest occupied molecular orbital (HOMO) and the lower unoccupied molecular orbital (LUMO) imply that berberine has a good ability of electron exchange with metal surface. The test results indicate that inhibition efficiency (IE%) increases with the inhibitor concentration and the highest IE can reach 99%. Adsorption of berberine on the coating surface follows Langmuir adsorption isotherm with a single molecular layer by chemisorption.

  2. Theoretical Study of Chloro-N-(4-methoxybenzylideneaniline Derivatives as Corrosion Inhibitors for Zinc in Hydrochloric Acid

    Directory of Open Access Journals (Sweden)

    S. Kumar

    2013-01-01

    Full Text Available The density functional theory (DFT was used to investigate the corrosion inhibition of three inhibitors on zinc. Quantum chemical parameters such as the energy of highest occupied molecular orbital (EHOMO, the energy of lowest unoccupied molecular orbital (ELUMO, energy gap (ΔE, hardness (η, softness (σ, electrophilicity index (ω, the fraction of electrons transferred (ΔN from inhibitor molecule to the metal surface, energy change when both processes occur, namely, charge transfer to the molecule and backdonation from the molecule (ΔEbackdonation, natural charge (qN, and Fukui functions have been calculated by using B3LYP/6-31+G(d basis set. The relation between the inhibition efficiency and quantum chemical parameters has been discussed in order to elucidate the inhibition mechanism of the chloro-N-(4-methoxybenzylideneaniline derivatives.

  3. Acid Mediated Ring Closing Metathesis: A Powerful Synthetic Tool Enabling the Synthesis of Clinical Stage Kinase Inhibitors.

    Science.gov (United States)

    William, Anthony D; Lee, Angeline C-H

    2015-01-01

    The powerful olefin metathesis reaction was employed for the construction of late-phase clinical agents SB1317 and SB1518. In both cases RCM seems to proceed only in the presence of an acid and to predominantly furnish trans isomers. In case of SB1518 it proceeded in the presence of acid HCl, while for SB1317, it mainly proceeds in the presence of TFA (trifluroacetic acid). PMID:26507218

  4. Absorption and Quantum Chemical studies on some DYES as Corrosion Inhibitors on Mild Steel in Acidic Medium / Thabo Peme

    OpenAIRE

    Peme, Thabo

    2014-01-01

    The corrosion inhibition of some selected dyes namely Sunset yellow (SS). Amaranth (AM). Allura red (AR). Tartrazine(TZ) and Fast green (FG) on mild steel in 0.5M HCI was studied at 30-60°C using weight loss, electrochernical and quantum chemical methods. Quantum calculation based on the density functional theory (DFT) was used to investigate the reactivities and selectivities of four (4) of the studied dyes. The effects of inhibitor concentration on the inhibition efficiency h...

  5. Quinoxaline derivatives as corrosion inhibitors for mild steel in hydrochloric acid medium: Electrochemical and quantum chemical studies

    Science.gov (United States)

    Olasunkanmi, Lukman O.; Kabanda, Mwadham M.; Ebenso, Eno E.

    2016-02-01

    The corrosion inhibition potential of four quinoxaline derivatives namely, 1-[3-(4-methylphenyl)-5-(quinoxalin-6-yl)-4,5-dihydropyrazol-1-yl]butan-1-one (Me-4-PQPB), 1-(3-(4-methoxyphenyl)-5-(quinoxalin-6-yl)-4,5-dihydropyrazol-1-yl)butan-1-one (Mt-4-PQPB), 1-[3-(3-methoxyphenyl)-5-(quinoxalin-6-yl)-4,5-dihydropyrazol-1-yl]butan-1-one (Mt-3-PQPB) and 1-[3-(2H-1,3-benzodioxol-5-yl)-5-(quinoxalin-6-yl)-4,5-dihydropyrazol-1-yl]butan-1-one (Oxo-1,3-PQPB) was studied for mild steel corrosion in 1 M HCl solution using electrochemical, spectroscopic techniques and quantum chemical calculations. The results of both potentiodynamic polarization and electrochemical impedance spectroscopic studies revealed that the compounds are mixed-type inhibitors and the order of corrosion inhibition efficiency at 100 ppm is Me-4-PQPB>Mt-3-PQPB>Oxo-1,3-PQPB>Mt-4-PQPB. Fourier transform infrared (FTIR) and ultraviolet-visible (UV-vis) spectroscopic analyses confirmed the presence of chemical interactions between the inhibitors and mild steel surface. The adsorption of the inhibitor molecules on mild steel surface was found to be both physisorption and chemisorption but predominantly chemisorption. The experimental data obey Langmuir adsorption isotherm. Scanning electron microscopy studies revealed the formation of protective films of the inhibitors on mild steel surface. Quantum chemical parameters obtained from density functional theory (DFT) calculations support experimental results.

  6. Electrochemical and quantum chemical studies of some indole derivatives as corrosion inhibitors for C38 steel in molar hydrochloric acid

    Energy Technology Data Exchange (ETDEWEB)

    Lebrini, M. [Laboratoire Materiaux et Molecules en Milieu Amazonien, CNRS 8172-UMR ECOFOG, Campus Trou Biran, Cayenne 97337, French Guiana (France); Robert, F. [Laboratoire Materiaux et Molecules en Milieu Amazonien, UAG-UMR ECOFOG, Campus Trou Biran, Cayenne 97337, French Guiana (France); Vezin, H. [Laboratoire de Chimie Organique et Macromoleculaire, UMR-CNRS 8009, USTL BatC4 F-59655 Villeneuve d' Ascq Cedex (France); Roos, C., E-mail: christophe.roos@guyane.univ-ag.f [Laboratoire Materiaux et Molecules en Milieu Amazonien, UAG-UMR ECOFOG, Campus Trou Biran, Cayenne 97337, French Guiana (France)

    2010-10-15

    A comparative study of 9H-pyrido[3,4-b]indole (norharmane) and 1-methyl-9H-pyrido[3,4-b]indole (harmane) as inhibitors for C38 steel corrosion in 1 M HCl solution at 25 {sup o}C was carried out. Potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques were applied to study the metal corrosion behavior in the absence and presence of different concentrations of these inhibitors. The OCP as a function of time were also established. Cathodic and anodic polarization curves show that norharmane and harmane are a mixed-type inhibitors. Adsorption of indole derivatives on the C38 steel surface, in 1 M HCl solution, follows the Langmuir adsorption isotherm model. The {Delta}G{sub ads}{sup o} values were calculated and discussed. The potential of zero charge (PZC) of the C38 steel in inhibited solution was studied by the EIS method, and a mechanism for the adsorption process was proposed. Raman spectroscopy confirmed that indole molecules strongly adsorbed onto the steel surface. The electronic properties of indole derivates, obtained using the AM1 semi-empirical quantum chemical approach, were correlated with their experimental efficiencies using the linear resistance model (LR).

  7. Calcium ionophore (A-23187 induced peritoneal eicosanoid biosynthesis: a rapid method to evaluate inhibitors of arachidonic acid metabolism in vivo

    Directory of Open Access Journals (Sweden)

    T. S. Rao

    1993-01-01

    Full Text Available The present investigation characterizes calcium ionophore (A-23187 induced peritoneal eicosanoid biosynthesis in the rat. Intraperitoneal injection of A-23187 (20 μg/rat stimulated marked biosynthesis of 6-keto-PGF1α (6-KPA, TxB2, LTC4 and LTB4, with no detectable changes on levels of PGE2. Levels of all eicosanoids decreased rapidly after a peak which was seen as early as 5 min. Enzyme markers of cellular contents of neutrophils and mononuclear cells, MPO and NAG respectively, decreased rapidly after ionophore injection; this was followed by increases after 60 min. Indomethacin, a selective cyclooxygenase inhibitor, and zileuton and ICI D-2138, two selective 5-lipoxygenase inhibitors attenuated prostaglandin and leukotriene pathways respectively. Oral administration of zileuton (20 mg/kg, p.o. inhibited LTB4 biosynthesis for up to 6 h suggesting a long duration of pharmacological activity in the rats consistent with its longer half-life. The rapid onset and the magnitude of increases in levels of eicosanoids render the ionophore induced peritoneal eicosanoid biosynthesis a useful model to evaluate pharmacological profiles of inhibitors of eicosanoid pathways in vivo.

  8. Identification of gamma-aminobutyric acid and its binding sites in Caenorhabditis elegans

    Energy Technology Data Exchange (ETDEWEB)

    Schaeffer, J.M.; Bergstrom, A.R.

    1988-01-01

    Gamma-aminobutyric acid (GABA), glutamate decarboxylase and GABA-transaminase were identified in the nematode Caenorhabditis elegans. The concentration of GABA in C. elegans is approximately 10-fold lower than the concentration of GABA in rat brain. Glutamate decarboxylase and GABA-transaminase, the GABA anabolic and catabolic enzymes, are also present in C. elegans. Crude membrane fractions were prepared from C. elegans and used to study specific (/sup 3/H) GABA binding sites. GABA binds to C. elegans membranes with high affinity and low capacity. Muscimol is a competitive inhibitor of specific GABA binding with a K/sub I/ value of 120 nM. None of the other GABA agonists or antagonists inhibited greater than 40% of the specific GABA binding at concentrations up to 10/sup -4/M. Thirteen spider venoms were examined as possible GABA agonists or antagonists, the venom from Calilena agelenidae inhibits specific GABA binding with a K/sub I/ value of 6 nl/ml. These results suggest that GABA has a physiological role as a neurotransmitter in C. elegans.

  9. Design, synthesis and biological evaluation of novel L-ascorbic acid-conjugated pentacyclic triterpene derivatives as potential influenza virus entry inhibitors.

    Science.gov (United States)

    Wang, Han; Xu, Renyang; Shi, Yongying; Si, Longlong; Jiao, Pingxuan; Fan, Zibo; Han, Xu; Wu, Xingyu; Zhou, Xiaoshu; Yu, Fei; Zhang, Yongmin; Zhang, Liangren; Zhang, Lihe; Zhou, Demin; Xiao, Sulong

    2016-03-01

    Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two pentacyclic triterpene derivatives (Q8 and Y3) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of pentacyclic triterpenes and l-ascorbic acid in mind, we synthesized a series of novel l-ascorbic acid-conjugated pentacyclic triterpene derivatives (18-26, 29-31, 35-40 and 42-43). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid-betulinic acid conjugate (30) showed the most significant anti-influenza activity with an EC50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30, and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of KD = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l-ascorbic acid-conjugated pentacyclic triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target. PMID:26866456

  10. Adaptation and transcriptome analysis of Aureobasidium pullulans in corncob hydrolysate for increased inhibitor tolerance to malic acid production.

    Directory of Open Access Journals (Sweden)

    Xiang Zou

    Full Text Available Malic acid is a dicarboxylic acid widely used in the food industry, and is also a potential C4 platform chemical. Corncob is a low-cost renewable feedstock from agricultural industry. However, side-reaction products (furfural, 5-hydroxymethylfurfural (HMF, formic acid, and acetic acid that severely hinder fermentation are formed during corncob pretreatment. The process for producing malic acid from a hydrolysate of corncob was investigated with a polymalic acid (PMA-producing Aureobasidium pullulans strain. Under the optimal hydrolysate sugar concentration 110 g/L, A. pullulans was further adapted in an aerobic fibrous bed bioreactor (AFBB by gradually increasing the sugar concentration of hydrolysate. After nine batches of fermentation, the production and productivity of malic acid reached 38.6 g/L and 0.4 g/L h, respectively, which was higher than that in the first batch (27.6 g/L and 0.29 g/L h, respectively. The adapted strain could grow under the stress of 0.5 g/L furfural, 3 g/L HMF, 2g/L acetic acid, and 0.5 g/L formic acid, whereas the wild type did not. Transcriptome analysis revealed that the differentially expressed genes were related to carbohydrate transport and metabolism, lipid transport and metabolism, signal transduction mechanism, redox metabolism, and energy production and conversion under 0.5 g/L furfural and 3 g/L HMF stress conditions. In total, 42 genes in the adapted strain were upregulated by 15-fold or more, and qRT-PCR also confirmed that the expression levels of key genes (i.e. SIR, GSS, CYS, and GSR involved in sulfur assimilation pathway were upregulated by over 10-fold in adapted strain for cellular protection against oxidative stress.

  11. Aqueous Extract of Kalmegh (Andrographis paniculata) Leaves as Green Inhibitor for Mild Steel in Hydrochloric Acid Solution

    OpenAIRE

    Ambrish Singh; Singh, V. K.; M.A. Quraishi

    2010-01-01

    The inhibition of the corrosion of mild steel in hydrochloric acid solution by the extract of Kalmegh (Andrographis paniculata) leaves extract has been studied using weight loss, electrochemical impedance spectroscopy, linear polarization, and potentiodynamic polarization techniques. Inhibition was found to increase with increasing concentration of the extract. The effect of temperature, immersion time, and acid concentration on the corrosion behavior of mild steel in 1 M HCl with addition of...

  12. Evaluation of antibacterial and antiviral activity of N-arylamides of 9-methyl and 9-methoxyphenazine-1-carboxylic acidsinhibitors of the phage T7 model transctiption

    Directory of Open Access Journals (Sweden)

    Hovorun D. M.

    2012-12-01

    Full Text Available Aim. Search for compounds with antibacterial and antiviral properties among N-arylamides of 9-substituted phenazine-1-carboxylic acids (PCA, inhibitors of the RNA synthesis. Methods. Influence of N-aryl-amides on the RNA synthesis was tested in vitro in the model system of the DNA-dependent RNA polymerase of phage T7 (T7 RNAP. Antimicrobial activities of the N-arylamides against bacteria Erysipelothrix rhusiopathiae VR-2 var. IVM, Klebsiella spp. and Escherichia coli ATCC25922 were investigated by the method of two-fold dilution in a liquid medium. Antiviral effects against Bovine Viral Diarrhea Virus (BVDV and cytotoxicity of the N-arylamides were evaluated using Madin-Darby bovine kidney (MDBK cells. Results. Twenty N-arylamides appeared to be efficacious inhibitors of the RNA synthesis at concent- rations of 0.48–61 µМ. The compound 16 proved to be the most effective inhibitor of T7 RNAP with the IC50 value being 0.48 µМ. Fourteen N-arylamides demonstrated antibacterial properties against gram positive and gram negative bacteria at the 0.1–10 µg/ml concentrations. A number of the N-arylamides revealed a multiplicity of their antimicrobial actions: 7 compounds against two bacteria and two compounds, 2 and 3, against three bacteria investigated. N-arylamides 16 and 26 showed high inhibitory activity as to BVDV with the IC50 values 0.43 and 0.88 µg/ml and SI values 160 and 10 correspondingly. Conclusions. The obtained data evidence that the most likely targets of the N-arylamides 9-substituted PCA in bacteria and viruses are their RNA synthesizing complexes.

  13. New Inducible Nitric Oxide Synthase and Cyclooxygenase-2 Inhibitors, Nalidixic Acid Linked to Isatin Schiff Bases via Certain l-Amino Acid Bridges

    Directory of Open Access Journals (Sweden)

    Ahmed M. Naglah

    2016-04-01

    Full Text Available A series of new Schiff bases were synthesized by condensation of isatins with the nalidixic acid-l-amino acid hydrazides. Prior to hydrazide formation, a peptide linkage has been prepared via coupling of nalidixic acid with appropriate l-amino acid methyl esters to yield 3a–c. The chemical structures of the new Schiff bases (5b and 5d–h were confirmed by means of IR, NMR, mass spectroscopic, and elemental analyses. The anti-inflammatory activity of these Schiff bases was evaluated via measurement of the expressed inducible nitric oxide synthase (iNOS and cyclooxygenase-2 (COX-2 in the lipopolysaccharide (LPS-stimulated RAW264.7 macrophage cells model. The Schiff bases exhibited significant dual inhibitory effect against the induction of the pro-inflammatory iNOS and COX-2 proteins with variable potencies. However, they strongly down-regulated the iNOS expression to the level of 16.5% ± 7.4%–42.2% ± 19.6% compared to the effect on COX-2 expression (<56.4% ± 3.1% inhibition at the same concentration (10 μM. The higher iNOS inhibition activity of the tested Schiff bases, relative to that of COX-2, seems to be a reflection of the combined suppressive effects exerted by their nalidixic acid, isatins (4a–c, and l-amino acid moieties against iNOS expression. These synthesized nalidixic acid-l-amino acid-isatin conjugates can be regarded as a novel class of anti-inflammatory antibacterial agents.

  14. Structures of Human Cyctochrome P450 2E1: Insights Into the Binding of Inhibitors And Both Small Molecular Weight And Fatty Acid Substrates

    Energy Technology Data Exchange (ETDEWEB)

    Porubsky, P.R.; Meneely, K.M.; Scott, E.E.

    2009-05-21

    Human microsomal cytochrome P-450 2E1 (CYP2E1) monooxygenates >70 low molecular weight xenobiotic compounds, as well as much larger endogenous fatty acid signaling molecules such as arachidonic acid. In the process, CYP2E1 can generate toxic or carcinogenic compounds, as occurs with acetaminophen overdose, nitrosamines in cigarette smoke, and reactive oxygen species from uncoupled catalysis. Thus, the diverse roles that CYP2E1 has in normal physiology, toxicity, and drug metabolism are related to its ability to metabolize diverse classes of ligands, but the structural basis for this was previously unknown. Structures of human CYP2E1 have been solved to 2.2 {angstrom} for an indazole complex and 2.6 {angstrom} for a 4-methylpyrazole complex. Both inhibitors bind to the heme iron and hydrogen bond to Thr{sup 303} within the active site. Complementing its small molecular weight substrates, the hydrophobic CYP2E1 active site is the smallest yet observed for a human cytochrome P-450. The CYP2E1 active site also has two adjacent voids: one enclosed above the I helix and the other forming a channel to the protein surface. Minor repositioning of the Phe{sup 478} aromatic ring that separates the active site and access channel would allow the carboxylate of fatty acid substrates to interact with conserved {sup 216}QXXNN{sup 220} residues in the access channel while positioning the hydrocarbon terminus in the active site, consistent with experimentally observed {omega}-1 hydroxylation of saturated fatty acids. Thus, these structures provide insights into the ability of CYP2E1 to effectively bind and metabolize both small molecule substrates and fatty acids.

  15. Elevated transaminases as a predictor of coma in a patient with anorexia nervosa: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Yoshida Shuhei

    2010-09-01

    Full Text Available Abstract Introduction Liver injury is a frequent complication associated with anorexia nervosa, and steatosis of the liver is thought to be the major underlying pathology. However, acute hepatic failure with transaminase levels over 1000 IU/mL and deep coma are very rare complications and the mechanism of pathogenesis is largely unknown. Case presentation A 37-year-old Japanese woman showed features of acute liver failure and hepatic coma which were not associated with hypoglycemia or hyper-ammonemia. Our patient's consciousness was significantly improved with the recovery of liver function and normalization of transaminase levels after administration of nutritional support. Conclusions Our case report demonstrates that transaminase levels had an inverse relationship with the consciousness of our patient, although the pathogenesis of coma remains largely unknown. This indicates that transaminase levels can be one of the key predictors of impending coma in patients with anorexia nervosa. Therefore, frequent monitoring of transaminase levels combined with rigorous treatment of the underlying nutritional deficiency and psychiatric disorder are necessary to prevent this severe complication.

  16. ASPARTATE TRANSAMINASE - IS IT USEFUL AS A BIOCHEMICAL MARKER AND AS A PREDICTOR OF SEVERITY OF PREGNANCY-INDUCED HYPERTENSION AND ITS COMPLICATION

    Directory of Open Access Journals (Sweden)

    Rupinder

    2016-03-01

    Full Text Available OBJECTIVES To compare serum Aspartate Transaminase of normotensive pregnant women with those of pre-eclamptic and eclamptic women. To determine the relationship of levels of serum Aspartate Transaminase with severity of pregnancy-induced hypertension and its complications. METHOD The study was carried out on pregnant hypertensive patients attending Outpatient Department of Obstetrics and Gynaecology Department, AMCH Dibrugarh, Assam from 1 st July 2013 to 30 th June 2014. Normotensive pregnant women were taken as controls. Each serum sample from the control group as well as study group was estimated for Aspartate Transaminase using standard methods, and a comparison is drawn and analysed using t-test and chi-square test. RESULTS Serum Aspartate Transaminase levels were high in the study group. The levels of this enzyme were normal in the control group. CONCLUSION Aspartate Transaminase levels in patients suffering from preeclampsia and its complications are consistently higher compared to the normotensive pregnant patients. To determine the usefulness of inclusion of this enzyme along with other cardiac enzymes in the panel of investigations of pregnant women universally needs further large scale comparative studies.

  17. Synthesis and Performance of Mannich Base Quaternary Ammonium Salt Acidizing Corrosion Inhibitor%曼尼希碱季铵盐酸化缓蚀剂的合成及性能

    Institute of Scientific and Technical Information of China (English)

    赵顺强; 孙永涛; 马增华; 付朝阳

    2014-01-01

    合成了一种新型的曼尼希碱季铵盐(BMQA)酸化缓蚀剂,通过静态失重法测试了缓蚀剂在不同浓度盐酸中的缓蚀性能。结果表明,90℃下,缓蚀剂 BMQA 在15%盐酸中加入0.1%,18%盐酸中加入0.2%,28%盐酸中加入0.5%,N80钢的腐蚀速率都能小于4 g·m-2·h-1。极化曲线测试表明该缓蚀剂是抑制阳极为主的混合型缓蚀剂,遵循 Langmuir 吸附等温式,能自发在金属表面进行化学吸附。%A new type of Mannich base quaternary ammonium salt was synthesized as an acidification corrosion inhibitor.The inhibition performance of this corrosion inhibitor was evaluated in hydrochloric acid with different concentrations by static weight loss method.The results showed that with 0.1% inhibitor in 15% hydrochloric acid, 0.2% inhibitor in 18% hydrochloric acid and 0.5% inhibitor in 28% hydrochloric acid,the corrosion rates of steel N80 were all lower than 4 g·m-2 ·h-1 at 90℃.Polarization curves indicate that the corrosion inhibitor is a mixed inhibitor but mainly prohibits the anodic corrosion process,obeys the Langmuir adsorption isothermal equation and can spontaneously absorb on the steel surface by chemisorption.

  18. Alkanediyl-α, ω-bis (dimethyl cetylammonium bromide gemini surfactants as novel corrosion inhibitors for mild steel in formic acid

    Directory of Open Access Journals (Sweden)

    Mohammad Mobin

    2012-12-01

    Full Text Available Gemini surfactants, butanediyl 1,4-bis(dimethyl cetylammonium bromide, pentanediyl 1,5 - bis (dimethyl cetylammonium bromide and hexanediyl 1,6 - bis (dimethyl cetylammonium bromide from Alkanediyl-α, ω-bis (dimethyl cetylammonium bromide series were synthesized in laboratory and were characterized by using Nuclear Magnetic Resonance (NMR spectroscopy. The surfactants were tested as corrosion inhibitors for mild steel in 20% formic acid. The influence of surfactants on mild steel corrosion inhibition was investigated by measuring the corrosion rate of mild steel in their absence and presence by weight loss measurements, solvent analysis of iron ions into the test solution and potentiodynamic polarization measurements. The surface morphology of the corroded steel samples in presence and absence of surfactants was evaluated by using Scanning Electron Microscopy (SEM. The synthesized gemini surfactants performed as excellent corrosion inhibitor, the inhibition efficiency (IE being in the range of 76.66-97.41%. The IE of surfactants is slightly affected by the spacer length. The IE increased with increase in surfactant concentration and temperature. The adsorption of gemini surfactants on the steel surface was found to obey Langmuir adsorption isotherm. The results of the potentiodynamic polarization studies are consistent with the results of weight loss studies.

  19. DFT theoretical study of 7-R-3methylquinoxalin-2(1H)-thiones (R=H; CH3; Cl) as corrosion inhibitors in hydrochloric acid

    International Nuclear Information System (INIS)

    Highlights: ► A theoretical study of three quinoxaline derivatives. ► We try to explain their experimental mild steel corrosion inhibition efficiencies. ► The solvent effect was also depicted using the PCM model. ► Most of the global reactivity descriptors agree well with the experimental results. ► The results show that the sulphur atom is probably the main adsorption site. - Abstract: Quantum chemical approach at B3LYP/6-31G(d,p) level of theory, was used to calculate some structural and electronic properties of three quinoxaline derivatives, recently reported as mild steel corrosion inhibitors in acidic media, to ascertain the correlation between their experimental inhibitive efficiencies and some of the computed parameters. The results of most of the global reactivity descriptors show that the experimental and theoretical studies agree well and confirm that Me-Q=S is a better inhibitor than Q=S and Cl-Q=S, respectively. In addition, the local reactivity, analyzed through Fukui functions, show that the sulphur atom will be the main adsorption site.

  20. Raltegravir: first in class HIV integrase inhibitor

    Directory of Open Access Journals (Sweden)

    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  1. Treatment with a histone deacetylase inhibitor, valproic acid, is associated with increased platelet activation in a large animal model of traumatic brain injury and hemorrhagic shock

    DEFF Research Database (Denmark)

    Dekker, Simone E; Sillesen, Martin; Bambakidis, Ted;

    2014-01-01

    BACKGROUND: We have previously shown that resuscitation with fresh frozen plasma (FFP) in a large animal model of traumatic brain injury (TBI) and hemorrhagic shock (HS) decreases the size of the brain lesion, and that addition of a histone deacetylase inhibitor, valproic acid (VPA), provides...... synergistic benefits. In this study, we hypothesized that VPA administration would be associated with a conservation of platelet function as measured by increased platelet activation after resuscitation. MATERIALS AND METHODS: Ten swine (42-50 kg) were subjected to TBI and HS (40% blood loss). Animals were.......05). Circulating transforming growth factor beta levels were elevated in the FFP + VPA group, but this did not reach statistical significance (11.20 ± 1.46 versus 8.09 ± 1.41 ng/mL; P = 0.17). Brain platelet endothelial cell adhesion molecule 1 levels were significantly lower in the FFP + VPA group compared...

  2. In silico modification of Zn2+ binding group of suberoylanilide hydroxamic acid (SAHA) by organoselenium compounds as Homo sapiens class II HDAC inhibitor of cervical cancer

    Science.gov (United States)

    Sumo Friend Tambunan, Usman; Bakri, Ridla; Aditya Parikesit, Arli; Ariyani, Titin; Dyah Puspitasari, Ratih; Kerami, Djati

    2016-02-01

    Cervical cancer is the most common cancer in women, and ranks seventh of all cancers worldwide, with 529000 cases in 2008 and more than 85% cases occur in developing countries. One way to treat this cancer is through the inhibition of HDAC enzymes which play a strategic role in the regulation of gene expression. Suberoyl Anilide Hydroxamic Acid (SAHA) or Vorinostat is a drug which commercially available to treat the cancer, but still has some side effects. This research present in silico SAHA modification in Zinc Binding Group (ZBG) by organoselenium compound to get ligands which less side effect. From molecular docking simulation, and interaction analysis, there are five best ligands, namely CC27, HA27, HB28, IB25, and KA7. These five ligands have better binding affinity than the standards, and also have interaction with Zn2+ cofactor of inhibited HDAC enzymes. This research is expected to produce more potent HDAC inhibitor as novel drug for cervical cancer treatment.

  3. Inhibitors of the Cdc34 acidic loop: A computational investigation integrating molecular dynamics, virtual screening and docking approaches

    Directory of Open Access Journals (Sweden)

    Alberto Arrigoni

    2014-01-01

    Here, we carried out a computational study based on molecular dynamics, virtual screening and docking to identify potential inhibitory compounds of Cdc34, modulating the acidic loop conformation. The molecules identified in this study have been designed to act as molecular hinges that can bind the acidic loop in its closed conformation, thus inhibiting the Cdc34-mediated ubiquitination cascade at the ubiquitin-charging step. In particular, we proposed a pharmacophore model featuring two amino groups in the central part of the model and two lateral aromatic chains, which respectively establish electrostatic interactions with the acidic loop (Asp 108 and Glu 109 and a hydrogen bond with Ser 139, which is one of the key residues for Cdc34 activity.

  4. I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles

    Energy Technology Data Exchange (ETDEWEB)

    Anilkumar, Gopinadhan N.; Lesburg, Charles A.; Selyutin, Oleg; Rosenblum, Stuart B.; Zeng, Qingbei; Jiang, Yueheng; Chan, Tin-Yau; Pu, Haiyan; Vaccaro, Henry; Wang, Li; Bennett, Frank; Chen, Kevin X.; Duca, Jose; Gavalas, Stephen; Huang, Yuhua; Pinto, Patrick; Sannigrahi, Mousumi; Velazquez, Francisco; Venkatraman, Srikanth; Vibulbhan, Bancha; Agrawal, Sony; Butkiewicz, Nancy; Feld, Boris; Ferrari, Eric; He, Zhiqing; Jiang, Chuan-kui; Palermo, Robert E.; Mcmonagle, Patricia; Huang, H.-C.; Shih, Neng-Yang; Njoroge, George; Kozlowski, Joseph A. (Merck)

    2012-05-03

    SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC{sub 50} = 0.9 {micro}M, replicon EC{sub 50} > 100 {micro}M) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC{sub 50} = 0.032 {micro}M, replicon EC{sub 50} = 1.4 {micro}M) and 7r (NS5B IC{sub 50} = 0.017 {micro}M, replicon EC{sub 50} = 0.3 {micro}M) with improved enzyme and replicon activity.

  5. 2,5-Bis(4-dimethylaminophenyl)-1,3,4-oxadiazole and 2,5-bis(4-dimethylaminophenyl)-1,3,4-thiadiazole as corrosion inhibitors for mild steel in acidic media

    Energy Technology Data Exchange (ETDEWEB)

    Bentiss, F.; Traisnel, M.; Vezin, H.; Hildebrand, H.F.; Lagrenee, M

    2004-11-01

    2,5-Bis(4-dimethylaminophenyl)-1,3,4-oxadiazole (DAPO) and 2,5-bis(4-dimethylaminophenyl)-1,3,4-thiadiazole (DAPT) have been synthesised and their inhibiting action on the corrosion of mild steel in 1 M HCl and 0.5 M H{sub 2}SO{sub 4} at 30 deg. C has been investigated by various corrosion monitoring techniques. At constant acid concentration, the inhibitor efficiency of both the compounds is found to increase with inhibitor concentration. DAPT is slightly more efficient in 0.5 M H{sub 2}SO{sub 4} than in 1 M HCl whereas DAPO is more efficient in 1 M HCl. Of the two, DAPT appears to be a better inhibitor. Potentiostatic polarisation studies show that both are mixed-type inhibitors in 1 M HCl but cathodic-type in 0.5 M H{sub 2}SO{sub 4}. The inhibitors function through adsorption following Langmuir isotherm in both the acids. The electronic properties of DAPO and DAPT, obtained using the AM1 semi-empirical quantum chemical approach, have been correlated with their experimental inhibition efficiencies using the linear resistance model (LR). These inhibitors are considered as a non-cytotoxic substances.

  6. The DNA replication inhibitor microcin B17 is a forty-three-amino-acid protein containing sixty percent glycine.

    Science.gov (United States)

    Davagnino, J; Herrero, M; Furlong, D; Moreno, F; Kolter, R

    1986-11-01

    Microcin B17 is a low-molecular-weight protein that inhibits DNA replication in a number of enteric bacteria. It is produced by bacterial strains which harbor a 70-kilobase plasmid called pMccB17. Four plasmid genes (named mcbABCD) are required for its production. The product of the mcbA gene was identified by labelling minicells. The mcbA gene product was slightly larger when a mutation in any of the other three production genes was present. This indicates that these genes are involved in processing the primary mcbA product to yield the active molecule. The mcbA gene product predicted from the nucleotide sequence has 69 amino acids including 28 glycine residues. Microcin B17 was extracted from the cells by boiling in 100 mM acetic acid, 1 mM EDTA, and purified to homogeneity in a single step by high-performance liquid chromatography through a C18 column. The N-terminal amino acid sequence and amino acid composition demonstrated that mcbA is the structural gene for microcin B17. The active molecule is a processed product lacking the first 26 N-terminal residues. The 43 remaining residues include 26 glycines. While microcin B17 is an exported protein, the cleaved N-terminal peptide does not have the characteristic properties of a "signal sequence", which suggests that it is secreted by a mechanism different from that used by most secreted proteins of E. coli.

  7. Hops (Humulus lupulus) ß-acid as an inhibitor of caprine rumen hyper-ammonia-producing bacteria in vitro

    Science.gov (United States)

    Antimicrobial plant secondary metabolites increase rumen efficiency and decrease waste products (i.e. ammonia, methane) in some cases. A promising source of bioactive secondary metabolites is the hops plant (Humulus lupulus L.), which produces '-acid, a suite of structurally similar, potent antibact...

  8. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase

    DEFF Research Database (Denmark)

    Petersen, Nikolaj H T; Olsen, Ole D; Groth-Pedersen, Line;

    2013-01-01

    Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destab...

  9. Deoxyiminoalditols from Aldonic Acids - VI. - Preparation of the Four Stereoisomeric 4-Amino-3-hydroxypyrrolidines from Bromodeoxytetronic Acids. Discovery of a New alfa-Mannosidase Inhibitor

    DEFF Research Database (Denmark)

    Lundt, Inge; Limberg, Gerrit; Zavilla, John

    1999-01-01

    A convenient four step synthesis of amino hydroxy pyrrolidines is presented. From the readily available D- and L-tetronic acids the four possible stereoisomeric 4-amino-3-hydroxy pyrrolidines 14, 15, 17 and 19 could be accessed as crystalline compounds, avoiding any chromatographic purification. ...

  10. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy

    DEFF Research Database (Denmark)

    Reimer, Christina; Søndergaard, Bo; Hilsted, Linda;

    2009-01-01

    -controlled trial with 120 healthy volunteers was conducted. Participants were randomized to 12 weeks of placebo or 8 weeks of esomeprazole 40 mg/d followed by 4 weeks with placebo. The Gastrointestinal Symptom Rating Scale (GSRS) was filled out weekly. A score of >2 on 1 of the questions regarding heartburn, acid...... dyspepsia, heartburn, or acid regurgitation in the PPI group was 13 of 59 (22%) at week 10, 13 of 59 (22%) at week 11, and 12 of 58 (21%) at week 12. Corresponding figures in the placebo group were 7% at week 10 (P = .034), 5% at week 11 (P = .013), and 2% at week 12 (P = .001). CONCLUSIONS: PPI therapy...

  11. Synthesis and Preliminary Biological Evaluation of 1,3,5-Triazine Amino Acid Derivatives to Study Their MAO Inhibitors

    Directory of Open Access Journals (Sweden)

    Sherine N. Khattab

    2015-09-01

    Full Text Available Three series of 4,6-dimethoxy-, 4,6-dipiperidino- and 4,6-dimorpholino-1,3,5-triazin-2-yl amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 7, 18, and 25 had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity.

  12. Introducing the Santolina chamaecyparissus Extract as a Suitable Green Inhibitor for 304 Stainless Steel Corrosion in Strong Acidic Medium

    Science.gov (United States)

    Shabani-Nooshabadi, Mehdi; Ghandchi, Maryam-Sadat

    2015-11-01

    The inhibitive action of extract of Santolina chamaecyparissus ( Santolina) as a green inhibitor on corrosion of 304 stainless steel (304 SS) in 6 M HCl solution was investigated by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy techniques, and scanning electron microscopic observations. The results of potentiodynamic polarization studies indicate that the extract shows mixed-type inhibition behavior and inhibition efficiency of 95.5 pct was achieved with the addition of 1.0 g L-1 extract. Impedance curves show that increasing Santolina concentration increases charge transfer resistance and decreases double-layer capacitance. The corrosion rate decreased with increasing concentration of extract and increased with the increase in temperature of the medium. The effect of temperature and related activation parameters was studied. Adsorption of the extract obeyed the Langmuir isotherm model. The negative value of the standard free energy of adsorption in the presence of the extract suggests the spontaneous adsorption of Santolina on 304 stainless steel surface. The inhibition efficiencies obtained from electrochemical tests were in good agreement with those obtained from weight loss measurements.

  13. Association between nasal carriage of Staphylococcus aureus and the human complement cascade activator serine protease C1 inhibitor (C1INH) valine vs. methionine polymorphism at amino acid position 480.

    NARCIS (Netherlands)

    Emonts, M.; Jongh, C.E. de; Houwing-Duistermaat, J.J.; Leeuwen, W.B. van; Groot, R. de; Verbrugh, H.A.; Hermans, P.W.M.; Belkum, A. van

    2007-01-01

    Staphylococcus aureus produces compounds that interfere with complement deposition. We hypothesized that humans have developed countermeasures to staphylococcal complement evasion and we screened for single nucleotide polymorphisms in the serine protease C1 inhibitor (C1INH) gene at amino acid posit

  14. Experimental study of the enhancement effect of aminopeptidase N inhibitor ubenimex on the differentiation induction activity of all-trans-retinoic acid in acute promyeiocytic leukemia cells and its mechanism

    Institute of Scientific and Technical Information of China (English)

    钱习军

    2006-01-01

    Objective To investigate the effect of aminopeptidase N inhibitor ubenimex on differentiation induction of alltrans -retinoic acid (ATRA) in acute promyelocytic leukemia (APL) cells and its mechanism. Methods The expression of CD11b was analyzed by flow cytometry and nitroblue-tetrazolium (NBT) reduction assay was per-

  15. Synchronization by Food Access Modifies the Daily Variations in Expression and Activity of Liver GABA Transaminase

    OpenAIRE

    Dalia De Ita-Pérez; Isabel Méndez; Olivia Vázquez-Martínez; Mónica Villalobos-Leal; Mauricio Díaz-Muñoz

    2014-01-01

    Daytime restricted feeding (DRF) is an experimental protocol that influences the circadian timing system and underlies the expression of a biological clock known as the food entrained oscillator (FEO). Liver is the organ that reacts most rapidly to food restriction by adjusting the functional relationship between the molecular circadian clock and the metabolic networks. γ-Aminobutyric acid (GABA) is a signaling molecule in the liver, and able to modulate the cell cycle and apoptosis. This stu...

  16. Synthesis and Evaluation of Optical 2-Benzyl-5-bromo-4- oxopentanoic Acids as Transition-state Analog Inhibitors against Carboxypeptidase A

    Institute of Scientific and Technical Information of China (English)

    JIN,Jing-Yi; WANG,Shou-Feng; XUAN,Wei; SHENG,Ji-Wen; WANG,Si-Hong; TIAN,Guan-Rong

    2008-01-01

    Both enantiomers of 2-benzyl-5-bromo-4-oxopentanoic acid were prepared utilizing the diazo ketones as the key intermediates. The compounds were assayed for inhibitory activity against carboxypeptidase A (CPA, EC 3.4.17.1). The (R)-form is 260-fold more potent than the corresponding (S)-form. The finding that (R)-form, which belongs to the L-series, is mostly responsible for the inhibitory activity accords with the substrate specificity of CPA.For comparison, both the optical forms of 2-benzyl-4-oxopentanoic acid were also synthesized and evaluated as the inhibitors against CPA. These results reveal that the introduction of a bromo group at the α-position of ketones can significantly enhance the electrophilicity of the carbonyl group. Further molecular docking study suggested that the gem-diol form of the α-bromo ketone, which mimics the transition state in the CPA catalytic process, could chelate the zinc ion in the active site of CPA and thus result in the strong inhibition.

  17. A Styrene-alt-Maleic Acid Copolymer Is an Effective Inhibitor of R5 and X4 Human Immunodeficiency Virus Type 1 Infection

    Directory of Open Access Journals (Sweden)

    Vanessa Pirrone

    2010-01-01

    Full Text Available An alternating copolymer of styrene and maleic acid (alt-PSMA differs from other polyanionic antiviral agents in that the negative charges of alt-PSMA are provided by carboxylic acid groups instead of sulfate or sulfonate moieties. We hypothesized that alt-PSMA would have activity against human immunodeficiency virus type 1 (HIV-1 comparable to other polyanions, such as the related compound, poly(sodium 4-styrene sulfonate (PSS. In assays using cell lines and primary immune cells, alt-PSMA was characterized by low cytotoxicity and effective inhibition of infection by HIV-1 BaL and IIIB as well as clinical isolates of subtypes A, B, and C. In mechanism of action assays, in which each compound was added to cells and subsequently removed prior to HIV-1 infection (“washout” assay, alt-PSMA caused no enhancement of infection, while PSS washout increased infection 70% above control levels. These studies demonstrate that alt-PSMA is an effective HIV-1 inhibitor with properties that warrant further investigation.

  18. A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2.

    Directory of Open Access Journals (Sweden)

    Daniela Annibali

    Full Text Available The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miR-103--restrain ID2 expression by directly targeting the coding sequence and 3' untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.

  19. Biological activities of Zn(II)-S-methyl-cysteine complex as antiradical, inhibitor of acid phosphatase enzyme and in vivo antidepressant effects.

    Science.gov (United States)

    Escudero, Graciela E; Martini, Nancy; Jori, Khalil; Jori, Nadir; Maresca, Nahuel R; Laino, Carlos H; Naso, Luciana G; Williams, Patricia A M; Ferrer, Evelina G

    2016-12-01

    The antidepressant effect of simple Zn(II) salts has been proved in several animal models of depression. In this study, a coordination metal complex of Zn(II) having a sulfur containing ligand is tested as antidepressant for the first time. Forced swimming test method on male Wistar rats shows a decrease in the immobility and an increase in the swimming behavior after treatment with [Zn(S-Met)2] (S-Met=S-methyl-l-cysteine) being more effective and remarkable than ZnCl2. The thiobarbituric acid and the pyranine consumption (hydroxyl and peroxyl radicals, respectively) methods were applied to evaluate the antioxidant activity of S-Met and [Zn(S-Met)2] showing evidence of attenuation of hydroxyl but not peroxyl radicals activities. UV-vis studies on the inhibition of acid phosphatase enzyme (AcP) demonstrated that S-methyl-l-cysteine did not produce any effect but, in contrast, [Zn(S-Met)2] complex behaved as a moderate inhibitor. Finally, bioavailability studies were performed by fluorescence spectroscopy denoting the ability of the albumin to transport the complex.

  20. Synthesis, molecular modeling and biological evaluation of novel 2-allyl amino 4-methyl sulfanyl butyric acid as α-amylase and α-glucosidase inhibitor

    Science.gov (United States)

    Balan, Kannan; Perumal, Perumal; Sundarabaalaji, Narayanan; Palvannan, Thayumanavan

    2015-02-01

    In the present study 2-allyl amino 4-methyl sulfanyl butyric acid (AMSB) was synthesized in good yield. AMSB was characterized by Fourier transforms infrared spectroscopy (FTIR), Nuclear magnetic resonance (NMR) (1H and 13C) and Liquid chromatography mass spectrometry (LCMS). The radical scavenging activity and reducing power assay of AMSB was assessed using 1-1-diphenyl 2-picryl hydrazyl (DPPH), 2,2‧-azino-bis (3-ethyl benzothiazoline-6-sulfonic acid) (ABTS) and ferric ion reducing antioxidant power assay (FRAP) and was found to be 44.1, 34.71 and 41.7 μg/ml respectively. The compound showed effective inhibition against α-amylase and α-glucosidase. AMSB was identified to be a reversible mixed noncompetitive inhibitor of α-amylase and α-glucosidase. The molecular docking study was carried out to evaluate the specific groove binding properties and affords valuable information of AMSB binding mode in the active site of α-glucosidase the study may lead to the which leads to the rational design of new class of antidiabetic drugs targeting α-glucosidase based on AMSB in near future.

  1. Application of Stabilized Silver Nanoparticles as Thin Films as Corrosion Inhibitors for Carbon Steel Alloy in 1 M Hydrochloric Acid

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    Ayman M. Atta

    2013-01-01

    Full Text Available Nanometer scaled materials have attracted tremendous interest as corrosion protective films due to their high ability to form self-assembled films on the metal surfaces. It is well known that the silver nanoparticles have higher reactivity towards aqueous acidic solution. The present work aims to prepare coated silver nanoparticles to protect carbon steel alloys from aqueous acidic corrosive media. In this respect, Ag nanoparticles colloid solutions were produced through reducing AgNO3 separately with trisodium citrate in an aqueous solution or in the presence of stabilizer such as poly(ethylene glycol thiol and poly(vinyl pyrrolidone. The morphology of the modified silver nanoparticles was investigated by TEM and DLS. UV-Vis absorption spectrum was used to study the effect of HCl on the stability of the dispersed silver nanoparticles. The corrosion inhibition efficiency of the poly (ethylene glycolthiol, the self-assembled monolayers of Ag nanoparticles, was determined by polarization method and electrochemical impedance spectroscopy (EIS. Polarization curves indicated that the coated silver poly (ethylene glycolthiol acted as a mixed type inhibitor. The data of inhibition efficiencies obtained measured by polarization measurements are in good agreement with those obtained with electrochemical impedance.

  2. The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

    Science.gov (United States)

    Touré, B Barry; Miller-Moslin, Karen; Yusuff, Naeem; Perez, Lawrence; Doré, Michael; Joud, Carol; Michael, Walter; DiPietro, Lucian; van der Plas, Simon; McEwan, Michael; Lenoir, Francois; Hoe, Madelene; Karki, Rajesh; Springer, Clayton; Sullivan, John; Levine, Kymberly; Fiorilla, Catherine; Xie, Xiaoling; Kulathila, Raviraj; Herlihy, Kara; Porter, Dale; Visser, Michael

    2013-02-14

    Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263. PMID:24900652

  3. Subtle Regulation of Potato Acid Invertase Activity by a Protein Complex of Invertase, Invertase Inhibitor, and SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE.

    Science.gov (United States)

    Lin, Yuan; Liu, Tengfei; Liu, Jun; Liu, Xun; Ou, Yongbin; Zhang, Huiling; Li, Meng; Sonnewald, Uwe; Song, Botao; Xie, Conghua

    2015-08-01

    Slowing down cold-induced sweetening (CIS) of potato (Solanum tuberosum) tubers is of economic importance for the potato industry to ensure high-quality products. The conversion of sucrose to reducing sugars by the acid invertase StvacINV1 is thought to be critical for CIS. Identification of the specific StvacINV1 inhibitor StInvInh2B and the α- and β-subunits of the interacting protein SUCROSE NONFERMENTING1-RELATED PROTEIN KINASE from the wild potato species Solanum berthaultii (SbSnRK1) has led to speculation that invertase activity may be regulated via a posttranslational mechanism that remains to be elucidated. Using bimolecular fluorescence complementation assays, this study confirmed the protein complex by pairwise interactions. In vitro kinase assays and protein phosphorylation analysis revealed that phosphorylation of SbSnRK1α is causal for StvacINV1 activity and that its active form blocks the inhibition of StInvInh2B by SbSnRK1β, whereas its inactive form restores the function of SbSnRK1β that prevents StInvInh2B from repressing StvacINV1. Overexpression of SbSnRK1α in CIS-sensitive potato confirmed that SbSnRK1α has significant effects on acid invertase-associated sucrose degradation. A higher level of SbSnRK1α expression was accompanied by elevated SbSnRK1α phosphorylation, reduced acid invertase activity, a higher sucrose-hexose ratio, and improved chip color. Our results lend new insights into a subtle regulatory mode of invertase activity and provide a novel approach for potato CIS improvement. PMID:26134163

  4. Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

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    C.M. Queiroz

    2008-05-01

    Full Text Available Intrahippocampal administration of kainic acid (KA induces synaptic release of neurotrophins, mainly brain-derived neurotrophic factor, which contributes to the acute neuronal excitation produced by the toxin. Two protein tyrosine kinase inhibitors, herbimycin A and K252a, were administered intracerebroventricularly, in a single dose, to attenuate neurotrophin signaling during the acute effects of KA, and their role in epileptogenesis was evaluated in adult, male Wistar rats weighing 250-300 g. The latency for the first Racine stage V seizure was 90 ± 8 min in saline controls (N = 4 which increased to 369 ± 71 and 322 ± 63 min in animals receiving herbimycin A (1.74 nmol, N = 4 and K252a (10 pmol, N = 4, respectively. Behavioral alterations were accompanied by diminished duration of EEG paroxysms in herbimycin A- and K252a-treated animals. Notwithstanding the reduction in seizure severity, cell death (60-90% of cell loss in KA-treated animals in limbic regions was unchanged by herbimycin A and K252a. However, aberrant mossy fiber sprouting was significantly reduced in the ipsilateral dorsal hippocampus of K252a-treated animals. In this model of temporal lobe epilepsy, both protein kinase inhibitors diminished the acute epileptic activity triggered by KA and the ensuing morphological alterations in the dentate gyrus without diminishing cell loss. Our current data indicating that K252a, but not herbimycin, has an influence over KA-induced mossy fiber sprouting further suggest that protein tyrosine kinase receptors are not the only factors which control this plasticity. Further experiments are necessary to elucidate the exact signaling systems associated with this K252a effect.

  5. Valproic acid inhibits the release of soluble CD40L induced by non-nucleoside reverse transcriptase inhibitors in human immunodeficiency virus infected individuals.

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    Donna C Davidson

    Full Text Available Despite the use of highly active antiretroviral therapies (HAART, a majority of Human Immunodeficiency Virus Type 1 (HIV infected individuals continually develop HIV - Associated Neurocognitive Disorders (HAND, indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistent with this notion, we have previously shown that levels of the inflammatory mediator soluble CD40 ligand (sCD40L are elevated in the plasma and cerebrospinal fluid (CSF of HIV infected, cognitively impaired individuals, and that excess sCD40L can contribute to blood brain barrier (BBB permeability in vivo, thereby signifying the importance of this inflammatory mediator in the pathogenesis of HAND. Here we demonstrate that the non-nucleoside reverse transcriptase inhibitor (NNRTI efavirenz (EFV induces the release of circulating sCD40L in both HIV infected individuals and in an in vitro suspension of washed human platelets, which are the main source of circulating sCD40L. Additionally, EFV was found to activate glycogen synthase kinase 3 beta (GSK3β in platelets, and we now show that valproic acid (VPA, a known GSK3β inhibitor, was able to attenuate the release of sCD40L in HIV infected individuals receiving EFV, and in isolated human platelets. Collectively these results have important implications in determining the pro-inflammatory role that some antiretroviral regimens may have. The use of antiretrovirals remains the best strategy to prevent HIV-associated illnesses, including HAND, however these drugs have clear limitations to this end, and thus, these results underscore the need to develop adjunctive therapies for HAND that can also minimize the undesired negative effects of the antiretrovirals.

  6. 5'-azido-N-1-naphthylphthalamic acid, a photolabile analog of the auxin transport inhibitor, N-1-naphthylphthalamic acid: synthesis and binding properties

    Energy Technology Data Exchange (ETDEWEB)

    Voet, J.G.; Howley, K.; Shumsky, J.S.

    1987-05-01

    The polar transport of the plant growth regulator, auxin (indole-3-acetic acid, IAAH), is thought to involve the participation of several proteins in the plasma membrane, including a specific, saturable, voltage independent H/sup +//IAA/sup -/ efflux carrier located preferentially at the basal end of each cell. Auxin transport is specifically inhibited by the herbicide, N-1-naphthylphthalamic acid (NPA), which binds specifically to a protein in the plasma membrane, thought to be either the IAA/sup -/ efflux carrier or an allosteric effector protein. They have synthesized and characterized a photolabile analog of NPA, 5'-azido-N-1-naphthylphthalamic acid (Az-NPA). This potential photoaffinity label for the NPA binding protein competes with /sup 3/H-NPA for binding sites on Curcurbita pepo L. (zucchini) stem cell membranes with K/sub j/ = 1.5 x 10/sup -7/ M. The K/sub i/ for NPA under these conditions is 2 x 10/sup -8/M, indicating that the affinity of Az-NPA for the membranes is only 7.5 fold lower than NPA. While the binding of 4.6 x 10/sup -6/ M Az-NPA to NPA binding sites is reversible in the dark, exposure to light results in a 30% loss in /sup 3/H-NPA binding ability. Pretreatment with 10/sup -4/ M NPA protects the membranes against photodestruction of /sup 3/H-NPA binding sites by Az-NPA, supporting the conclusion that Az-NPA destroys these sites by specific covalent attachment.

  7. The bile acid sensor FXR protects against dyslipidemia and aortic plaques development induced by the HIV protease inhibitor ritonavir in mice.

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    Andrea Mencarelli

    Full Text Available BACKGROUND: Although human immunodeficiency virus (HIV-related morbidity and mortality rates in patients treated with a combination of high active antiretroviral therapy (HAART have declined, significant metabolic/vascular adverse effects associated with the long term use of HIV protease inhibitors (PIs have emerged as a significant side effect. Here we illustrate that targeting the bile acid sensor farnesoid X receptor (FXR protects against dyslipidemia and vascular injury induced HIV-PIs in rodents. METHODOLOGY/PRINCIPAL FINDINGS: Administration of the HIV PI ritonavir to wild type mice increased plasma triacylglycerols and cholesterol levels and this effect was exacerbated by dosing ritonavir to mice harbouring a disrupted FXR. Dyslipidemia induced by ritonavir associated with a shift in the liver expression of signature genes, Sterol Regulatory Element-Binding Protein (SREBP-1 and fatty acid synthase. Treating wild type mice with the FXR agonist (chenodeoxycholic acid, CDCA protected against development of dyslipidemia induced by ritonavir. Administration of ritonavir to ApoE(-/- mice, a strain that develop spontaneously atherosclerosis, increased the extent of aortic plaques without worsening the dyslipidemia. Treating these mice with CDCA reduced the extent of aortic plaques by 70% without changing plasma lipoproteins or the liver expression of signature genes. A beneficial effect on aortic plaques was also obtained by treating ApoE(-/- mice with gemfibrozil, a PPARα agonist. FXR activation counter-regulated induction of expression/activity of CD36 caused by HIV-PIs in circulating monocytes and aortic plaques. In macrophages cell lines, CDCA attenuated CD36 induction and uptake of acetylated LDL caused by ritonavir. Natural and synthetic FXR ligands reduced the nuclear translocation of SREBP1c caused by ritonavir. CONCLUSIONS/SIGNIFICANCE: Activation of the bile acid sensor FXR protects against dyslipidemia and atherosclerotic caused by

  8. A novel fermentation strategy for removing the key inhibitor acetic acid and efficiently utilizing the mixed sugars from lignocellulosic hydrolysates

    Energy Technology Data Exchange (ETDEWEB)

    Mark A. Eiteman PHD; Elliot Altman Phd

    2009-02-11

    As part of preliminary research efforts, we have completed several experiments which demonstrate 'proof of concept.' These experiments addressed the following three questions: (1) Can a synthetic mixed sugar solution of glucose and xylose be efficiently consumed using the multi-organism approach? (2) Can this approach be used to accumulate a model product? (3) Can this approach be applied to the removal of an inhibitor, acetate, selectively from mixtures of xylose and glucose? To answer the question of whether this multi-organism approach can effectively consume synthetic mixed sugar solutions, we first tested substrate-selective uptake using two strains, one unable to consume glucose and one unable to consume xylose. The xylose-selective strain ALS998 has mutations in the three genes involved in glucose uptake, rendering it unable to consume glucose: ptsG codes for the Enzyme IICB{sup Glc} of the phosphotransferase system (PTS) for carbohydrate transport (Postma et al., 1993), manZ codes for the IID{sup Man} domain of the mannose PTS permease (Huber, 1996), glk codes for glucokinase (Curtis and Epstein 1975) We also constructed strain ALS1008 which has a knockout in the xylA gene encoding for xylose isomerase, rendering ALS1008 unable to consume xylose. Two batch experiments and one continuous bioprocess were completed. In the first experiment, each strain was grown separately in a defined medium of 8 g/L xylose and 15 g/L glucose which represented xylose and glucose concentrations that can be generated by actual biomass. In the second experiment, the two strains were grown together in batch in the same defined, mixed-sugar medium. In a third experiment, we grew the strains continuously in a 'chemostat', except that we shifted the concentrations of glucose and xylose periodically to observe how the system would respond. (For example, we shifted the glucose concentration suddenly from 15 g/L to 30 g/L in the feed).

  9. Multicomponent Synthesis and Evaluation of New 1,2,3-Triazole Derivatives of Dihydropyrimidinones as Acidic Corrosion Inhibitors for Steel

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    Rodrigo González-Olvera

    2016-02-01

    Full Text Available An efficient one-pot synthesis of 1,2,3-triazole derivatives of dihydropyrimidinones has been developed using two multicomponent reactions. The aldehyde-1,2,3-triazoles were obtained in good yields from in situ-generated organic azides and O-propargylbenzaldehyde. The target heterocycles were synthesized through the Biginelli reaction in which the aldehyde-1,2,3-triazoles reacted with ethyl acetoacetate and urea in the presence of Ce(OTf3 as the catalyst. The corrosion inhibition of steel grade API 5 L X52 in 1 M HCl by the synthesized compounds was investigated using the electrochemical impedance spectroscopy technique. The measurements revealed that these heterocycles are promising candidates to inhibit acidic corrosion of steel.

  10. Multicomponent Synthesis and Evaluation of New 1,2,3-Triazole Derivatives of Dihydropyrimidinones as Acidic Corrosion Inhibitors for Steel.

    Science.gov (United States)

    González-Olvera, Rodrigo; Román-Rodríguez, Viridiana; Negrón-Silva, Guillermo E; Espinoza-Vázquez, Araceli; Rodríguez-Gómez, Francisco Javier; Santillan, Rosa

    2016-02-22

    An efficient one-pot synthesis of 1,2,3-triazole derivatives of dihydropyrimidinones has been developed using two multicomponent reactions. The aldehyde-1,2,3-triazoles were obtained in good yields from in situ-generated organic azides and O-propargylbenzaldehyde. The target heterocycles were synthesized through the Biginelli reaction in which the aldehyde-1,2,3-triazoles reacted with ethyl acetoacetate and urea in the presence of Ce(OTf)₃ as the catalyst. The corrosion inhibition of steel grade API 5 L X52 in 1 M HCl by the synthesized compounds was investigated using the electrochemical impedance spectroscopy technique. The measurements revealed that these heterocycles are promising candidates to inhibit acidic corrosion of steel.

  11. Gambogic Acid Is a Tissue-Specific Proteasome Inhibitor In Vitro and In Vivo

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    Xiaofen Li

    2013-01-01

    Full Text Available Gambogic acid (GA is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.

  12. Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

    Science.gov (United States)

    Palma, E.; Ragozzino, D. A.; Di Angelantonio, S.; Spinelli, G.; Trettel, F.; Martinez-Torres, A.; Torchia, G.; Arcella, A.; Di Gennaro, G.; Quarato, P. P.; Esposito, V.; Cantore, G.; Miledi, R.; Eusebi, F.

    2004-01-01

    The properties of γ-aminobutyric acid (GABA) type A receptors (GABAA receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABAA receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat α1β2γ2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABAA receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABAA receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABAA-receptor β1, β2, β3, and γ2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABAA receptors. Blockage of phosphatases stabilizes the TLE GABAA receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy. PMID:15218107

  13. Exogenous retinoic acid and cytochrome P450 26B1 inhibitor modulate meiosis-associated genes expression in canine testis, an in vitro model.

    Science.gov (United States)

    Kasimanickam, V; Kasimanickam, R

    2014-04-01

    Pharmacological approaches to control spermatogenesis are required to resolve overpopulation in dogs. The objective of the study was to investigate the regulation of meiosis-associated and male germ cell-related genes, stimulated by retinoic acid gene 8 (STRA8), synaptonemal complex protein 3 (SYCP3), dosage suppressor of mck1 (DMC1), doublesex and mab-3 related transcription factor 1 (DMRT1) and deleted in azoospermia-like (DAZL) following exogenous administration of retinoic acid (RA) and after the modulation of endogenous RA by a cytochrome P450, family 26, subfamily B, polypeptide 1 inhibitor (CYP26B1-I; R115866) in an in vitro testis model. Testicles of five healthy, medium-sized and mixed-breed dogs were used for the organotypic cultures. All-trans-RA at 2 μM, CYP26B1-I at 1 μM and the control dimethyl sulphoxide (DMSO) were administered to the testes cultures, and the cultures were maintained for 24 h. Genes STRA8, DAZL and DMRT1 were significantly up-regulated as a result of the direct and indirect increase in the RA levels in the testis, subsequent to the exogenous administration of all-trans-RA and CYP26B1 inhibitor. Up-regulation of STRA8 was very prominent compared to DAZL and DMRT, and the drastic up-regulation of STRA8 was also observed with CY26B1-I than with all-trans-RA. No significant differences were found with the early meiotic markers, SYCP3 and DMC1 with RA, CY26B1-I and vehicle treatments. Because DAZL encodes a germ cell-specific RNA-binding protein, required for the induction of STRA8 and initiation of meiosis, we might see the expression differences temporally with the stage of spermatogenesis. DMRT1 is a unique gonad- and stage-specific transcription factor, directly activates STRA8 and has the temporal influence on its expression. Protein expression of DAZL and STRA8 was greater in RA- and CYP26B1-I-treated testis culture, whereas DMRT1 showed greater protein expression for RA treatment, but not for CYP26B1-I treatment compared to

  14. Eucalyptus ESTs associated with resistance to herbicide inhibitors of aromatic and branched-chain amino acid synthesis

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    Edivaldo Domingues Velini

    2005-01-01

    Full Text Available Herbicides inhibit enzymatic systems of plants. Acetolactate synthase (ALS, EC = 4.1.3.18 and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS, EC 2.5.1.19 are key enzymes for herbicide action. Hundreds of compounds inhibit ALS. This enzyme is highly variable, enabling the selective control of weeds in a number of crops. Glyphosate, the only commercial herbicide inhibiting EPSPS is widely used for non-selective control of weeds in many crops. Recently, transgenic crops resistant to glyphosate were developed and have been used by farmers. The aim of this study was the data mining of eucalypt expressed sequence tags (ESTs in the FORESTs Genome Project database (https://forests.esalq.usp.br related to these enzymes. Representative amino acid sequences from the NCBI database associated with ALS and EPSPS were blasted with ESTs from the FORESTs database using the tBLASTx option of the blast tool. The best blasting reads and clusters from FORESTs, represented as nucleotide sequences, were blasted back with the NCBI database to evaluate the level of similarity with available sequences from different species. One and seven clusters were identified as showing high similarity with EPSPS and ALS sequences from the literature, respectively. The alignment of EPSPS sequences allowed the identification of conserved regions that can be used to design specific primers for additional sequencings.

  15. In Vivo Screening Using Transgenic Zebrafish Embryos Reveals New Effects of HDAC Inhibitors Trichostatin A and Valproic Acid on Organogenesis.

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    Ling Li

    Full Text Available The effects of endocrine disrupting chemicals (EDCs on reproduction are well known, whereas their developmental effects are much less characterized. However, exposure to endocrine disruptors during organogenesis may lead to deleterious and permanent problems later in life. Zebrafish (Danio rerio transgenic lines expressing the green fluorescent protein (GFP in specific organs and tissues are powerful tools to uncover developmental defects elicited by EDCs. Here, we used seven transgenic lines to visualize in vivo whether a series of EDCs and other pharmaceutical compounds can alter organogenesis in zebrafish. We used transgenic lines expressing GFP in pancreas, liver, blood vessels, inner ear, nervous system, pharyngeal tooth and pectoral fins. This screen revealed that four of the tested chemicals have detectable effects on different organs, which shows that the range of effects elicited by EDCs is wider than anticipated. The endocrine disruptor tetrabromobisphenol-A (TBBPA, as well as the three drugs diclofenac, trichostatin A (TSA and valproic acid (VPA induced abnormalities in the embryonic vascular system of zebrafish. Moreover, TSA and VPA induced specific alterations during the development of pancreas, an observation that was confirmed by in situ hybridization with specific markers. Developmental delays were also induced by TSA and VPA in the liver and in pharyngeal teeth, resulting in smaller organ size. Our results show that EDCs can induce a large range of developmental alterations during embryogenesis of zebrafish and establish GFP transgenic lines as powerful tools to screen for EDCs effects in vivo.

  16. In Vivo Screening Using Transgenic Zebrafish Embryos Reveals New Effects of HDAC Inhibitors Trichostatin A and Valproic Acid on Organogenesis.

    Science.gov (United States)

    Li, Ling; Bonneton, François; Tohme, Marie; Bernard, Laure; Chen, Xiao Yong; Laudet, Vincent

    2016-01-01

    The effects of endocrine disrupting chemicals (EDCs) on reproduction are well known, whereas their developmental effects are much less characterized. However, exposure to endocrine disruptors during organogenesis may lead to deleterious and permanent problems later in life. Zebrafish (Danio rerio) transgenic lines expressing the green fluorescent protein (GFP) in specific organs and tissues are powerful tools to uncover developmental defects elicited by EDCs. Here, we used seven transgenic lines to visualize in vivo whether a series of EDCs and other pharmaceutical compounds can alter organogenesis in zebrafish. We used transgenic lines expressing GFP in pancreas, liver, blood vessels, inner ear, nervous system, pharyngeal tooth and pectoral fins. This screen revealed that four of the tested chemicals have detectable effects on different organs, which shows that the range of effects elicited by EDCs is wider than anticipated. The endocrine disruptor tetrabromobisphenol-A (TBBPA), as well as the three drugs diclofenac, trichostatin A (TSA) and valproic acid (VPA) induced abnormalities in the embryonic vascular system of zebrafish. Moreover, TSA and VPA induced specific alterations during the development of pancreas, an observation that was confirmed by in situ hybridization with specific markers. Developmental delays were also induced by TSA and VPA in the liver and in pharyngeal teeth, resulting in smaller organ size. Our results show that EDCs can induce a large range of developmental alterations during embryogenesis of zebrafish and establish GFP transgenic lines as powerful tools to screen for EDCs effects in vivo. PMID:26900852

  17. Cardioprotective effects of fatty acid amide hydrolase inhibitor URB694, in a rodent model of trait anxiety.

    Science.gov (United States)

    Carnevali, Luca; Vacondio, Federica; Rossi, Stefano; Macchi, Emilio; Spadoni, Gilberto; Bedini, Annalida; Neumann, Inga D; Rivara, Silvia; Mor, Marco; Sgoifo, Andrea

    2015-12-14

    In humans, chronic anxiety represents an independent risk factor for cardiac arrhythmias and sudden death. Here we evaluate in male Wistar rats bred for high (HAB) and low (LAB) anxiety-related behavior, as well as non-selected (NAB) animals, the relationship between trait anxiety and cardiac electrical instability and investigate whether pharmacological augmentation of endocannabinoid anandamide-mediated signaling exerts anxiolytic-like and cardioprotective effects. HAB rats displayed (i) a higher incidence of ventricular tachyarrhythmias induced by isoproterenol, and (ii) a larger spatial dispersion of ventricular refractoriness assessed by means of an epicardial mapping protocol. In HAB rats, acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), with URB694 (0.3 mg/kg), (i) decreased anxiety-like behavior in the elevated plus maze, (ii) increased anandamide levels in the heart, (iii) reduced isoproterenol-induced occurrence of ventricular tachyarrhythmias, and (iv) corrected alterations of ventricular refractoriness. The anti-arrhythmic effect of URB694 was prevented by pharmacological blockade of the cannabinoid type 1 (CB1), but not of the CB2, receptor. These findings suggest that URB694 exerts anxiolytic-like and cardioprotective effects in HAB rats, the latter via anandamide-mediated activation of CB1 receptors. Thus, pharmacological inhibition of FAAH might be a viable pharmacological strategy for the treatment of anxiety-related cardiac dysfunction.

  18. Impact of nitrification inhibitor with organic manure and urea on nitrogen dynamics and N2O emission in acid sulphate soil

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    Shordar Mohamed Shamsuzzaman

    2016-03-01

    Full Text Available ABSTRACT The accurate prediction of N transformation is an important requisite for optimizing N use efficiency in cropping systems. An incubation study was conducted to verify the impacts of nitrification inhibitor (NI with organic manure (OM and urea on N dynamics and N2O emission in acid sulphate soil. The conducted experiment was two-level factorial with 4 N sources (N1 = 100% of N from urea, N2 = 75% of N from urea + 25% N from rice straw, N3 = 75% of N from urea + 25% of N from cow dung and N4 = 75% of N from urea + 25% of N from poultry dung and two levels of NI (with and without DCD. The NI (Dicyandiamide - DCD with OM + urea enhanced mineral N contents and it was the highest (255.07 µg∙g-1 for urea with DCD applications. The highest net N-mineralization (213.07 µg∙g-1 was recorded for the application of urea with DCD and net nitrification (16.26 µg∙g-1 was recorded for the application of urea alone, but the highest cumulative N2O emission (5.46 µg∙g-1 was in urea + poultry dung (PD. In addition, DCD most effectively inhibited net nitrification (28.78% and N2O emission (32.40% from cow dung (CD and urea in the tested soils. The combination of DCD with CD and urea was more effective in reducing N2O emissions (43.69%. These results suggest that the DCD with CD and urea may be the most potential combination to reduce nitrification and N2O emission as well as N loss from acid sulphate soil.

  19. Impact of nitrification inhibitor with organic manure and urea on nitrogen dynamics and N2O emission in acid sulphate soil

    Directory of Open Access Journals (Sweden)

    Shordar Mohamed Shamsuzzaman

    2015-01-01

    Full Text Available ABSTRACT The accurate prediction of N transformation is an important requisite for optimizing N use efficiency in cropping systems. An incubation study was conducted to verify the impacts of nitrification inhibitor (NI with organic manure (OM and urea on N dynamics and N2O emission in acid sulphate soil. The conducted experiment was two-level factorial with 4 N sources (N1 = 100% of N from urea, N2 = 75% of N from urea + 25% N from rice straw, N3 = 75% of N from urea + 25% of N from cow dung and N4 = 75% of N from urea + 25% of N from poultry dung and two levels of NI (with and without DCD. The NI (Dicyandiamide - DCD with OM + urea enhanced mineral N contents and it was the highest (255.07 µg∙g-1 for urea with DCD applications. The highest net N-mineralization (213.07 µg∙g-1 was recorded for the application of urea with DCD and net nitrification (16.26 µg∙g-1 was recorded for the application of urea alone, but the highest cumulative N2O emission (5.46 µg∙g-1 was in urea + poultry dung (PD. In addition, DCD most effectively inhibited net nitrification (28.78% and N2O emission (32.40% from cow dung (CD and urea in the tested soils. The combination of DCD with CD and urea was more effective in reducing N2O emissions (43.69%. These results suggest that the DCD with CD and urea may be the most potential combination to reduce nitrification and N2O emission as well as N loss from acid sulphate soil.

  20. Epigenetic priming of AML blasts for all-trans retinoic acid-induced differentiation by the HDAC class-I selective inhibitor entinostat.

    Directory of Open Access Journals (Sweden)

    Nadja Blagitko-Dorfs

    Full Text Available All-trans retinoic acid (ATRA has only limited single agent activity in AML without the PML-RARα fusion (non-M3 AML. In search of a sensitizing strategy to overcome this relative ATRA resistance, we investigated the potency of the HDAC class-I selective inhibitor entinostat in AML cell lines Kasumi-1 and HL-60 and primary AML blasts. Entinostat alone induced robust differentiation of both cell lines, which was enhanced by the combination with ATRA. This "priming" effect on ATRA-induced differentiation was at least equivalent to that achieved with the DNA hypomethylating agent decitabine, and could overall be recapitulated in primary AML blasts treated ex vivo. Moreover, entinostat treatment established the activating chromatin marks acH3, acH3K9, acH4 and H3K4me3 at the promoter of the RARβ2 gene, an essential mediator of retinoic acid (RA signaling in different solid tumor models. Similarly, RARβ2 promoter hypermethylation (which in primary blasts from 90 AML/MDS patients was surprisingly infrequent could be partially reversed by decitabine in the two cell lines. Re-induction of the epigenetically silenced RARβ2 gene was achieved only when entinostat or decitabine were given prior to ATRA treatment. Thus in this model, reactivation of RARβ2 was not necessarily required for the differentiation effect, and pharmacological RARβ2 promoter demethylation may be a bystander phenomenon rather than an essential prerequisite for the cellular effects of decitabine when combined with ATRA. In conclusion, as a "priming" agent for non-M3 AML blasts to the differentiation-inducing effects of ATRA, entinostat is at least as active as decitabine, and both act in part independently from RARβ2. Further investigation of this treatment combination in non-M3 AML patients is therefore warranted, independently of RARβ2 gene silencing by DNA methylation.

  1. Biosynthesis of the proteasome inhibitor syringolin A: the ureido group joining two amino acids originates from bicarbonate

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    Schellenberg Barbara

    2009-10-01

    Full Text Available Abstract Background Syringolin A, an important virulence factor in the interaction of the phytopathogenic bacterium Pseudomonas syringae pv. syringae B728a with its host plant Phaseolus vulgaris (bean, was recently shown to irreversibly inhibit eukaryotic proteasomes by a novel mechanism. Syringolin A is synthesized by a mixed non-ribosomal peptide synthetase/polyketide synthetase and consists of a tripeptide part including a twelve-membered ring with an N-terminal valine that is joined to a second valine via a very unusual ureido group. Analysis of sequence and architecture of the syringolin A synthetase gene cluster with the five open reading frames sylA-sylE allowed to formulate a biosynthesis model that explained all structural features of the tripeptide part of syringolin A but left the biosynthesis of the unusual ureido group unaccounted for. Results We have cloned a 22 kb genomic fragment containing the sylA-sylE gene cluster but no other complete gene into the broad host range cosmid pLAFR3. Transfer of the recombinant cosmid into Pseudomonas putida and P. syringae pv. syringae SM was sufficient to direct the biosynthesis of bona fide syringolin A in these heterologous organisms whose genomes do not contain homologous genes. NMR analysis of syringolin A isolated from cultures grown in the presence of NaH13CO3 revealed preferential 13C-labeling at the ureido carbonyl position. Conclusion The results show that no additional syringolin A-specific genes were needed for the biosynthesis of the enigmatic ureido group joining two amino acids. They reveal the source of the ureido carbonyl group to be bicarbonate/carbon dioxide, which we hypothesize is incorporated by carbamylation of valine mediated by the sylC gene product(s. A similar mechanism may also play a role in the biosynthesis of other ureido-group-containing NRPS products known largely from cyanobacteria.

  2. Amelioration of glomerulosclerosis with all-trans retinoic acid is linked to decreased plasminogen activator inhibitor-1 and α-smooth muscle actin

    Institute of Scientific and Technical Information of China (English)

    Xia LIU; Lei L(U); Bei-bei TAO; Ai-ling ZHOU; Yi-chun ZHU

    2011-01-01

    Aim:To examine the effects of all-trans retinoic acid (atRA) on renal morphology and function as well as on renal plasminogen activator inhibitor-1 (PAI-1) expression and plasmin activity in rats with 5/6 nephrectomy.Methods:Adult male Sprague Dawley rats were given 5/6 nephrectomy or sham operation. Renal function was measured 2 weeks later. The nephrectomized rats were assigned to groups matched for proteinuria and treated with vehicle or atRA (5 or 10 mg/kg by gastric gavage once daily) for the next 12 weeks. Rats with sham operation were treated with vehicle. At the end of the treatments,kidneys were collected for histological examination, Western blot analysis, and enzymatic activity measurements.Results:The 5/6 nephrectomy promoted hypertension, renal dysfunction, and glomerulosclerosis. These changes were significantly reduced in the atRA-treated group. The expressions of PAI-1 and α-smooth muscle actin (α-SMA) were significantly increased in the vehicle-treated nephrectomized rats. Treatment with atRA significantly reduced the expressions of PAI-1 and α-SMA. However, piasmin activity remained unchanged following atRA treatment.Conclusion:Treatment with atRA ameliorates glomerulosclerosis and improves renal function in rats with 5/6 nephrectomy. This is associated with a decrease in PAI-1 and α-SMA, but not with a change in plasmin activity.

  3. The Interaction between an Acidic Transcriptional Activator and Its Inhibitor: The Molecular Basis of Ga14p Recognition by Ga180p

    Energy Technology Data Exchange (ETDEWEB)

    Thoden, James B.; Ryan, Louise A.; Reece, Richard J.; Holden, Hazel M. (Manchester); (UW)

    2009-02-16

    The GAL genes, which encode the enzymes required for normal galactose metabolism in yeast, are transcriptionally regulated by three proteins: Gal4p, an activator; Gal80p, an inhibitor; and Gal3p, a galactose sensor. These proteins control the switch between inert and active gene expression. The transcriptional activation function of Gal4p is rendered inactive in the presence of Gal80p. Here we present the three-dimensional structure of a complex between the acidic activation domain of Gal4p and Gal80p. The transactivation domain initiates with an extended region of polypeptide chain followed by two turns of an amphipathic alpha-helix. It fits into and across a deep cleft within the Gal80p dimer with the protein-protein interface defined primarily by hydrophobic interactions. A disordered loop in the apo-Gal80p structure (Asp-309 to Ser-316) becomes well-defined upon binding of the transactivation domain. This investigation provides a new molecular scaffold for understanding previous biochemical and genetic studies.

  4. Effect of Soy Sauce on Serum Uric Acid Levels in Hyperuricemic Rats and Identification of Flazin as a Potent Xanthine Oxidase Inhibitor.

    Science.gov (United States)

    Li, Huipin; Zhao, Mouming; Su, Guowan; Lin, Lianzhu; Wang, Yong

    2016-06-15

    This is the first report on the ability of soy sauce to effectively reduce the serum uric acid levels and xanthine oxidase (XOD) activities of hyperuricemic rats. Soy sauce was partitioned sequentially into ethyl acetate and water fractions. The ethyl acetate fraction with strong XOD inhibition effect was purified further. On the basis of xanthine oxidase inhibitory (XOI) activity-guided purification, nine compounds including 3,4-dihydroxy ethyl cinnamate, diisobutyl terephthalate, harman, daidzein, flazin, catechol, thymine, genistein, and uracil were obtained. It was the first time that 3,4-dihydroxy ethyl cinnamate and diisobutyl terephthalate had been identified from soy sauce. Flazin with hydroxymethyl furan ketone group at C-1 and carboxyl at C-3 exhibited the strongest XOI activity (IC50 = 0.51 ± 0.05 mM). According to fluorescence quenching and molecular docking experiments, flazin could enter into the catalytic center of XOD to interact with Lys1045, Gln1194, and Arg912 mainly by hydrophobic forces and hydrogen bonds. Flazin, catechol, and genistein not only were potent XOD inhibitors but also held certain antioxidant activities. According to ADME (absorption, distribution, metabolism, and excretion) simulation in silico, flazin had good oral bioavailability in vivo. PMID:27181598

  5. Simultaneous saccharification and co-fermentation of dry diluted acid pretreated corn stover at high dry matter loading: Overcoming the inhibitors by non-tolerant yeast.

    Science.gov (United States)

    Zhu, Jia-Qing; Qin, Lei; Li, Wen-Chao; Zhang, Jian; Bao, Jie; Huang, Yao-Dong; Li, Bing-Zhi; Yuan, Ying-Jin

    2015-12-01

    Dry dilute acid pretreatment (DDAP) is a promising method for lignocellulose bioconversion, although inhibitors generated during the pretreatment impede the fermentation severely. We developed the simultaneous saccharification and co-fermentation (SScF) of DDAP pretreated biomass at high solid loading using xylose fermenting Saccharomyces cerevisiae, SyBE005. Effect of temperature on SScF showed that ethanol yield at 34°C was 10.2% higher than that at 38°C. Ethanol concentration reached 29.5 g/L at 15% (w/w) dry matter loading, while SScF almost ceased at the beginning at 25% (w/w) dry matter loading of DDAP pretreated corn stover. According to the effect of the diluted hydrolysate on the fermentation of strain SyBE005, a fed-batch mode was developed for the SScF of DDAP pretreated corn stover with 25% dry matter loading without detoxification, and 40.0 g/L ethanol was achieved. In addition, high yeast inoculation improved xylose utilization and the final ethanol concentration reached 47.2 g/L. PMID:26363500

  6. Broth Microdilution Method To Detect Extended-Spectrum β-Lactamases and AmpC β-Lactamases in Enterobacteriaceae Isolates by Use of Clavulanic Acid and Boronic Acid as Inhibitors

    Science.gov (United States)

    Jeong, Seok Hoon; Song, Wonkeun; Kim, Jae-Seok; Kim, Han-Sung; Lee, Kyu Man

    2009-01-01

    This study was designed to evaluate the performance of the broth microdilution (BMD) method to detect production of extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases in Enterobacteriaceae by using clavulanic acid (CA) and boronic acid (BA) as ESBL and AmpC β-lactamase inhibitors, respectively. A total of 100 clinical isolates of Enterobacteriaceae were analyzed. Mueller-Hinton broth containing serial twofold dilutions of cefotaxime (CTX), ceftazidime (CAZ), aztreonam (ATM), or cefepime (FEP) with or without either or both CA and BA was prepared. An eightfold or greater decrease in the MIC of CTX, CAZ, ATM, or FEP in the presence of CA and BA was considered a positive result for ESBL and plasmid-mediated AmpC β-lactamase (PABL), respectively. In tests with CA, expanded-spectrum β-lactams containing BA (CTX-BA, CAZ-BA, ATM-BA, and FEP-BA) showed higher positive rates in detecting ESBL producers than those without BA. The combination of CTX- and CAZ-based BMD tests with CA and BA showed sensitivity and specificity of 100% for the detection of ESBLs and PABLs. The BMD testing could be applicable for routine use in commercially available semiautomated systems for the detection of ESBLs and PABLs in Enterobacteriaceae. PMID:19710269

  7. Silencing Brassinosteroid Receptor BRI1 Impairs Herbivory-elicited Accumulation of Jasmonic Acid-isoleucine and Diterpene Glycosides, but not Jasmonic Acid and Trypsin Proteinase Inhibitors in Nicotiana attenuata

    Institute of Scientific and Technical Information of China (English)

    Da-Hai Yang; lan T.Baldwin; Jianqiang Wu

    2013-01-01

    The brassinosteroid (BR) receptor,BR insensitive 1 (BRI1),plays a critical role in plant development,but whether BRI1-mediated BR signaling is involved in plant defense responses to herbivores was largely unknown.Here,we examined the function of BRI1 in the resistance of Nicotiana attenuata (Solanaceae) to its specialist insect herbivore Manduca sexta.Jasmonic acid (JA) and JA-isoleucine conjugate (JA-Ile) are important hormones that mediate resistance to herbivores and we found that after wounding or simulated herbivory NaBRI1 had little effect on JA levels,but was important for the induction of JA-Ile.Further experiments revealed that decreased JAR (the enzyme for JA-Ile production) activity and availability of lie in NaBRI1-silenced plants were likely responsible for the low JA-Ile levels.Consistently,M.sexta larvae gained more weight on NaBRI1-silenced plants than on the control plants.Quantification of insect feeding-induced secondary metabolites revealed that silencing NaBRI1 resulted in decreased levels of carbon-rich defensive secondary metabolites (hydroxygeranyllinalool diterpene glycosides,chlorogenic acid,and rutin),but had little effect on the nitrogen-rich ones (nicotine and trypsin proteinase inhibitors).Thus,NaBRI1-mediated BR signaling is likely involved in plant defense responses to M.sexta,including maintaining JA-Ile levels and the accumulation of several carbon-rich defensive secondary metabolites.

  8. Study of Triclabendazole (TCBZ Effect on Aspartate Transaminase (AST Activity of Fasciola gigantica Parasite and Liver Enzyme Activity Assay

    Directory of Open Access Journals (Sweden)

    Shima Shafaei

    2015-10-01

    Full Text Available  Background: Aspartate transaminase (AST is an important enzyme in parasite and liver tissue. The purpose of this investigation is to evaluate triclabendazole (TCBZ effect on AST activity of Fasciola gigantica parasite. To compare of enzyme level of parasite and its host tissue, enzyme activity of F. gigantica parasite and liver tissues were also determined. Method:The livers were collected from sheep slaughtered in local slaughterhouse and living F. gigantica parasites were isolated. The washed parasites were cultured in buffe rmedia with or without Triclabendazole (Egaten®; 15μg/mL in an incubator at 37° C. Extractions of collected parasites and liver tissues were prepared by homogenizing buffer in a Mortar and pestle. Extraction samples were examined for protein measurement, AST activity assay and protein recognition. Results:The results of AST assay revealed, enzyme activity for treated and untreated is not significant. Healthy liver tissue shows significantly higher enzyme activity than parasite. Enzyme activity for healthy and infected liver tissues was significant. Enzymatic proteins including Cathepsin L & B (Protease were recognized in parasite samples. Conclusion:Although AST could not be concerned as an indicator for efficiency treatment, however may be involved as a biomarker for biochemical comparison of parasite and host tissue.

  9. Generic HPLC platform for automated enzyme reaction monitoring: Advancing the assay toolbox for transaminases and other PLP-dependent enzymes.

    Science.gov (United States)

    Börner, Tim; Grey, Carl; Adlercreutz, Patrick

    2016-08-01

    Methods for rapid and direct quantification of enzyme kinetics independent of the substrate stand in high demand for both fundamental research and bioprocess development. This study addresses the need for a generic method by developing an automated, standardizable HPLC platform monitoring reaction progress in near real-time. The method was applied to amine transaminase (ATA) catalyzed reactions intensifying process development for chiral amine synthesis. Autosampler-assisted pipetting facilitates integrated mixing and sampling under controlled temperature. Crude enzyme formulations in high and low substrate concentrations can be employed. Sequential, small (1 µL) sample injections and immediate detection after separation permits fast reaction monitoring with excellent sensitivity, accuracy and reproducibility. Due to its modular design, different chromatographic techniques, e.g. reverse phase and size exclusion chromatography (SEC) can be employed. A novel assay for pyridoxal 5'-phosphate-dependent enzymes is presented using SEC for direct monitoring of enzyme-bound and free reaction intermediates. Time-resolved changes of the different cofactor states, e.g. pyridoxal 5'-phosphate, pyridoxamine 5'-phosphate and the internal aldimine were traced in both half reactions. The combination of the automated HPLC platform with SEC offers a method for substrate-independent screening, which renders a missing piece in the assay and screening toolbox for ATAs and other PLP-dependent enzymes.

  10. Dysregulated microRNA clusters in response to retinoic acid and CYP26B1 inhibitor induced testicular function in dogs.

    Science.gov (United States)

    Kasimanickam, Vanmathy R; Kasimanickam, Ramanathan K; Dernell, William S

    2014-01-01

    Spermatogenesis is a multistep synchronized process. Diploid spermatogonia differentiate into haploid spermatozoa following mitosis, meiosis and spermiogenesis. Division and differentiation of male germ cells is achieved through the sequential expression of several genes. Numerous mRNAs in the differentiating germ cells undergo post-transcriptional and translational regulation. MiRNAs are powerful negative regulators of mRNA transcription, stability, and translation and recognize their mRNA targets through base-pairing. Retinoic acid (RA) signaling is essential for spermatogenesis and testicular function. Testicular RA level is critical for RA signal transduction. This study investigated the miRNAs modulation in an RA- induced testicular environment following the administration of all-trans RA (2 µM) and CYP26B1- inhibitor (1 µM) compared to control. Eighty four canine mature miRNAs were analyzed and their expression signatures were distinguished using real-time PCR based array technology. Of the miRNAs analyzed, miRNA families such as miR-200 (cfa-miR-200a, cfa-miR-200b and cfa-miR-200c), Mirlet-7 (cfa-let-7a, cfa-let-7b, cfa-let-7c, cfa-let-7g and cfa-let-7f), miR-125 (cfa-miR-125a and cfa-miR-125b), miR-146 (cfa-miR-146a and cfa-miR-146b), miR-34 (cfa-miR-34a, cfa-miR-34b and cfa-miR-34c), miR-23 (cfa-miR-23a and cfa-miR-23b), cfa-miR-184, cfa-miR-214 and cfa-miR-141 were significantly up-regulated with testicular RA intervention via administration of CYP26B1 inhibitor and all-trans-RA and species of miRNA such as cfa-miR-19a, cfa-miR-29b, cfa-miR-29c, cfa-miR-101 and cfa-miR-137 were significantly down-regulated. This study explored information regarding chromosome distribution, human orthologous sequences and the interaction of target genes of miRNA families significantly distinguished in this study using prediction algorithms. This study importantly identified dysregulated miRNA species resulting from RA-induced spermatogenesis. The present contribution

  11. Dysregulated microRNA clusters in response to retinoic acid and CYP26B1 inhibitor induced testicular function in dogs.

    Directory of Open Access Journals (Sweden)

    Vanmathy R Kasimanickam

    Full Text Available Spermatogenesis is a multistep synchronized process. Diploid spermatogonia differentiate into haploid spermatozoa following mitosis, meiosis and spermiogenesis. Division and differentiation of male germ cells is achieved through the sequential expression of several genes. Numerous mRNAs in the differentiating germ cells undergo post-transcriptional and translational regulation. MiRNAs are powerful negative regulators of mRNA transcription, stability, and translation and recognize their mRNA targets through base-pairing. Retinoic acid (RA signaling is essential for spermatogenesis and testicular function. Testicular RA level is critical for RA signal transduction. This study investigated the miRNAs modulation in an RA- induced testicular environment following the administration of all-trans RA (2 µM and CYP26B1- inhibitor (1 µM compared to control. Eighty four canine mature miRNAs were analyzed and their expression signatures were distinguished using real-time PCR based array technology. Of the miRNAs analyzed, miRNA families such as miR-200 (cfa-miR-200a, cfa-miR-200b and cfa-miR-200c, Mirlet-7 (cfa-let-7a, cfa-let-7b, cfa-let-7c, cfa-let-7g and cfa-let-7f, miR-125 (cfa-miR-125a and cfa-miR-125b, miR-146 (cfa-miR-146a and cfa-miR-146b, miR-34 (cfa-miR-34a, cfa-miR-34b and cfa-miR-34c, miR-23 (cfa-miR-23a and cfa-miR-23b, cfa-miR-184, cfa-miR-214 and cfa-miR-141 were significantly up-regulated with testicular RA intervention via administration of CYP26B1 inhibitor and all-trans-RA and species of miRNA such as cfa-miR-19a, cfa-miR-29b, cfa-miR-29c, cfa-miR-101 and cfa-miR-137 were significantly down-regulated. This study explored information regarding chromosome distribution, human orthologous sequences and the interaction of target genes of miRNA families significantly distinguished in this study using prediction algorithms. This study importantly identified dysregulated miRNA species resulting from RA-induced spermatogenesis. The present

  12. In vitro and in vivo activity of a novel locked nucleic acid (LNA-inhibitor-miR-221 against multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Maria Teresa Di Martino

    Full Text Available BACKGROUND & AIM: The miR-221/222 cluster is upregulated in malignant plasma cells from multiple myeloma (MM patients harboring the t(4;14 translocation. We previously reported that silencing of miR-221/222 by an antisense oligonucleotide induces anti-MM activity and upregulates canonical miR-221/222 targets. The in vivo anti-tumor activity occurred when miR-221/222 inhibitors were delivered directly into MM xenografts. The aim of the present study was to evaluate the anti-MM activity of a novel phosphorothioate modified backbone 13-mer locked nucleic acid (LNA-Inhibitor-miR-221 (LNA-i-miR-221 specifically designed for systemic delivery. METHODS: In vitro anti-MM activity of LNA-i-miR-221 was evaluated by cell proliferation and BrdU uptake assays. In vivo studies were performed with non-obese diabetic/severe combined immunodeficient (NOD.SCID mice bearing t(4;14 MM xenografts, which were intraperitoneally or intravenously treated with naked LNA-i-miR-221. RNA extracts from retrieved tumors were analyzed for miR-221 levels and modulation of canonical targets expression. H&E staining and immunohistochemistry were performed on retrieved tumors and mouse vital organs. RESULTS: In vitro, LNA-i-miR-221 exerted strong antagonistic activity against miR-221 and induced upregulation of the endogenous target p27Kip1. It had a marked anti-proliferative effect on t(4;14-translocated MM cells but not on MM cells not carrying the translocation and not overexpressing miR-221. In vivo, systemic treatment with LNA-i-miR-221 triggered significant anti-tumor activity against t(4;14 MM xenografts; it also induced miR-221 downregulation, upregulated p27Kip1 and reduced Ki-67. No behavioral changes or organ-related toxicity were observed in mice as a consequence of treatments. CONCLUSIONS: LNA-i-miR-221 is a highly stable, effective agent against t(4;14 MM cells, and is suitable for systemic use. These data provide the rationale for the clinical development of LNA

  13. Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD).

    Science.gov (United States)

    Press, Neil J; Taylor, Roger J; Fullerton, Joseph D; Tranter, Pamela; McCarthy, Clive; Keller, Thomas H; Arnold, Nicola; Beer, David; Brown, Lyndon; Cheung, Robert; Christie, Julie; Denholm, Alastair; Haberthuer, Sandra; Hatto, Julia D I; Keenan, Mark; Mercer, Mark K; Oakman, Helen; Sahri, Helene; Tuffnell, Andrew R; Tweed, Morris; Trifilieff, Alexandre

    2015-09-10

    Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis. PMID:26288344

  14. Indispensable but insufficient role of renal D-amino acid oxidase in chiral inversion of NG-nitro-D-arginine.

    Science.gov (United States)

    Xin, Yan-Fei; Li, Xin; Hao, Bin; Gong, Nian; Sun, Wen-Qiang; Konno, Ryuichi; Wang, Yong-Xiang

    2010-06-01

    Unidirectionally chiral inversion of N(G)-nitro-D-arginine (D-NNA) to its L-enantiomer (L-NNA) occurred in rats, and it was blocked markedly (ca. 80%) by renal vascular ligation, and entirely (100%) by the D-amino acid oxidase (DAO) inhibitor sodium benzoate, suggesting that renal DAO is essential for the inversion. However, the doses of sodium benzoate administrated were extremely high (e.g., 400 mg/kg) due to its low potency. It is thus possible that sodium benzoate-mediated blockade of D-NNA inversion might be due to its nonspecific (or non-DAO-related) effects. In addition, after D-NNA was incubated with the pure enzyme of DAO in vitro without tissue homogenates, L-NNA was not produced, even though D-NNA was disposed. We propose that this occurred because D-NNA was first converted to its corresponding alpha-keto acid by DAO and then to L-NNA by transaminase(s); however, there was no direct evidence for this process. The goal of this study is to further elucidate the process of D-NNA chiral inversion both in vivo and in in vitro tissue homogenates by comparing mutant ddY/DAO(-/-) mice that lack DAO activity entirely compared to normal ddY/DAO(+/+) mice and Swiss mice. Furthermore, the ability to produce L-NNA from D-NNA-corresponding alpha-keto acids (N(G)-nitroguanidino-2-oxopentanoic acid) produced by porcine kidney-derived DAO (pkDAO) was also studied in the DAO inhibitor-pretreated rats. We found that D-NNA chiral inversion occurred in Swiss mice and ddY/DAO(+/+) mice both in vivo and in in vitro kidney homogenates, but not in ddY/DAO(-/-) mice, correlated to their DAO activities. The alpha-keto acid (N(G)-nitro-guanidino-2-oxopentanoic acid) from D-NNA was able to produce L-NNA, and subsequent vasoconstriction and pressor responses. These results indicate that the role of renal DAO is indispensible but insufficient for chiral inversion of D-NNA and other neutral and polar D-amino acids, and unidentified aminotransferase(s) are involved in a subsequent

  15. Interaction of new kinase inhibitors cabozantinib and tofacitinib with human serum alpha-1 acid glycoprotein. A comprehensive spectroscopic and molecular Docking approach

    Science.gov (United States)

    Ajmal, Mohammad Rehan; Abdelhameed, Ali Saber; Alam, Parvez; Khan, Rizwan Hasan

    2016-04-01

    In the current study we have investigated the interaction of newly approved kinase inhibitors namely Cabozantinib (CBZ) and Tofacitinib (TFB) with human Alpha-1 acid glycoprotein (AAG) under simulated physiological conditions using fluorescence quenching measurements, circular dichroism, dynamic light scattering and molecular docking methods. CBZ and TFB binds to AAG with significant affinity and the calculated binding constant for the drugs lie in the order of 104. With the increase in temperature the binding constant values decreased for both CBZ and TFB. The fluorescence resonance energy transfer (FRET) from AAG to CBZ and TFB suggested the fluorescence intensity of AAG was quenched by the two studied drugs via the formation of a non-fluorescent complex in the static manner. The molecular distance r value calculated from FRET is around 2 nm for both drugs, fluorescence spectroscopy data was employed for the study of thermodynamic parameters, standard Gibbs free energy change at 300K was calculated as - 5.234 kcal mol- 1 for CBZ-AAG interaction and - 6.237 kcal mol- 1 for TFB-AAG interaction, standard enthalpy change and standard entropy change for CBZ-AAG interaction are - 9.553 kcal mol- 1 and - 14.618 cal mol- 1K- 1 respectively while for AAG-TFB interaction, standard enthalpy and standard entropy change was calculated as 4.019 kcal mol- 1 and 7.206 cal mol- 1K- 1 respectively. Protein binding of the two drugs caused the tertiary structure alterations. Dynamic light scattering measurements demonstrated the reduction in the hydrodynamic radii of the protein. Furthermore molecular docking results suggested the Hydrophobic interaction and hydrogen bonding were the interactive forces in the binding process of CBZ to AAG while in case of TFB only hydrophobic interactions were found to be involved, overlap of the binding site for two studied drugs on the AAG molecule was revealed by docking results.

  16. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells

    International Nuclear Information System (INIS)

    Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent. PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots. Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 μM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-β5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition. This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent

  17. Novel Insights Into The Mode of Inhibition of Class A SHV-1 Beta-Lactamases Revealed by Boronic Acid Transition State Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    W Ke; J Sampson; C Ori; F Prati; S Drawz; C Bethel; R Bonomo; F van den Akker

    2011-12-31

    Boronic acid transition state inhibitors (BATSIs) are potent class A and C {beta}-lactamase inactivators and are of particular interest due to their reversible nature mimicking the transition state. Here, we present structural and kinetic data describing the inhibition of the SHV-1 {beta}-lactamase, a clinically important enzyme found in Klebsiella pneumoniae, by BATSI compounds possessing the R1 side chains of ceftazidime and cefoperazone and designed variants of the latter, compounds 1 and 2. The ceftazidime and cefoperazone BATSI compounds inhibit the SHV-1 {beta}-lactamase with micromolar affinity that is considerably weaker than their inhibition of other {beta}-lactamases. The solved crystal structures of these two BATSIs in complex with SHV-1 reveal a possible reason for SHV-1's relative resistance to inhibition, as the BATSIs adopt a deacylation transition state conformation compared to the usual acylation transition state conformation when complexed to other {beta}-lactamases. Active-site comparison suggests that these conformational differences might be attributed to a subtle shift of residue A237 in SHV-1. The ceftazidime BATSI structure revealed that the carboxyl-dimethyl moiety is positioned in SHV-1's carboxyl binding pocket. In contrast, the cefoperazone BATSI has its R1 group pointing away from the active site such that its phenol moiety moves residue Y105 from the active site via end-on stacking interactions. To work toward improving the affinity of the cefoperazone BATSI, we synthesized two variants in which either one or two extra carbons were added to the phenol linker. Both variants yielded improved affinity against SHV-1, possibly as a consequence of releasing the strain of its interaction with the unusual Y105 conformation.

  18. Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: a Connectivity Mapping analysis and an experimental study.

    Science.gov (United States)

    Zhuo, Wenlei; Zhang, Liang; Zhu, Yi; Xie, Qichao; Zhu, Bo; Chen, Zhengtang

    2015-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as a powerful targeting therapeutic agent for treatment of lung adenocarcinoma for years. Nevertheless, the efficacy of TKI was hampered by the appearance of acquired TKI-resistance. In the present study, we aimed to search, predict, and screen the agents that can overcome the acquired TKI-resistance of lung adenocarcinoma by using the expression profiles of differentially expressed genes (DEGs) and Connectivity map (CMAP). The profiles of DEGs were obtained by searching GEO microarray database, and then, they were submitted to CMAP for analysis in order to predict and screen the agent that might reverse the TKI-resistance of lung cancer cells. Next, the effects of the selected agent on TKI-resistant cancer cells were tested and the possible signaling pathways were also evaluated. As a result, valproic acid (VPA) was selected. Then, we used a low-concentration of VPA that has little effect on the cell growth for analysis. Interestingly, the results showed that treatment with a combination of VPA and Erlotinib significantly led to a decrease in cell viability and an increase in cell apoptosis for TKI-resistant HCC827-ER cells, relative to those treated with VPA or Erlotinib alone. Further experiments confirmed that inhibition of MAPK and AKT might be involved in this process. Analyzing the DEGs through the CMAP is a good strategy for exploitation of anti-tumor agents. VPA might markedly increase the sensitivity of TKI-resistant lung adenocarcinoma cells to Erlotinib, thus reversing the acquired TKI-resistance of cancer cells and raising VPA as a potential agent for TKI-resistant lung cancer therapy. PMID:26328250

  19. [Transaminase activity of the cortical layer of the kidney of rats of different ages and sex after administration of hydrocortisone and insulin].

    Science.gov (United States)

    Poletaeva, K A

    1971-01-01

    Response of cortical layer of rat kidney to separate and combined administration of hydrocortisone and insulin, as manifested by the activity of aspartate-alpha-ketoglutarate transaminase (Asp-T) and alanine-alpha-ketoglutarate transaminase (Ala-T), varied in males and females of different age. Prolonged administration of insulin to normal preadolescent rats and to adult males and females did not affect the activity of Asp-T and Ala-T in the cortical layer of kidney. During simultaneous prolonged administration of hydrocortisone and insulin to preadolescent male rats, there occurred no increase in the activity of Asp-T induced by administration of hydrocortisone alone. During simultaneous prolonged administration of hydrocortisone and insulin to adult male rats, activity of Asp-T of the cortical layer of kidney remained at the same level at after administration of hydrocortisone alone. PMID:5317624

  20. The effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status: a randomized trial among chronic hepatitis C virus-infected patients

    DEFF Research Database (Denmark)

    Groenbaek, K.; Friis, H.; Hansen, Max;

    2006-01-01

    Objective To assess the effect of antioxidant supplementation on hepatitis C viral load, transaminases and oxidative status. Methods We performed a randomized, placebo-controlled, double-blind trial to assess the effect of antioxidant supplementation on serum alanine aminotransferase, plasma hepa...... and catalase) or plasma levels of oxidative markers (malondialdehyde and 2-amino-adipic semialdehyde) were found. Conclusion Supplementation with vitamin C, E and selenium increased the antioxidant status, but had no effects on alanine aminotransferase, viral load or oxidative markers....

  1. Cloning-Independent Expression and Analysis of ω-Transaminases by Use of a Cell-Free Protein Synthesis System▿ †

    OpenAIRE

    Kwon, Yong-Chan; Lee, Kyung-Ho; Kim, Ho-Cheol; Han, Kyuboem; Seo, Joo-Hyun; Kim, Byung-Gee; Kim, Dong-Myung

    2010-01-01

    Herewith we report the expression and screening of microbial enzymes without involving cloning procedures. Computationally predicted putative ω-transaminase (ω-TA) genes were PCR amplified from the bacterial colonies and expressed in a cell-free protein synthesis system for subsequent analysis of their enzymatic activity and substrate specificity. Through the cell-free expression analysis of the putative ω-TA genes, a number of enzyme-substrate pairs were identified in a matter of hours. We e...

  2. Elevated transaminases as a predictor of coma in a patient with anorexia nervosa: a case report and review of the literature

    OpenAIRE

    Yoshida Shuhei; Shimada Masahiko; Kornek Miroslaw; Kim Seong-Jun; Shimada Katsunosuke; Schuppan Detlef

    2010-01-01

    Abstract Introduction Liver injury is a frequent complication associated with anorexia nervosa, and steatosis of the liver is thought to be the major underlying pathology. However, acute hepatic failure with transaminase levels over 1000 IU/mL and deep coma are very rare complications and the mechanism of pathogenesis is largely unknown. Case presentation A 37-year-old Japanese woman showed features of acute liver failure and hepatic coma which were not associated with hypoglycemia or hyper-a...

  3. Comparison of Therapeutic Response and Clinical Outcome between HCV Patients with Normal and Abnormal Alanine Transaminase Levels.

    Directory of Open Access Journals (Sweden)

    Cheng-Kung Wu

    Full Text Available Patients with chronic hepatitic C (HCV infection and normal serum alanine transaminase (ALT levels were considered to have mild disease. In Taiwan, these patients were not suggested for interferon (IFN based therapies. The aim of study is to compare therapeutic outcomes between HCV patients with normal and elevated ALT levels.We conducted a retrospective study on 3241 HCV patients treated by IFN based therapies. Patients with normal ALT levels were classified as group A (n = 186 while those with elevated ALT levels were group B (n = 3055.At baseline, incidence of diabetes mellitus, low platelet counts and cirrhosis were significantly higher in group B patients. The sustained virologic response (SVR rate was comparable between the 2 groups (65.3% vs. 65.3%, P = .993. But significantly higher incidence of HCC development after HCV treatment was observed in group B (7.4% vs. 3.2%, P = .032. No significant differences with respect to the outcome of liver decompensation, spontaneous bacterial peritonitis, and mortality were noted between 2 groups. Multivariate analysis showed younger age, female gender, non-HCV genotype 1, lower viral load, higher platelet counts and non-cirrhosis were favorable factors for achieving SVR, rather than ALT levels. Further analysis revealed older age, cirrhosis, lower platelet levels and non- peg-interferon treatment are risk factors of HCC development.HCV patients with normal ALT levels had similar response to antiviral therapy and low rate of HCC development after therapy. Antiviral therapies begun at early course of HCV infection may be beneficial to prevent disease progression.

  4. Valores de transaminasas en cabras criollas infectadas con Trypanosoma vivax Transaminases values in Creole goats infected with Trypanosoma vivax

    Directory of Open Access Journals (Sweden)

    Emir Espinoza

    2002-01-01

    Full Text Available La presente comunicación reporta los valores de las enzimas transaminasas, Aspartatoaminotransferasa (AST y Alaninaaminotransferasa (ALT encontrados en sueros de cabras infectadas con la cepa de Trypanosoma vivax Stock (TvIIV y sus controles. Las determinaciones se realizaron durante un lapso experimental de diez semanas, divididos en dos períodos iguales (pre y post-infección por intermedio de un método colorimétrico, utilizando kits comerciales. Los datos fueron analizados mediante la prueba t Student's. En el caso de la AST, la comparación de las medias parciales de ambos grupos infectado y control, no indicó diferencias estadísticas. Con respecto a la ALT, la contrastación de las medias parciales de pre y post-infección del grupo de cabras infectadas, señaló diferencias significativas (PThe present communication reports the transaminases enzymes values Aspartatoaminotransferase (AST and Alaninaaminotransferase (ALT in serum from goats infected with the Trypanosoma vivax Stock (TvIIV. The determinations were realized during a ten week experimental period divided into two equal periods (pre- and post-infection by colorimetric method, using commercial kits. The dates were analyzed through the t Student's test. In the AST case, the comparison between partial means of infected and control groups did not show any statistical differences. In relation to ALT, the contrast of partial means to pre- and post-infection from infected goats group indicated significant differences (P<0.01.

  5. Osteocompatibility of Biofilm Inhibitors

    OpenAIRE

    Rawson, Monica; Haggard, Warren; Jennings, Jessica A.

    2014-01-01

    The demand for infection prevention therapies has led to the discovery of several biofilm inhibitors. These inhibiting signals are released by bacteria, fungi, or marine organisms to signal biofilm dispersal or disruption in Gram-positive, Gram-negative, and fungal microorganisms. The purpose of this study was to test the biocompatibility of five different naturally-produced biofilm chemical dispersal and inhibition signals with osteoblast-like cells: D-amino acids (D-AA), lysostaphin (LS), f...

  6. OA02.02. Phytochemical constituents and antioxidative property of Musa acuminata flower as green corrosion inhibitor of mild steel in acid media

    OpenAIRE

    N. Gunavathy; ,

    2013-01-01

    Purpose: Corrosion is a major problem that must be confronted for safety, environmental and economic reasons. Organic compounds used as corrosion inhibitors are expensive, toxic and non biodegradable. The present investigation deals with the aim of finding eco friendly and cost effective natural inhibitor. The adsorption characteristic of phytochemical of Musa acuminata ‘nendran’ flower [MAN (F)] was studied to assess the mechanism of corrosion inhibition. Method: The inhibitive effect MAN (F...

  7. Effect of Functional Bread Rich in Potassium, γ-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure, Glucose Metabolism and Endothelial Function

    Science.gov (United States)

    Becerra-Tomás, Nerea; Guasch-Ferré, Marta; Quilez, Joan; Merino, Jordi; Ferré, Raimon; Díaz-López, Andrés; Bulló, Mònica; Hernández-Alonso, Pablo; Palau-Galindo, Antoni; Salas-Salvadó, Jordi

    2015-01-01

    Abstract Because it has been suggested that food rich in γ-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24-hour BP, glucose metabolism, and endothelial function. A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2-week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained. After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and −0.63 mm Hg in diastolic BP for CB; −0.71 mm Hg in systolic BP and −1.08 mm Hg in diastolic BP for LSB; and −0.75 mm Hg in systolic BP and −2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters. Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to-moderate hypertension. Further studies are warranted to clarify the

  8. The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Gambogic acid (GA) is a major active ingredient of gamboge, a widely used traditional Chinese medicine that has been reported to be a potent cytotoxic agent against some malignant tumors. Many studies have shown that the NF-kappa B signaling pathway plays an important role in anti-apoptosis and the drug resistance of tumor cells during chemotherapy. In this study, the effects and mechanisms of GA and the NF-kappa B inhibitor celastrol on oral cancer cells were investigated. Three human oral squamous cell carcinoma cell lines, Tca8113, TSCC and NT, were treated with GA alone, celastrol alone or GA plus celastrol. Cytotoxicity was assessed by MTT assay. The rate of apoptosis was examined with annexin V/PI staining as well as transmission electronic microscopy in Tca8113 cells. The level of constitutive NF-kappa B activity in oral squamous cell carcinoma cell lines was determined by immunofluorescence assays and nuclear extracts and electrophoretic mobility shift assays (EMSAs) in vitro. To further investigate the role of NF-kappa B activity in GA and celastrol treatment in oral squamous cell carcinoma, we used the dominant negative mutant SR-IκBα to inhibit NF-kappa B activity and to observe its influence on the effect of GA. The results showed that GA could inhibit the proliferation and induce the apoptosis of the oral squamous cell carcinoma cell lines and that the NF-kappa B pathway was simultaneously activated by GA treatment. The minimal cytotoxic dose of celastrol was able to effectively suppress the GA-induced NF-kappa B pathway activation. Following the combined treatment with GA and the minimal cytotoxic dose of celastrol or the dominant negative mutant SR-IκBα, proliferation was significantly inhibited, and the apoptotic rate of Tca8113 cells was significantly increased. The combination of GA and celastrol has a synergistic antitumor effect. The effect can be primarily attributed to apoptosis induced by a decrease in NF-kappa B pathway activation. The

  9. Glutamine transaminase K intranephron localization in rats determined by urinary excretion after treatment with segment-specific nephrotoxicants

    Energy Technology Data Exchange (ETDEWEB)

    Trevisan, A.; Fanelli, G.; Bicciato, F.; Stocco, E. [Laboratory of Industrial Toxicology, Univ. of Padova (Italy); Cristofori, P. [Medicine Safety Evaluation, Pathology Department, GlaxoWellcome S.p.A., Verona (Italy)

    1998-07-01

    Glutamine transaminase K(GTK) excretion assessed in urine and by kidney histology was evaluated in rats after single treatment with 1.0 mg/kg i.p. of mercuric chloride, 100 mg/kg i.p. of hexachloro-1:3-butadiene (both S{sub 3}, pars recta, segment-specific nephrotoxicants) and 25 mg/kg s.c. of potassium dichromate (S{sub 1}-S{sub 2}, pars convoluta, segment-specific nephrotoxicant). The aim was to correlate segment-specific injury and enzyme excretion in order to assess, using non-vasive methods, localization of GTK along the proximal tubule. Mercuric chloride and hexachloro-1:3-butadiene produced early focal damage in the pars recta (focal necrosis was shown 10 h after treatment, and diffuse necrosis appeared later at 34 and 24 h after treatment). Changes of the pars convoluta were occasional and delayed (72 h after treatment for both substances). On the contrary, potassium dichromate induced damage of the pars convoluta (vacuolar degeneration and focal necrosis were evident 24 h and 48 h after treatment, respectively), whereas the pars recta was affected later (focal vacuolar degeneration was observed 72 h after treatment). Increase urinary GTK excretion was early after treatment with mercuric chloride and hexachloro-1:3-butadiene (significant increase was observed within 10 h), with a peak for both substances 24 h after treatment, in agreement with the necrosis of the pars recta. Potassium dichromate induced a significant increase of enzyme excretion in urine also 24 h after injection, according to histological features showing vacuolar degeneration of the pars convoluta; the peak of excretion was reached 48 h after treatment (delay was due, probably, to s.c. administration). The results show that GTK increased in urine after treatment with S{sub 3}and S {sub 1}-S {sub 2} specific nephrotoxicants; the combination of histological examination and urinary enzyme supports the evidence that the enzyme is distributed along the whole of the proximal tubule. (orig

  10. The Efficacy of Silymarin in Decreasing Transaminase Activities in Non-Alcoholic Fatty Liver Disease: A Randomized Controlled Clinical Trial

    Directory of Open Access Journals (Sweden)

    Ali-Akbar Hajaghamohammadi

    2008-08-01

    Full Text Available Background and Aims: Non-alcoholic fatty liver disease (NAFLD is one of the most common causes of increased liver enzymes. According to statistical reports, 20%-40% of Western population and 5%-30% of the population of Pacific and Asian countries are afflicted with this disease. The prevalence of NAFLD is higher in hyperlipidemic, diabetic and obese people. Considering the high prevalence of NAFLD and its complications and lack of consensus on its treatment, we were motivated to study the efficacy of silymarin on this disease. Methods: In this randomized clinical trial, 50 patients including 32 men (64% and 18 women (36% were divided into case and control groups. The mean age of case group was 40.3 and for control group was 39.9 years. All patients had elevated liver enzymes and had increased liver echogenicity (lipid accumulation on sonography. The case group was treated with one tablet containing 140 mg silymarin per day for two months and the control group was treated in the same manner with placebo. Before and after the study, weight, body mass index (BMI and liver transaminases levels were measured for each patient.Results: The difference between the mean weight and BMI measured before and after the study was not statistically significant in both case and control groups. But the mean ALT and AST levels deceased from 103.1 to 41.4 and 53.7 to 29.1 IU/mL, respectively in case group which was statistically significant (P<0.001 & P<0.001. In the control group, the decrease in mean ALT and AST, with decrease of 7.8 and 2.2 IU/mL, respectively, was not statistically significant.Conclusions: Considering the significant drop in liver enzymes following administration of silymarin, it seems that after conducting similar studies in order to determine the appropriate doses and treatment periods, this cheap and easy to access drug can be prescribed for treatment of NAFLD.

  11. Long-term day-and-night rotating shift work poses a barrier to the normalization of alanine transaminase.

    Science.gov (United States)

    Lin, Yu-Cheng; Hsieh, I-Chun; Chen, Pau-Chung

    2014-05-01

    To evaluate the impact of day-and-night rotating shift work (RSW) on liver health, we performed a retrospective analysis of the association between long-term RSW exposure and the normalization of plasma alanine transaminase (ALT) levels over a five-year period. The data from physical examinations, blood tests, abdominal sonographic examinations, personal histories, and occupational records were collected from a cohort of workers in a semiconductor manufacturing company. The sample population was divided into three subgroups for analysis, according to self-reported shift work status over the five-year interval: persistent daytime workers, workers exposed intermittently to RSW (i-RSW), and workers exposed persistently to RSW (p-RSW). Records were analyzed for 1196 male workers with an initial mean age of 32.5 years (SD 6.0 years), of whom 821 (68.7%) were identified as rotating shift workers, including 374 i-RSW (31.3%) and 447 p-RSW workers (37.4%). At the beginning of the follow-up, 275 were found to have elevated ALT (e-ALT): 25.1% daytime workers, 23.0% i-RSW workers, and 21.3% p-RSW workers (p = 0.098). Of those with e-ALT at the beginning, 101 workers showed normalized serum ALT levels at the end of five-year follow-up: 40 (10.7%) of 375 daytime workers, 32 (8.6%) of 374 i-RSW workers, and 29 (6.5%) of 447 p-RSW workers (p = 0.016). Compared with the workers having persistent e-ALT at the end of follow-up, the workers normalized serum ALT levels had significantly lesser exposures to RSW during follow-up. By performing multivariate logistic regression analyses, and comparing with the persistent daytime co-workers, after controlling for confounding variables (age, occupational factors, educational levels, lifestyle factors, metabolic syndrome, hepatovirus infection, and fatty liver), analysis indicated that the workers exposed to p-RSW were 46% less likely (OR, 0.54; 95% CI, 0.30-0.95; p = 0.03) to attain normal ALT levels within a five-year interval

  12. The proteosome inhibitor MG132 attenuates Retinoic Acid Receptor trans-activation and enhances trans-repression of Nuclear Factor κB. Potential relevance to chemo-preventive interventions with retinoids

    Directory of Open Access Journals (Sweden)

    Rosier Randy N

    2004-03-01

    Full Text Available Abstract Background Nuclear factor kappa B (NFκB is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression. Interestingly, NFκB blockade results in the reciprocal induction of retinoic acid receptors (RARs. Given the established property of RARs as negative regulators of malignant progression, we postulated that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression. Using Line 1 tumor cells as a model for signal regulation of metastatic gene expression, we investigated the reciprocal interactions between NFκB and RARs in response to the pan-RAR agonist, all-trans retinoic acid (at-RA and the pan-RAR antagonist, AGN193109. Results At-RA [0.1–1 μM] dose-dependently activated RAR and coordinately trans-repressed NFκB, while AGN193109 [1–10 μM] dose-dependently antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro-metastatic matrix metalloprotease 9 (MMP 9 and its endogenous inhibitor, the tissue inhibitor of metalloprotease 1 (TIMP 1, in a manner consistent with the putative roles of NFκB and RAR in malignant progression. Activation of RAR concurs with its ubiquitination and proteosomal degradation. Accordingly, the proteosome inhibitor, MG132 [5 μM], blocked RAR degradation, quelled RAR trans-activation and enhanced RAR trans-repression of NFκB. Conclusion We conclude that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.

  13. Mechanism of (NH{sub 4})S{sub 2}O{sub 8} to enhance the anti-corrosion performance of Mo-Ce inhibitor on X80 steel in acid solution

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Yanhua [School of Materials Science and Engineering, Southwest Petroleum University, Chengdu 610500 (China); Zhuang, Jia, E-mail: zj-656@163.com [School of Materials Science and Engineering, Southwest Petroleum University, Chengdu 610500 (China); Zeng, Xianguang [Material Corrosion and Protection Key Laboratory of Sichuan Province, Zigong 643000 (China); Institute of Materials and Chemical Engineering, Sichuan University of Science and Engineering, Zigong 643000 (China)

    2014-09-15

    Highlights: • The 1000 mg/L Na{sub 2}MoO{sub 4} and 500 mg/L Ce(NO{sub 3}){sub 3} has best synergistic effect. • The (NH{sub 4}){sub 2}S{sub 2}O{sub 8} made the valence transformation of cerium (Ce{sup 3+} → Ce{sup 4+}) come true. • The anti-corrosion performance of Mo-Ce inhibitor was improved by (NH{sub 4}){sub 2}S{sub 2}O{sub 8}. • The coordination ability of inhibitor complexes was improved by (NH{sub 4}){sub 2}S{sub 2}O{sub 8}. • The bonding force and adsorption between inhibitor and steel surface was enhanced. - Abstract: Ce(NO{sub 3}){sub 3} and Na{sub 2}MoO{sub 4} are adopted to form (Mo-Ce) composite corrosion inhibitor in allusion to the corrosion problem of steel in acidic conditions. The experimental results showed that the anticorrosion effects were enhanced and the inhibition efficiencies were increased by (NH{sub 4}){sub 2}S{sub 2}O{sub 8}. The reason of enhancement is the increase of coordination bonds amount between Ce{sup 4+} and MoO{sub 4}{sup 2−}, the augment of combining sites of interface between anti-corrosion film and steel, and the reinforce of adsorption caused by the transformation of Ce{sup 3+} to Ce{sup 4+} by oxidants. The process and conditions for transformation of Ce{sup 3+} to Ce{sup 4+} and formation of complexes are discussed. The related thermodynamic and kinetic parameters are calculated and the possibility for (NH{sub 4}){sub 2}S{sub 2}O{sub 8} to improve the performance of Mo-Ce corrosion inhibitor is proved.

  14. Effects of inhibitors of protein synthesis and intracellular transport on the gamma-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, G H; Meier, E;

    1990-01-01

    differentiation and GABA receptor expression was investigated in cultured cerebellar granule cells. After 4 days in culture the neurons were exposed to the inhibitors for 6 h in the simultaneous presence of THIP. Subsequently, cultures were either fixed for electron microscopic examination or used for preparation...... of membranes for [3H]GABA binding assays. In some experiments the functional activity of the newly induced low-affinity GABA receptors was assessed by investigation of the ability of GABA to inhibit neurotransmitter release from the neurons. These experiments were performed to differentiate between...... an intracellular and a plasma membrane localization of the receptors. In all experiments cultures treated with THIP alone served as controls. The inhibitors of protein synthesis totally abolished the ability of THIP to induce low-affinity GABA receptors. In contrast, the inhibitors of intracellular transport...

  15. The amino acid sequence of a 20 kDa bifunctional subtilisin/alpha-amylase inhibitor from bran [correction of brain] of rice (Oryza sativa L.) seeds.

    Science.gov (United States)

    Ohtsubo, K; Richardson, M

    1992-08-31

    A 20 kDa bifunctional inhibitor of the microbial proteinase, subtilisin, and the alpha-amylase from the larvae of the red flour beetle (Tribolium castaneum) was purified from bran of rice seeds by saline extraction, precipitation with ammonium sulphate, ion-exchange chromatography on DEAE-Cellulose and Toyopearl CM-650, and preparative HPLC on Vydac C18. The complete primary structure was determined by automatic degradation of the intact, reduced and S-alkylated protein, and by manual DABITC/PITC micro-sequencing of peptides obtained from the protein following separate enzymic digestions with trypsin, pepsin, chymotrypsin, elastase and the protease from S. aureus V8. The protein sequence, which contained 176 residues, showed strong homology with similar bifunctional inhibitors previously isolated from wheat and barley which are related to the Kunitz family of proteinase inhibitors from legume seeds. PMID:1511747

  16. Sunflower trypsin inhibitor-1.

    Science.gov (United States)

    Korsinczky, Michael L J; Schirra, Horst Joachim; Craik, David J

    2004-10-01

    SFTI-1 is a bicyclic 14 amino acid peptide that was originally isolated from the seeds of the sunflower Helianthus annuus. It is a potent inhibitor of trypsin, with a sub-nanomolar K(i) value and is homologous to the active site region of the well-known family of serine protease inhibitors known as the Bowman-Birk trypsin inhibitors. It has a cyclic backbone that is cross-braced by a single disulfide bridge and a network of hydrogen bonds that result in a well-defined structure. SFTI-1 is amenable to chemical synthesis, allowing for the creation of synthetic variants. Alterations to the structure such as linearising the backbone or removing the disulfide bridge do not reduce the potency of SFTI-1 significantly, and minimising the peptide to as few as nine residues results in only a small decrease in reactivity. The creation of linear variants of SFTI-1 also provides a tool for investigating putative linear precursor peptides. The mechanism of biosynthesis of SFTI-1 is not yet known but it seems likely that it is a gene-coded product that has arisen from a precursor protein that may be evolutionarily related to classic Bowman-Birk inhibitors. PMID:15544530

  17. 曼尼希碱型缓蚀剂的研究现状与展望%Prospect and Progress of Resarch on New Acidizing Corrosion Inhibitor

    Institute of Scientific and Technical Information of China (English)

    周也

    2012-01-01

    结合现有的国内外对新型缓蚀剂的研究现状,阐述了曼尼希碱型缓蚀剂的合成及缓蚀机理,讨论了其应用现状和发展前景。%Combined existing domestic and foreign synthesis of Mannich base inhibitors and corrosion status and development prospects. research status of new corrosion inhibitor. inhibition mechanism. Also discussed its Explained application

  18. CORROSION INHIBITION AND SYNERGISTIC EFFECT OF GREEN SCALE INHIBITOR POLYEPOXYSUCCINIC ACID%绿色阻垢剂聚环氧琥珀酸的缓蚀协同效应

    Institute of Scientific and Technical Information of China (English)

    熊蓉春; 周庆; 魏刚

    2003-01-01

    The corrosion inhibition of a kind of green scale inhibitor, polyepoxysuccinic acid (PESA) was studied based on dynamic experiments. In addition, the synergistic effect among PESA, Zn2+ and sodium gluconate was also investigated. According to the experimental data, when only PESA is used, it had fairly good effect on steel. The synergy between PESA and Zn2+ or sodium gluconate was poor. However, the synergistic effect of PESA, Zn2+ and sodium gluconate is very good. Further experiments show that the corrosion inhibition of PESA is mainly affected by oxygen atom inserted.

  19. Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules

    Directory of Open Access Journals (Sweden)

    Das Undurti N

    2008-10-01

    Full Text Available Abstract Lowering plasma low density lipoprotein-cholesterol (LDL-C, blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a β blocker, and an angiotensin converting enzyme (ACE inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by ~80%. Essential fatty acids (EFAs and their long-chain metabolites: γ-linolenic acid (GLA, dihomo-GLA (DGLA, arachidonic acid, eicosapentaenoic acid (EPA, and docosahexaenoic acid (DHA and other products such as prostaglandins E1 (PGE1, prostacyclin (PGI2, PGI3, lipoxins (LXs, resolvins, protectins including neuroprotectin D1 (NPD1 prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-γ ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of ω-3 and ω-6 fatty acids and the co

  20. Effects of the methane-inhibitors nitrate, nitroethane, lauric acid, Lauricidin**R and the Hawaiian marine algae, Chaetoceros, on ruminal fermentation in vitro

    Science.gov (United States)

    The effects of several methane-inhibitors on rumen fermentation were compared during three 24 h consecutive batch cultures of ruminal microbes in the presence of nonlimiting amounts of hydrogen. After the initial incubation series, methane production was reduced greater than 92% from that of nontre...

  1. Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.

    Science.gov (United States)

    Elgaher, Walid A M; Sharma, Kamal K; Haupenthal, Jörg; Saladini, Francesco; Pires, Manuel; Real, Eleonore; Mély, Yves; Hartmann, Rolf W

    2016-08-11

    We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity. PMID:27339173

  2. In situ detoxification of dry dilute acid pretreated corn stover by co-culture of xylose-utilizing and inhibitor-tolerant Saccharomyces cerevisiae increases ethanol production.

    Science.gov (United States)

    Zhu, Jia-Qing; Li, Xia; Qin, Lei; Li, Wen-Chao; Li, Hui-Ze; Li, Bing-Zhi; Yuan, Ying-Jin

    2016-10-01

    Co-culture of xylose-utilizing and inhibitor-tolerant Saccharomyces cerevisiae was developed for bioethanol production from undetoxified pretreated biomass in simultaneously saccharification and co-fermentation (SSCF) process. Glucose accumulation during late fermentation phase in SSCF using xylose-utilizing strain can be eliminated by the introduction of inhibitor-tolerant strain. Effect of different ratios of two strains was investigated and xylose-utilizing strain to inhibitor-tolerant strain ratio of 10:1 (w/w) showed the best xylose consumption and the highest ethanol yield. Inoculating of xylose-utilizing strain at the later stage of SSCF (24-48h) exhibited lower ethanol yield than inoculating at early stage (the beginning 0-12h), probably due to the reduced enzymatic efficiency caused by the unconsumed xylose and oligomeric sugars. Co-culture SSCF increased ethanol concentration by 21.2% and 41.0% comparing to SSCF using individual inhibitor-tolerant and xylose-utilizing strain (increased from 48.5 and 41.7g/L to 58.8g/L), respectively, which suggest this co-culture system was very promising. PMID:27387414

  3. Biodegradation of the Microbial Metabolic Inhibitors of Iignocellulose Hydrolyzed by Dilute Acid%木质纤维稀酸水解物微生物代谢抑制物的生物降解

    Institute of Scientific and Technical Information of China (English)

    吴黎明; 周玉恒; 陈海珊; 张厚瑞

    2012-01-01

    Dilute acid is an important catalyst for generating fermentable sugar through lignocellulose hydrolysis. But this process will be accompanied by production of a large number of microbial metabolic inhibitors, which serious-ly affects the fermentation of hydrolysates. In this paper, we described the types of fermentative inhibitors, the mecha-nism of their formation and the metabolism of their toxicology, as well as the research advances on techniques for bio-logical detoxification and the biological degradation pathways of different inhibitors. Furthermore, we analyzed its de-velopment based on previous researches.%稀酸是木质纤维素水解生成可发酵性糖的重要催化剂,但会伴随产生大量的微生物代谢抑制物。严重影响水解物的可发酵性。文中介绍了发酵抑制物的种类、形成机理、代谢毒理,以及不同抑制物的生物降解途径与生物脱毒方法的研究进展,在此基础上对其发展方向作了进一步分析。

  4. Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin.

    Science.gov (United States)

    Gill, Iqbal; Patel, Ramesh

    2006-02-01

    An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.

  5. Succinic semialdehyde as a substrate for the formation of gamma-aminobutyric acid.

    Science.gov (United States)

    van Bemmelen, F J; Schouten, M J; Fekkes, D; Bruinvels, J

    1985-11-01

    The conversion of succinic semialdehyde into gamma-aminobutyric acid (GABA) by GABA-transaminase was measured in rat brain homogenate in the presence of different concentrations of the cosubstrate glutamate. The calculated kinetic parameters of succinic semialdehyde for GABA-transaminase were a limiting Km value of 168 microM and a limiting Vmax value of 38 mumol g-1 h-1. Combination with previously obtained data for the conversion of GABA into succinic semialdehyde revealed a kEq value of 0.04, indicating that equilibrium of GABA-transaminase is biased toward the formation of GABA. The increased formation of GABA in the presence of succinic semialdehyde was not due to an increased conversion of glutamate into GABA by glutamic acid decarboxylase. Therefore these results indicate that succinic semialdehyde can act as a precursor for GABA synthesis.

  6. Cellular Inhibition of Checkpoint Kinase 2 (Chk2) and Potentiation of Camptothecins and Radiation by the Novel Chk2 Inhibitor PV1019 [7-Nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide

    Energy Technology Data Exchange (ETDEWEB)

    Jobson, Andrew G.; Lountos, George T.; Lorenzi, Philip L.; Llamas, Jenny; Connelly, John; Cerna, David; Tropea, Joseph E.; Onda, Akikazu; Zoppoli, Gabriele; Kondapaka, Sudhir; Zhang, Guangtao; Caplen, Natasha J.; Cardellina, II, John H.; Yoo, Stephen S.; Monks, Anne; Self, Christopher; Waugh, David S.; Shoemaker, Robert H.; Pommier, Yves; (NIH)

    2010-04-05

    Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated pathway, which is activated by genomic instability and DNA damage, leading to either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored therapeutic target against cancer cells. We recently reported 4,4'-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC 744039) [7-nitro-1H-indole-2-carboxylic acid {l_brace}4-[1-(guanidinohydrazone)-ethyl]-phenyl{r_brace}-amide], which is a selective submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019 bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2 autophosphorylation (which represents the cellular kinase activation of Chk2), Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019 also protects normal mouse thymocytes against ionizing radiation-induced apoptosis, and it shows synergistic antiproliferative activity with topotecan, camptothecin, and radiation in human tumor cell lines. We also show that PV1019 and Chk2 small interfering RNAs can exert antiproliferative activity themselves in the cancer cells with high Chk2 expression in the NCI-60 screen. These data indicate that PV1019 is a potent and selective inhibitor of Chk2 with chemotherapeutic and radiosensitization potential.

  7. 缬氨酸转氨酶拆分DL-缬氨酸的催化条件%Study on chiral resolution of DL-valine valine catalyzed by valine-pyruvate transaminase

    Institute of Scientific and Technical Information of China (English)

    张飞; 魏涛; 刘寅; 韩亚伟; 何培新

    2013-01-01

    利用具有缬氨酸转氨酶活性的工程菌对DL-缬氨酸进行拆分,考察了反应温度、pH值、底物摩尔比、底物浓度和金属离子对酶活性和底物转化率的影响.结果显示,该催化反应的最适反应条件为:反应温度是45℃,pH =9,L-缬氨酸与丙酮酸的摩尔比1∶8,DL-缬氨酸初始浓度为0.6 mol/L、丙酮酸初始浓度为2.4 mol/L,0.5 mmol/L的Mg2+和Na+对酶活性有明显的促进作用.%An engineered strain with catalytic activity of valine-pyruvate transaminase was used in chiral resolution of DL-valine.The effect of reaction conditions such as reaction temperature, pH, substrate mole ratio, substrate concentration and metal ions on enzyme activity was studied.Results showed that the optimal conditions were 45 ℃ and pH9.The optimal substrate ratio of L-valine to pyruvic acid was 1:8 ( mol: mol).The initial substrate concentration of DL-xaline and pyruvic acid were 0.6 mol/L and 2.4 mol/L respectively.Enzyme activity was improved by addition of 0.5 mmol/L Mg2+ and Na+.

  8. Efficient Complex Surfactants from the Type of Fatty Acids as Corrosion Inhibitors for Mild Steel C1018 in CO{sub 2}-Environments

    Energy Technology Data Exchange (ETDEWEB)

    Abbasov, Vagif M.; Abd Ellatee, Hany M.; Aliyeva, Leylufer I.; Ismayilov, Ismayil T.; Qasimov, Elmar E.; Narmin, Mamedova M. [National Academy of Sciences of Azerbaijan, Baku (Azerbaijan)

    2013-02-15

    The efficiency of three complex surfactants based on sunflower oil and nitrogen containing compounds as corrosion inhibitors for mild steel in CO{sub 2}-saturated 1% NaCl solution, has been determined by weight loss and LPR corrosion rate measurements. These compounds inhibit corrosion even at very low concentrations. The inhibition process was attributed to the formation of an adsorbed film on the metal surface that protects the metal against corrosive media. The inhibition efficiency increases with increasing the concentration of the studied inhibitors. Maximum inhibition efficiency of the surfactants is observed at concentrations around its critical micellar concentration (CMC). Adsorption of complex surfactants on the mild steel surface is in agreement with the Langmuir adsorption isotherm model, and the calculated Gibbs free energy values confirm the chemical nature of the adsorption. Energy dispersive X-ray fluorescence microscopy (EDRF) observations of the electrode surface confirmed the existence of such an adsorbed film.

  9. Folic acid mitigated cardiac dysfunction by normalizing the levels of tissue inhibitor of metalloproteinase and homocysteine-metabolizing enzymes postmyocardial infarction in mice

    OpenAIRE

    Qipshidze, Natia; Tyagi, Neetu; Sen, Utpal; Givvimani, Srikanth; Metreveli, Naira; LOMINADZE, DAVID; Tyagi, Suresh C

    2010-01-01

    Myocardial infarction (MI) results in significant metabolic derangement, causing accumulation of metabolic by product, such as homocysteine (Hcy). Hcy is a nonprotein amino acid generated during nucleic acid methylation and demethylation of methionine. Folic acid (FA) decreases Hcy levels by remethylating the Hcy to methionine, by 5-methylene tetrahydrofolate reductase (5-MTHFR). Although clinical trials were inconclusive regarding the role of Hcy in MI, in animal models, the levels of 5-MTHF...

  10. INFLUENCE OF VACUUM-PULSE DRYING ON THE CONTENT OF FREE AMINO ACIDS, TRYPSINE INHIBITOR ACTIVITY AND COMPOSITION OF VOLATILE COMPONENTS OF MUSHROOMS

    OpenAIRE

    Shcheglova, I.; Vereshchagin, A.

    2015-01-01

    Wild-growing mushrooms traditionally are considered one of the sources of food fibers, vegetable proteins, macro and micronutrients, and also flavor components. However, the composition of mushrooms includes antinutritional substances capable to selectively reduce the absorption of certain nutrients. These are primarily antienzymes or proteinase inhibitors, which reduce the absorption of proteins. Previous studies have indicated applicability of vacuum-pulse drying to improve the nutritional ...

  11. Plants as a source of green corrosion inhibitors on mild steel in hydrochloric acid: The case of oil extract of leaves of Pistacia lentiscus from Saidia Morocco

    OpenAIRE

    Aouinti, Fatima; Elmsellem, Hicham; Bachiri, Ali; Fauconnier, Marie-Laure; Chetouani, Ahmed; Chaouki, Belbachir; Aouniti, Abdelouahad; HAMMOUTI, Belkheir

    2014-01-01

    The aim of this work was to characterize the essential oils of Pistacia lentiscus (P.L) from Saidia Morocco and analysis by gas chromatograph interfaced with a mass spectrometer (GC-MS). The Corrosion inhibition effect of organic oil and extract of leaves of Pistacia lentiscus (P.L) of mild steel in 1M HCl solution was carried out using, gravimetric, electrochemical polarization and EIS methods. Experiments are performed by varying concentration of the inhibitor. The inhibition efficiency inc...

  12. Corrosion inhibitors from expired drugs.

    Science.gov (United States)

    Vaszilcsin, Nicolae; Ordodi, Valentin; Borza, Alexandra

    2012-07-15

    This paper presents a method of expired or unused drugs valorization as corrosion inhibitors for metals in various media. Cyclic voltammograms were drawn on platinum in order to assess the stability of pharmaceutically active substances from drugs at the metal-corrosive environment interface. Tafel slope method was used to determine corrosion rates of steel in the absence and presence of inhibitors. Expired Carbamazepine and Paracetamol tablets were used to obtain corrosion inhibitors. For the former, the corrosion inhibition of carbon steel in 0.1 mol L(-1) sulfuric acid solution was about 90%, whereas for the latter, the corrosion inhibition efficiency of the same material in the 0.25 mol L(-1) acetic acid-0.25 mol L(-1) sodium acetate buffer solution was about 85%.

  13. Cadmium absorption inhibitors for soil

    Energy Technology Data Exchange (ETDEWEB)

    Kitamura, S.

    1974-05-25

    Cadmium absorption by soil is one cause of soil pollution. Cadmium adsorption inhibitors were prepared by mixing alginic acid which contained brown algae (Ascophyllum nodosum) and an inorganic material, shell fossils. This mixture was highly effective in preventing cadmium absorption by the soil.

  14. Highly Efficient Synthesis of Two Hyaluronan Trisaccharide Analogues for Potential Hyaluronic Acid Synthases Inhibitors%透明质酸三糖模拟物的高效合成

    Institute of Scientific and Technical Information of China (English)

    魏国华; 杜宇国; Khushi L. Matta

    2009-01-01

    The syntheses of two hyaluronan trisaccharide analogues, naphthyl 0-(3-methoxy-B-D-glucopy-ranosyluronic acid)-(1,3)-O-(2-acetamido-2-deoxy-B-D-glucopyranosyl)-(1,4)-0-B-D-glucopyranosyluronic acid and naphthyl O-(3-methoxy-2-acetamido-2-deoxy-B-D-glucopyranosyl)-(1,4)-O-(B-D-glucopyranosylu-ronic acid)-(1,3 )-O-2-acetamido-2-deoxy-B-D-glucopyranoside, were described. Construction of the target molecules was achieved through a combination of BF_3·Et_2O/toluene system and trichloroacetimidate glycosyia-tion methodology. This is the first report on the synthesis of the 3-methoxyl derivatives, which represent the smallest fragments that incorporate all the structural features of polymeric hyaluronan and can be used for potential hyaluronic acid synthases inhibitors.%设计合成了2个透明质酸(HA)模拟物1和2, 通过最小基团MeO的引入修饰, 模拟天然HA片段的特性, 用于透明质酸合成酶(HAS)催化机理与抑制剂的研究.

  15. Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Ce; Geders, Todd W.; Park, Sae Woong; Wilson, Daniel J.; Boshoff, Helena I.; Abayomi, Orishadipe; Barry, III, Clifton E.; Schnappinger, Dirk; Finzel, Barry C.; Aldrich, Courtney C. (Weill-Med); (UMM); (NIAID)

    2011-11-16

    BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal 5'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 {angstrom} resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.

  16. Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3 Single Amino Acid near the Active Site Influences Inhibitor Sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Bum Soo; Allali-Hassani, Abdellah; Tempel, Wolfram; Finerty, Jr., Patrick J.; MacKenzie, Farrell; Dimov, Svetoslav; Vedadi, Masoud; Park, Hee-Won (Toronto)

    2010-07-06

    Human choline kinase (ChoK) catalyzes the first reaction in phosphatidylcholine biosynthesis and exists as ChoK{alpha} ({alpha}1 and {alpha}2) and ChoK{beta} isoforms. Recent studies suggest that ChoK is implicated in tumorigenesis and emerging as an attractive target for anticancer chemotherapy. To extend our understanding of the molecular mechanism of ChoK inhibition, we have determined the high resolution x-ray structures of the ChoK{alpha}1 and ChoK{beta} isoforms in complex with hemicholinium-3 (HC-3), a known inhibitor of ChoK. In both structures, HC-3 bound at the conserved hydrophobic groove on the C-terminal lobe. One of the HC-3 oxazinium rings complexed with ChoK{alpha}1 occupied the choline-binding pocket, providing a structural explanation for its inhibitory action. Interestingly, the HC-3 molecule co-crystallized with ChoK{beta} was phosphorylated in the choline binding site. This phosphorylation, albeit occurring at a very slow rate, was confirmed experimentally by mass spectroscopy and radioactive assays. Detailed kinetic studies revealed that HC-3 is a much more potent inhibitor for ChoK{alpha} isoforms ({alpha}1 and {alpha}2) compared with ChoK{beta}. Mutational studies based on the structures of both inhibitor-bound ChoK complexes demonstrated that Leu-401 of ChoK{alpha}2 (equivalent to Leu-419 of ChoK{alpha}1), or the corresponding residue Phe-352 of ChoK{beta}, which is one of the hydrophobic residues neighboring the active site, influences the plasticity of the HC-3-binding groove, thereby playing a key role in HC-3 sensitivity and phosphorylation.

  17. Some Phthalocyanine and Naphthalocyanine Derivatives as Corrosion Inhibitors for Aluminium in Acidic Medium: Experimental, Quantum Chemical Calculations, QSAR Studies and Synergistic Effect of Iodide Ions.

    Science.gov (United States)

    Dibetsoe, Masego; Olasunkanmi, Lukman O; Fayemi, Omolola E; Yesudass, Sasikumar; Ramaganthan, Baskar; Bahadur, Indra; Adekunle, Abolanle S; Kabanda, Mwadham M; Ebenso, Eno E

    2015-08-28

    The effects of seven macrocyclic compounds comprising four phthalocyanines (Pcs) namely 1,4,8,11,15,18,22,25-octabutoxy-29H,31H-phthalocyanine (Pc1), 2,3,9,10,16,17,23,24-octakis(octyloxy)-29H,31H-phthalocyanine (Pc2), 2,9,16,23-tetra-tert-butyl-29H,31H-phthalocyanine (Pc3) and 29H,31H-phthalocyanine (Pc4), and three naphthalocyanines namely 5,9,14,18,23,27,32,36-octabutoxy-2,3-naphthalocyanine (nPc1), 2,11,20,29-tetra-tert-butyl-2,3-naphthalocyanine (nPc2) and 2,3-naphthalocyanine (nP3) were investigated on the corrosion of aluminium (Al) in 1 M HCl using a gravimetric method, potentiodynamic polarization technique, quantum chemical calculations and quantitative structure activity relationship (QSAR). Synergistic effects of KI on the corrosion inhibition properties of the compounds were also investigated. All the studied compounds showed appreciable inhibition efficiencies, which decrease with increasing temperature from 30 °C to 70 °C. At each concentration of the inhibitor, addition of 0.1% KI increased the inhibition efficiency compared to the absence of KI indicating the occurrence of synergistic interactions between the studied molecules and I(-) ions. From the potentiodynamic polarization studies, the studied Pcs and nPcs are mixed type corrosion inhibitors both without and with addition of KI. The adsorption of the studied molecules on Al surface obeys the Langmuir adsorption isotherm, while the thermodynamic and kinetic parameters revealed that the adsorption of the studied compounds on Al surface is spontaneous and involves competitive physisorption and chemisorption mechanisms. The experimental results revealed the aggregated interactions between the inhibitor molecules and the results further indicated that the peripheral groups on the compounds affect these interactions. The calculated quantum chemical parameters and the QSAR results revealed the possibility of strong interactions between the studied inhibitors and metal surface. QSAR analysis on the

  18. Some Phthalocyanine and Naphthalocyanine Derivatives as Corrosion Inhibitors for Aluminium in Acidic Medium: Experimental, Quantum Chemical Calculations, QSAR Studies and Synergistic Effect of Iodide Ions.

    Science.gov (United States)

    Dibetsoe, Masego; Olasunkanmi, Lukman O; Fayemi, Omolola E; Yesudass, Sasikumar; Ramaganthan, Baskar; Bahadur, Indra; Adekunle, Abolanle S; Kabanda, Mwadham M; Ebenso, Eno E

    2015-01-01

    The effects of seven macrocyclic compounds comprising four phthalocyanines (Pcs) namely 1,4,8,11,15,18,22,25-octabutoxy-29H,31H-phthalocyanine (Pc1), 2,3,9,10,16,17,23,24-octakis(octyloxy)-29H,31H-phthalocyanine (Pc2), 2,9,16,23-tetra-tert-butyl-29H,31H-phthalocyanine (Pc3) and 29H,31H-phthalocyanine (Pc4), and three naphthalocyanines namely 5,9,14,18,23,27,32,36-octabutoxy-2,3-naphthalocyanine (nPc1), 2,11,20,29-tetra-tert-butyl-2,3-naphthalocyanine (nPc2) and 2,3-naphthalocyanine (nP3) were investigated on the corrosion of aluminium (Al) in 1 M HCl using a gravimetric method, potentiodynamic polarization technique, quantum chemical calculations and quantitative structure activity relationship (QSAR). Synergistic effects of KI on the corrosion inhibition properties of the compounds were also investigated. All the studied compounds showed appreciable inhibition efficiencies, which decrease with increasing temperature from 30 °C to 70 °C. At each concentration of the inhibitor, addition of 0.1% KI increased the inhibition efficiency compared to the absence of KI indicating the occurrence of synergistic interactions between the studied molecules and I(-) ions. From the potentiodynamic polarization studies, the studied Pcs and nPcs are mixed type corrosion inhibitors both without and with addition of KI. The adsorption of the studied molecules on Al surface obeys the Langmuir adsorption isotherm, while the thermodynamic and kinetic parameters revealed that the adsorption of the studied compounds on Al surface is spontaneous and involves competitive physisorption and chemisorption mechanisms. The experimental results revealed the aggregated interactions between the inhibitor molecules and the results further indicated that the peripheral groups on the compounds affect these interactions. The calculated quantum chemical parameters and the QSAR results revealed the possibility of strong interactions between the studied inhibitors and metal surface. QSAR analysis on the

  19. Some Phthalocyanine and Naphthalocyanine Derivatives as Corrosion Inhibitors for Aluminium in Acidic Medium: Experimental, Quantum Chemical Calculations, QSAR Studies and Synergistic Effect of Iodide Ions

    Directory of Open Access Journals (Sweden)

    Masego Dibetsoe

    2015-08-01

    Full Text Available The effects of seven macrocyclic compounds comprising four phthalocyanines (Pcs namely 1,4,8,11,15,18,22,25-octabutoxy-29H,31H-phthalocyanine (Pc1, 2,3,9,10,16,17,23,24-octakis(octyloxy-29H,31H-phthalocyanine (Pc2, 2,9,16,23-tetra-tert-butyl-29H,31H-phthalocyanine (Pc3 and 29H,31H-phthalocyanine (Pc4, and three naphthalocyanines namely 5,9,14,18,23,27,32,36-octabutoxy-2,3-naphthalocyanine (nPc1, 2,11,20,29-tetra-tert-butyl-2,3-naphthalocyanine (nPc2 and 2,3-naphthalocyanine (nP3 were investigated on the corrosion of aluminium (Al in 1 M HCl using a gravimetric method, potentiodynamic polarization technique, quantum chemical calculations and quantitative structure activity relationship (QSAR. Synergistic effects of KI on the corrosion inhibition properties of the compounds were also investigated. All the studied compounds showed appreciable inhibition efficiencies, which decrease with increasing temperature from 30 °C to 70 °C. At each concentration of the inhibitor, addition of 0.1% KI increased the inhibition efficiency compared to the absence of KI indicating the occurrence of synergistic interactions between the studied molecules and I− ions. From the potentiodynamic polarization studies, the studied Pcs and nPcs are mixed type corrosion inhibitors both without and with addition of KI. The adsorption of the studied molecules on Al surface obeys the Langmuir adsorption isotherm, while the thermodynamic and kinetic parameters revealed that the adsorption of the studied compounds on Al surface is spontaneous and involves competitive physisorption and chemisorption mechanisms. The experimental results revealed the aggregated interactions between the inhibitor molecules and the results further indicated that the peripheral groups on the compounds affect these interactions. The calculated quantum chemical parameters and the QSAR results revealed the possibility of strong interactions between the studied inhibitors and metal surface. QSAR

  20. The gastric acid secretagogue gastrin-releasing peptide and the inhibitor oxyntomodulin do not exert their effect directly on the parietal cell in the rat

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Holst, J J

    1988-01-01

    Previous studies suggested that gastrin-releasing peptide (a neuropeptide found in rat oxyntic mucosa) and oxyntomodulin (a glucagon-containing peptide of mammalian gut) could directly affect the acid secretion of the parietal cells. We therefore studied their effect on gastric acid production in...... and histamine-stimulated parietal cells confirmed that the cells retained the normal morphology of intracellular organelles and that the cells responded to physiological stimulation by marked expansion of the intracellular canaliculi.......Previous studies suggested that gastrin-releasing peptide (a neuropeptide found in rat oxyntic mucosa) and oxyntomodulin (a glucagon-containing peptide of mammalian gut) could directly affect the acid secretion of the parietal cells. We therefore studied their effect on gastric acid production...... in vitro by measuring [14C]-aminopyrine accumulation, a reliable index of H+ generation, in isolated rat parietal cells. However, neither gastrin-releasing peptide nor oxyntomodulin influenced basal acid secretion or histamine-stimulated gastric acid secretion. Electron-microscopic studies of unstimulated...

  1. Study on the synthesis and performance evaluation of a kind of acidizing corrosion inhibitor%一种酸化缓蚀剂的合成及性能研究

    Institute of Scientific and Technical Information of China (English)

    孙天祥; 李丛妮; 李浩; 杨俊伟

    2011-01-01

    以甲醛、乙二胺、苯乙酮为反应主要原料,利用Mannich反应合成了曼尼希碱缓蚀剂.最佳合成条件:反应温度50℃,反应时间12 h,pH值为4,苯乙酮、甲醛、乙二胺物质的量比为2∶4∶1.用静态失重法对其缓蚀性能进行了综合评价.结果表明,在90℃、15%的盐酸中加入1%的缓蚀剂,N-80钢片的腐蚀速率可以达到2.473 g/(m2·h),具有良好的缓蚀性能.%A new acidizing corrosion inhibitor was synthesized by Mannich reaction with formaldehyde, ethylenediamine and acetophenone as the raw materials. The optimal synthetic conditions were found as follows:reaction temperature 50 *C ,the reaction time 12 h,pH value 4.0,molar ratio of acetophenone, formaldehyde and ethylenediamine 2^4:1. The performance of corrosion inhibitor was evaluated by zero-gravity test. The results indicated that at 90 X. ,20% HC1 with 1.0% corrosion inhibitor, the corrosion rate was 2.473 g/(m2 ? H) ,the inhibition efficiency was the best.

  2. ac impedance, X-ray photoelectron spectroscopy and density functional theory studies of 3,5-bis(n-pyridyl)-1,2,4-oxadiazoles as efficient corrosion inhibitors for carbon steel surface in hydrochloric acid solution

    Energy Technology Data Exchange (ETDEWEB)

    Outirite, Moha; Lagrenee, Michel; Lebrini, Mounim [Unite de Catalyse et de Chimie du Solide, UMR-CNRS 8181, ENSCL, B.P. 90108, F-59652 Villeneuve d' Ascq Cedex (France); Traisnel, Michel; Jama, Charafeddine [Laboratoire des Procedes d' Elaboration des Revetements Fonctionnels, PERF UMR-CNRS 8008, ENSCL, B.P. 90108, F-59652 Villeneuve d' Ascq Cedex (France); Vezin, Herve [Laboratoire de Chimie Organique et Macromoleculaire, UMR-CNRS 8009, USTL Bat C4, F-59655 Villeneuve d' Ascq Cedex (France); Bentiss, Fouad, E-mail: fbentiss@enscl.f [Laboratoire de Chimie de Coordination et d' Analytique, Faculte des Sciences, Universite Chouaib Doukkali, B.P. 20, M-24000 El Jadida (Morocco)

    2010-02-01

    The corrosion inhibition properties of a new class of oxadiazole derivatives, namely 3,5-bis(n-pyridyl)-1,2,4-oxadiazoles (n-DPOX) for C38 carbon steel corrosion in 1 M HCl medium were analysed by electrochemical impedance spectroscopy (EIS). An adequate structural model of the interface was used and the values of the corresponding parameters were calculated and discussed. The experimental results showed that these compounds are excellent inhibitors for the C38 steel corrosion in acid solution and that the protection efficiency increased with increasing the inhibitors concentration. Electrochemical impedance data demonstrate that the addition of the n-DPOX derivatives in the corrosive solution decreases the charge capacitance and simultaneously increases the function of the charge/discharge of the interface, facilitating the formation of an adsorbed layer over the steel surface. Adsorption of these inhibitors on the steel surface obeys to the Langmuir adsorption isotherm. X-ray photoelectron spectroscopy (XPS) and the thermodynamic data of adsorption showed that inhibition of steel corrosion in normal hydrochloric solution by n-DPOX is due to the formation of a chemisorbed film on the steel surface. Quantum chemical calculations using the Density Functional Theory (DFT) and the Quantitative Structure Activity Relationship (QSAR) approach were performed on n-DPOX derivatives to determine the relationship between molecular structure and their inhibition efficiencies. The results of the quantum chemical calculations and experimental inhibition efficiency were subjected to correlation analysis and indicate that their inhibition effect is closely related to E{sub HOMO}, E{sub LUMO}, and dipole moment (mu).

  3. Catabolism of Branched Chain Amino Acids Supports Respiration but Not Volatile Synthesis in Tomato Fruits

    Institute of Scientific and Technical Information of China (English)

    Andrej Kochevenko; Wagner L.Araújo; Gregory S.Maloney; Denise M.Tieman; Phuc Thi Do; Mark G.Taylor; Harry J.Klee; Alisdair R.Fernie

    2012-01-01

    The branched-chain amino acid transaminases (BCATs) have a crucial role in metabolism of the branched-chain amino acids leucine,isoleucine,and valine.These enzymes catalyze the last step of synthesis and the initial step of degradation of these amino acids.Although the biosynthetic pathways of branched chain amino acids in plants have been extensively investigated and a number of genes have been characterized,their catabolism in plants is not yet completely understood.We previously characterized the branched chain amino acid transaminase gene family in tomato,revealing both the subcellular localization and kinetic properties of the enzymes encoded by six genes.Here,we examined possible functions of the enzymes during fruit development.We further characterized transgenic plants differing in the expression of branched chain amino acid transaminases 1 and 3,evaluating the rates of respiration in fruits deficient in BCAT1 and the levels of volatiles in lines overexpressing either BCAT1 or BCAT3.We quantitatively tested,via precursor and isotope feeding experiments,the importance of the branched chain amino acids and their corresponding keto acids in the formation of fruit volatiles.Our results not only demonstrate for the first time the importance of branched chain amino acids in fruit respiration,but also reveal that keto acids,rather than amino acids,are the likely precursors for the branched chain flavor volatiles.

  4. Effect of gamma irradiation on the activity of alanine and aspartate transaminases in subcellular fractions of the brain and heart in white rats

    Energy Technology Data Exchange (ETDEWEB)

    Plenin, A.E.

    1973-01-01

    In experiments on rats, the activity of alanine (I) and aspartate transaminases (II) was studied in homogenates and subcellular fractions of the brain and myocardium under normal conditions and for 30 days after ..gamma.. irradiation at 40 rads. The activity of II in brain homogenates increased 1 hour after irradiation but decreased by 20 percent on day 3; it decreased again on days 7 and 15. The activity of brain I increased after 1 hour and 3 days but then returned to normal. The activity of I in heart homogenates increased in all the periods after irradiation. The subcellular fractions exhibited phase changes in the activity of the enzymes. These changes were different in nature from those observed after X and ..gamma.. irradiation at the same dose.

  5. 3-Nitropropionic Acid is a Suicide Inhibitor of MitochondrialRespiration that, Upon Oxidation by Complex II, Forms a Covalent AdductWith a Catalytic Base Arginine in the Active Site of the Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Li-shar; Sun, Gang; Cobessi, David; Wang, Andy C.; Shen,John T.; Tung, Eric Y.; Anderson, Vernon E.; Berry, Edward A.

    2005-12-01

    We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 {angstrom} resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation.

  6. 3-Nitropropionic Acid is a Suicide Inhibitor of Mitochondrial Respiration that, Upon Oxidation by Complex II, Forms a Covalent Adduct With a Catalytic Base Arginine in the Active Site of the Enzyme

    International Nuclear Information System (INIS)

    We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 (angstrom) resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation

  7. Synthesis of screening substrates for the directed evolution of sialic acid aldolase: towards tailored enzymes for the preparation of influenza A sialidase inhibitor analogues.

    Science.gov (United States)

    Woodhall, Thomas; Williams, Gavin; Berry, Alan; Nelson, Adam

    2005-05-01

    The stereoselective synthesis of two epimeric screening substrates, (4R, 5R, 6R)- and (4S, 5R, 6R)-6-dipropylcarbamoyl-2-oxo-4,5,6-trihydroxy-hexanoic acid, for the directed evolution of sialic acid aldolase is described. The complementary methods relied on stereoselective indium-mediated additions of ethyl alpha-bromomethyl acrylate to functionalised aldehydes. With an alpha-hydroxy aldehyde, (2R, 3R)-2,3-dihydroxy-4-oxo butanoic acid dipropylamide, the addition was chelation controlled, and the syn product, (6R, 5R, 4S)-6-dipropylcarbamoyl-2-methylidene-4,5,6-trihydroxy-hexanoic acid ethyl ester, was obtained. In contrast, the stereochemical outcome of the addition to (2R, 3R)-N,N-dipropyl-2,3-O-isopropylidene-4-oxobutyramide was consistent with Felkin-Anh control, and the anti adduct, (4R, 5R, 6R)-6-dipropylcarbamoyl-2-methylidene-4-hydroxy-5,6-O-isopropylidene-hexanoic acid ethyl ester, was the major product. Ozonolysis and deprotection gave the screening substrates as mixtures of furanose and pyranose forms, in good yields.

  8. A thermodynamical, electrochemical and surface investigation of Bis (indolyl methanes as Green corrosion inhibitors for mild steel in 1 M hydrochloric acid solution

    Directory of Open Access Journals (Sweden)

    Chandrabhan Verma

    2016-10-01

    Full Text Available The influence of three Bis (indolyl methanes (BIMs namely, 3,3′-((4-nitrophenyl methylene bis (1H-indole (BIM-1, 3,3′-(phenyl methylene bis (1H-indole (BIM-2 and 4-((1H-indol-2-yl(1H-indol-3-yl methyl phenol (BIM-3 on the mild steel corrosion in 1 M HCl was studied by weight loss, electrochemical, scanning electron microscopy (SEM, and dispersive X-ray spectroscopy (EDX methods. Results showed that BIM-3 shows maximum inhibition efficiency of 98.06% at 200 mg L−1 concentration. Polarization study revealed that the BIMs act as mixed type inhibitors. Adsorption of BIMs on the mild steel surface obeyed the Langmuir adsorption isotherm. The weight loss and electrochemical results were well supported by SEM and EDX studies.

  9. Propanoyl(1Z-N-(2,6-dimethylphenyl-2-oxopropanehydrazonoate as inhibitor for corrosion of 6061 Al alloy15 % (v SiC(p composite in hydrochloric acid media

    Directory of Open Access Journals (Sweden)

    Achutha Kini U

    2012-10-01

    Full Text Available ABSTRACT: The corrosion inhibition effect of Propanoyl(1Z-N-(2,6-dimethylphenyl-2-oxopropanehydrazonoate (PDOH in the corrosion of 6061 Aluminium alloy-15%(v SiC(p composite in 0.5 and 1M hydrochloric acid medium at four different temperatures (30, 40, 50 and 60 ⁰C was investigated using potentio-static polarization (Tafel extrapolation and Linear polarization and weight loss methods. The results obtained reveal that PDOH is an efficient corrosion inhibitor with around 96% inhibition efficiency within the range of temperature studied. Leftward and downward shifts in Tafel plots were observed with the addition of the inhibitor, indicating that PDOH inhibits the corrosion process effectively, and that it is a cathodic inhibitor. Corrosion rate increases and inhibition efficiency decreases with increase in temperature. Results obtained by Tafel extrapolation, linear polarization, and weight loss methods are in agreement. The adsorption of the inhibitor onto the surface of the 6061 Al alloy 15 % (v SiC(p composite is found to obey Temkins' adsorption isotherm that verifies the assumption of mono-layer adsorption on a uniform homogeneous composite surface with an interaction in the adsorption layer. The inhibition is therefore governed by the physisorption mechanism.ABSTRAK: Kesan perencatan kakisan Propanoyl(1Z-N-(2,6-dimethylphenyl-2-oxopropanehydrazonoate (PDOH ke atas kakisan komposit aloi Al 6061-15%(v SiC(p dalam media asid hidroklorik 0.5 dan 1M pada suhu-suhu yang berbeza (30, 40, 50 dan 60⁰C telah dikaji menggunakan polarisasi statik-upaya (extrapolarisasi Tafel dan polarisasi Linear dan kaedah kehilangan berat. Keputusan diperolehi menunjukkan PDOH adalah perencat yang efisien dengan 96 % keupayaan perencatan bagi julat suhu yag dikaji. Anjakan ke kiri dan ke bawah plot Tafel dapat dilihat dengan penambahan perencat, menunjukkan PDOH merencatkan proses kakisan dengan berkesan, dan ia adalah perencat katodik. Dengan peningkatan suhu

  10. Iminolactones as Tools for Inversion of the Absolute Configuration of alpha-Amino Acids and as Inhibitors of Cancer Cell Proliferation

    DEFF Research Database (Denmark)

    Jensen, Christina Mernøe; Chow, Hsiao-Qing; Chen, Ming;

    2016-01-01

    A library of iminolactones was prepared by esterification of several 2-hydroxyketones, of which some were of terpenoid origin while others were obtained via synthesis, with a number of N-protected D- and L--amino acids. After N-deprotection of the intermdiate esters, the free amines spontaneousl...

  11. Mitochondrial myopathy in rats fed with a diet containing beta-guanidine propionic acid, an inhibitor of creatine entry in muscle cells.

    OpenAIRE

    Gori, Z.; De Tata, V.; Pollera, M.; Bergamini, E

    1988-01-01

    In rats with phosphoryl-creatine depletion (fed a standard Randoin-Causeret diet containing 1% beta-guanidine propionic acid) abnormal mitochondria were observed in slow skeletal muscles, often containing paracrystalline inclusions very like those induced by ischaemia or mitochondrial poisons and in human mitochondrial myopathy.

  12. Proinflammatory cytokines and bile acids upregulate ΔNp73 protein, an inhibitor of p53 and p73 tumor suppressors.

    Directory of Open Access Journals (Sweden)

    Elena Zaika

    Full Text Available Gastroesophageal reflux disease (GERD is the main etiological factor behind the recent rapid increase in the incidence of esophageal adenocarcinoma. During reflux, esophageal cells are exposed to bile at low pH resulting in cellular damage and inflammation, which are known to facilitate cancer development. In this study, we investigated the regulation of p73 isoform, ΔNp73α, in the reflux condition. Previous studies have reported that ΔNp73 exhibits anti-apoptotic and oncogenic properties through inhibition of p53 and p73 proteins. We found that direct exposure of esophageal cells to bile acids in an acidic environment alters the phosphorylation of ΔNp73, its subcellular localization and increases ΔNp73 protein levels. Upregulation of ΔNp73 was also observed in esophageal tissues collected from patients with GERD and Barrett's metaplasia, a precancerous lesion in the esophagus associated with gastric reflux. c-Abl, p38 MAPK, and IKK protein kinases were identified to interact in the regulation of ΔNp73. Their inhibition with chemotherapeutic agents and siRNA suppresses ΔNp73. We also found that pro-inflammatory cytokines, IL-1β and TNFα, are potent inducers of ΔNp73α, which further enhance the bile acids/acid effect. Combined, our studies provide evidence that gastroesophageal reflux alters the regulation of oncogenic ΔNp73 isoform that may facilitate tumorigenic transformation of esophageal metaplastic epithelium.

  13. Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid

    Directory of Open Access Journals (Sweden)

    Lizano-Soberón Marcela

    2006-12-01

    Full Text Available Abstract Background DNA hypermethylation and histone deacetylation are epigenetic events that contribute to the absence or downregulated expression of different components of the tumor recognition complex. These events affect the processing and presentation of antigenic peptides to CTLs by HLA class-I molecules. In this work evaluated the effect of the DNA hypomethylating agent hydralazine and the histone deacetylase inhibitor valproic acid, on the expression of HLA class-I molecules and on the antigen-specific immune recognition of cervical cancer cells. Methods Cell lines C33A (HPV-, CaSki (HPV-16+ and MS751 (HPV-18+ were treated with hydralazine and valproic acid to assess the expression of HLA class-I molecules by flow cytometry and RT-PCR. Promoter methylation of HLA class-I -A, -B and C, was also evaluated by Methylation-Specific PCR. Primary cervical tumors of four HLA-A*0201 allele patients were typed for HPV and their CTL's stimulated in vitro with the T2 cell line previously loaded with 50 μM of the HPV peptides. Cytotoxicity of stimulated CTL's was assayed against Caski and MS751 cells pre-treated with hydralazine and valproic acid. Results Valproic acid and hydralazine/valproic acid up-regulated the constitutive HLA class-I expression as evaluated by flow cytometry and RT-PCR despite constitutive promoter demethylation at these loci. Hydralazine and valproic acid in combination but no IFN-gamma hyperacetylated histone H4 as evaluated by ChiP assay. The antigenic immune recognition of CaSki and MS751 cells by CTLs specific to HPV-16/18 E6 and E7-derived epitopes, was increased by VA and H/VA and the combination of H/VA/IFN-gamma. Conclusion These results support the potential use of hydralazine and valproic acid as an adjuvant for immune intervention in cervical cancer patients whenever clinical protocols based on tumor antigen recognition is desirable, like in those cases where the application of E6 and E7 based therapeutic vaccines

  14. Korelasi paparan benzene melalui pengukuran kadar trans-trans Muconic Acid (t,t-MA) dengan kadar enzim transaminase dan total protein pada pekerja SPBU Pertamina kota Medan

    OpenAIRE

    Musthari

    2016-01-01

    Since evidence of health problems caused by exposure to benzene, then benzene is one of the chemicals that are most harmful to human health. The development of the oil and gas industry in Indonesia can not be separated relevance of the use of a wide range of chemicals. Gasoline is one of the oil products containing benzene (C6H6), which serves to increase the octane rating. Impact of acute benzene exposure in the form of disorders of the nervous system, lack of oxygen supply...

  15. HDAC Inhibitors.

    Science.gov (United States)

    Olzscha, Heidi; Bekheet, Mina E; Sheikh, Semira; La Thangue, Nicholas B

    2016-01-01

    Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and deacetylation is dictated by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Important substrates for HATs and HDACs are histones, where lysine acetylation generally leads to an open and transcriptionally active chromatin conformation. Histone deacetylation forces the compaction of the chromatin with subsequent inhibition of transcription and reduced gene expression. Unbalanced HAT and HDAC activity, and therefore aberrant histone acetylation, has been shown to be involved in tumorigenesis and progression of malignancy in different types of cancer. Therefore, the development of HDAC inhibitors (HDIs) as therapeutic agents against cancer is of great interest. However, treatment with HDIs can also affect the acetylation status of many other non-histone proteins which play a role in different pathways including angiogenesis, cell cycle progression, autophagy and apoptosis. These effects have led HDIs to become anticancer agents, which can initiate apoptosis in tumor cells. Hematological malignancies in particular are responsive to HDIs, and four HDIs have already been approved as anticancer agents. There is a strong interest in finding adequate biomarkers to predict the response to HDI treatment. This chapter provides information on how to assess HDAC activity in vitro and determine the potency of HDIs on different HDACs. It also gives information on how to analyze cellular markers following HDI treatment and to analyze tissue biopsies from HDI-treated patients. Finally, a protocol is provided on how to detect HDI sensitivity determinants in human cells, based on a pRetroSuper shRNA screen upon HDI treatment. PMID:27246222

  16. Protease Inhibitors from Marine Venomous Animals and Their Counterparts in Terrestrial Venomous Animals

    OpenAIRE

    Mourão, Caroline B.F.; Elisabeth F Schwartz

    2013-01-01

    The Kunitz-type protease inhibitors are the best-characterized family of serine protease inhibitors, probably due to their abundance in several organisms. These inhibitors consist of a chain of ~60 amino acid residues stabilized by three disulfide bridges, and was first observed in the bovine pancreatic trypsin inhibitor (BPTI)-like protease inhibitors, which strongly inhibit trypsin and chymotrypsin. In this review we present the protease inhibitors (PIs) described to date from marine venomo...

  17. 缬氨酸转氨酶基因原核表达载体构建及表达%Construction and expression of prokaryotic vector of valine-pyruvate transaminase gene

    Institute of Scientific and Technical Information of China (English)

    张飞; 魏涛; 刘寅; 何培新

    2013-01-01

    构建了具有缬氨酸转氨酶基因的大肠杆菌工程菌,对该酶表达条件进行了优化.PCR结果表明,扩增出一特异DNA条带且长度与avtA基因长度1 254 bp符合.通过纸层析检测,筛选到了阳性克隆,但是酶活偏低.SDS-PAGE凝胶电泳显示目的蛋白表达量较低.酶表达优化结果显示:蛋白胨浓度12 g/L,IPTG浓度0.4 mmol/L,经过8h诱导,酶活达到最大值.%The engineered strain of Escherichia coli with valine-pyruvate transaminase gene was constructed and the expression condition for valine-pyruvate transaminase was optimized. The result of PCR showed that a special DNA band was amplified and the length of the band was accord with the length of avtA, 1 254 bp. Activity of valine-pyruvate transaminase was found by paper chromatography but the enzyme activity was not high. The expression of valine-pyruvate transaminase was evaluated by SDS-PAGE and a high expression was displayed. The optimal conditions were peptone 12 g/L,IPTG 0. 4 mmol/L and induced time 8 h.

  18. Advances in β-1actamase inhibitor clavulanic acid%β-内酰胺酶抑制剂克拉维酸研究进展

    Institute of Scientific and Technical Information of China (English)

    孟勇; 张国华; 王忠彦; 官家发

    2003-01-01

    综述了临床使用的β-内酰胺酶抑制剂克拉维酸(clavulanic acid,CA)产生菌的种类、作用机理、生物合成、代谢调控、以及提高克拉维酸产量的策略等方面的最新研究进展.

  19. Crystal Structure of the Homo sapiens Kynureninase-3-Hydroxyhippuric Acid Inhibitor Complex: Insights into the Molecular Basis Of Kynureninase Substrate Specificity

    Energy Technology Data Exchange (ETDEWEB)

    Lima,Santiago; Kumar,Sunil; Gawandi,Vijay; Momany,Cory; Phillips,Robert S.; (Georgia)

    2009-02-23

    Homo sapiens kynureninase is a pyridoxal-5'-phosphate dependent enzyme that catalyzes the hydrolytic cleavage of 3-hydroxykynurenine to yield 3-hydroxyanthranilate and L-alanine as part of the tryptophan catabolic pathway leading to the de novo biosynthesis of NAD{sup +}. This pathway results in quinolinate, an excitotoxin that is an NMDA receptor agonist. High levels of quinolinate have been correlated with the etiology of neurodegenerative disorders such as AIDS-related dementia and Alzheimer's disease. We have synthesized a novel kynureninase inhibitor, 3-hydroxyhippurate, cocrystallized it with human kynureninase, and solved the atomic structure. On the basis of an analysis of the complex, we designed a series of His-102, Ser-332, and Asn-333 mutants. The H102W/N333T and H102W/S332G/N333T mutants showed complete reversal of substrate specificity between 3-hydroxykynurenine and L-kynurenine, thus defining the primary residues contributing to substrate specificity in kynureninases.

  20. Design, synthesis and evaluation of malonic acid-based PTP1B inhibitors%丙二酸类PTP1B抑制剂的设计、合成及活性研究

    Institute of Scientific and Technical Information of China (English)

    杜欣; 张书恩; 刘军政; 聂菲璘; 叶菲; 田金英; 肖志艳

    2012-01-01

    蛋白酪氨酸磷酸酶(protein tyrosine phosphatase,PTP) 1B是治疗2型糖尿病(T2DM)及肥胖症的潜在靶点.磷酸酪氨酸(pTyr)是PTP1B去磷酸化作用的底物,本文以丙二酸基团模拟pTyr分子中的磷酸酯,设计合成了丙二酸类PTP1B抑制剂1~7.抑酶活性评价显示,化合物3和4对人重组PTP1B的半数抑制浓度IC50分别为7.66和1.88 μtmol·L-1.%Protein tyrosine phosphatase (FTP) IB is a potential target for the treatment of diabetes and obesity. Phosphotyrosine (pTyr) is the substrate for PTP1B dephosphorylation. Malonic acid moiety was used herein as a mimic of the phosphate group in pTyr, and novel malonic acid derivatives 1-7 were designed, synthesized and evaluated as PTP1B inhibitors. Results from enzymatic assays indicated that compounds 3 and 4 exhibited potent inhibition against human recombinant PTP1B with IC50 values of 7.66 and 1.88 umol-L"1, respectively.

  1. Efeito do Exercício com 1 e 3 Minutos de Intervalo de Descanso Entre as Séries na Atividade Sérica das Transaminases

    Directory of Open Access Journals (Sweden)

    Ramon Martins Alves

    2011-12-01

    Full Text Available O treinamento de força (TF intenso ocasiona danos na estrutura muscular, que podem ser detectados por meio de marcadores indiretos. OBJETIVO. Verificar se há alterações na atividade da creatina quinase (CK, da aspartato transaminase (AST e alanina transaminase (ALT com o TF em diferentes intervalos entre séries e exercícios. MÉTODOS. Treze voluntários (± 21,8 anos; ±173,6 cm; ±68,3 kg realizaram o teste de uma repetição máxima (1RM nos exercícios: supino reto, puxada (pulley, desenvolvimento sentado, tríceps (pulley e rosca bíceps. Após sete dias, todos foram submetidos a uma coleta de sangue (PRE e realizaram 4 séries máximas até a falha concêntrica com intensidade de 85% de 1RM e intervalos de 1 ou 3 minutos entre as séries e exercícios. Todos retornaram ao mesmo local 24, 48 e 72 horas após a sessão para mais uma coleta de sangue. Repetindo os procedimentos após uma semana, porém os voluntários que realizaram o teste com intervalo de 1 minuto na semana seguinte manteriam intervalos de 3 minutos e vice-versa. Realizou-se ANOVA mantendo como significância p<0,05. RESULTADOS. Houve redução significativa do número de repetições a cada série de todos os exercícios com 1 e 3 minutos de intervalo. Observou-se um aumento significativo da atividade sérica de CK e de AST 24, 48 e 72 horas utilizando ambos os intervalos. ALT não se alterou. CONCLUSÃO. O TF causou aumento na atividade de CK e AST, mas sem apresentar diferenças com os intervalos utilizados. Porém, pequenos intervalos reduzem o volume total de repetições.

  2. 3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model

    Directory of Open Access Journals (Sweden)

    Zaheer Ul-Haq

    2016-04-01

    Full Text Available Urease enzyme (EC 3.5.1.5 has been determined as a virulence factor in pathogenic microorganisms that are accountable for the development of different diseases in humans and animals. In continuance of our earlier study on the helicobacter pylori urease inhibition by barbituric acid derivatives, 3D-QSAR (three dimensional quantitative structural activity relationship advance studies were performed by Comparative Molecular Field Analysis (CoMFA and Comparative Molecular Similarity Indices Analysis (CoMSIA methods. Different partial charges were calculated to examine their consequences on the predictive ability of the developed models. The finest developed model for CoMFA and CoMSIA were achieved by using MMFF94 charges. The developed CoMFA model gives significant results with cross-validation (q2 value of 0.597 and correlation coefficients (r2 of 0.897. Moreover, five different fields i.e., steric, electrostatic, and hydrophobic, H-bond acceptor and H-bond donors were used to produce a CoMSIA model, with q2 and r2 of 0.602 and 0.98, respectively. The generated models were further validated by using an external test set. Both models display good predictive power with r2pred ≥ 0.8. The analysis of obtained CoMFA and CoMSIA contour maps provided detailed insight for the promising modification of the barbituric acid derivatives with an enhanced biological activity.

  3. 聚天冬氨酸阻垢剂的制备及性能评价%Preparation and Performance Evaluation of Poly-aspartic Acid Scale Inhibitor

    Institute of Scientific and Technical Information of China (English)

    杨红丽; 姬彩云

    2015-01-01

    Poly-aspartic acid has good scale inhibition effect. Using maleic anhydride and ammonium chloride, poly-aspartic acid was prepared by hot-polymerization. And the optimum reaction conditions were obtained by or-thogonal experiment as follows:molar ratio of maleic anhydride/ammonium chloride was 1∶1. 2,reaction teampra-ture was 140℃,and reaction time was 5h.%聚天冬氨酸具有较好的阻垢效果。采用热引发聚合,以马来酸酐、氯化铵为原料,制备了绿色阻垢剂聚天冬氨酸,通过正交实验确定了最佳合成条件,并对其进行了性能评价。最佳合成条件为:马来酸酐和氯化铵的摩尔比为1∶1.2,反应温度为140℃,反应时间为5 h。

  4. [Liver damage in a patient treated with a vitamin K antagonist, a statin and an ACE inhibitor].

    Science.gov (United States)

    Bruggisser, M; Terraciano, L; Rätz Bravo, A; Haschke, M

    2010-10-20

    We report the case of a 71-year-old male patient who presented at the emergency room with episodes of epistaxis and jaundice. The patient was on therapy with phenprocoumon, atorvastatin and perindopril. Findings on admission included prominent elevation of transaminases and bilirubin and a high INR due to impaired liver function and oral anticoagulation. After exclusion of other causes like viral or autoimmune hepatitis and after having obtained a liver biopsy, a diagnosis of drug induced liver damage (DILI) was made. Epidemiology, pathophysiology and clinical signs of DILI are discussed with a special focus on coumarines, statins and ACE-inhibitors. PMID:20960395

  5. QSAR study of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2 using LS-SVM and GRNN based on principal components.

    Science.gov (United States)

    Shahlaei, Mohsen; Sabet, Razieh; Ziari, Maryam Bahman; Moeinifard, Behzad; Fassihi, Afshin; Karbakhsh, Reza

    2010-10-01

    Quantitative relationships between molecular structure and methionine aminopeptidase-2 inhibitory activity of a series of cytotoxic anthranilic acid sulfonamide derivatives were discovered. We have demonstrated the detailed application of two efficient nonlinear methods for evaluation of quantitative structure-activity relationships of the studied compounds. Components produced by principal component analysis as input of developed nonlinear models were used. The performance of the developed models namely PC-GRNN and PC-LS-SVM were tested by several validation methods. The resulted PC-LS-SVM model had a high statistical quality (R(2)=0.91 and R(CV)(2)=0.81) for predicting the cytotoxic activity of the compounds. Comparison between predictability of PC-GRNN and PC-LS-SVM indicates that later method has higher ability to predict the activity of the studied molecules.

  6. Purification and characterization of a platelet aggregation inhibitor acidic phospholipase A2 from Indian saw-scaled viper (Echis carinatus) venom.

    Science.gov (United States)

    Kemparaju, K; Krishnakanth, T P; Veerabasappa Gowda, T

    1999-12-01

    An acidic phospholipase A2 (EC-I-PLA2) has been purified from the Indian saw-scaled viper (Echis carinatus) venom through a combination of column chromatography and electrophoresis. EC-I-PLA2 has a molecular weight of 16000 by SDS-PAGE. It was focussed between pH 4.2 and 4.8 by isoelectro focussing. EC-I-PLA2 was non-lethal to mice and devoid of neurotoxicity, myotoxicity, anticoagulant activity and cytotoxicity. It induced mild oedema in the foot pads of mice. The purified PLA2 inhibited ADP, collagen and epinephrine induced human platelet aggregation and the inhibition was both dose and time dependent. PMID:10519645

  7. 酿酒酵母和嗜鞣管囊酵母对稀酸水解抑制物的耐受性%Tolerance of Saccharomyces cerevisiae and Pachysolen tannophilus to Diluted Acid Hydrolysis Inhibitor

    Institute of Scientific and Technical Information of China (English)

    杨培周; 郑志; 罗水忠; 姜绍通; 陈淼林; 高书蕊

    2012-01-01

    The tolerance of Saccharomyces cerevisiae and Pachysolen tannophilus to inhibitors including furfural, 5-hydroxymethyl furfural and levulinic acid in diluted acid hydrolysis from rape straw was investigated. S. cerevisiae was capable of tolerating 2 g/L furfural, 2 g/L 5-hydroxymethyl furfural and 8 g/L levulinic acid in glucose broth. However, ethanol production by P. tannophilus was strongly inhibited in xylose broth added with 2 g/L furfural, 2 g/L 5-hydroxymethyl furfural and 8 g/L levulinic acid, respectively. In glucose broth containing 2 g/L furfural, the ethanol yields of S. cerevisiae and P. tannophilus were respectively 85. 05% and 46. 70% compared with those of the control, while in xylose broth added with 2 g/L furfural, the ethanol yield of P. tannophilus was 12.40% compared with that of the control. Enzymatic hydrolysis of rape straw could effectively relieve the inhibition of 2 g/L furfural on both the S. cerevisiae and P. tannophilus, whose ethanol yields were respectively 98. 40% and 91. 00% compared with those of the control. The results showed that the tolerance capacity of S. cerevisiae on fermentation inhibitors including furfural, 5-hydroxymethyl furfural and levulinic acid was stronger than that of P. tannophilus.%研究了酿酒酵母和嗜鞣管囊酵母对油菜秸秆稀酸水解抑制物糠醛、5-羟甲基糠醛和乙酰丙酸的耐受性.酿酒酵母能够耐受分别含有2 g/L糠醛、2 g/L 5-羟甲基糠醛和8g/L乙酰丙酸的葡萄糖发酵液;分别含有2g/L糠醛、2 g/L 5-羟甲基糠醛和8 g/L乙酰丙酸的木糖发酵液严重抑制嗜鞣管囊酵母发酵木糖产乙醇.在含有2 g/L糠醛的葡萄糖发酵液中,酿酒酵母和嗜鞣管囊酵母的乙醇质量浓度分别为对照的85.05%和46.70%,而在以木糖为底物的发酵液中,嗜鞣管囊酵母的乙醇质量浓度为对照的12.40%.油菜秸秆水解液能够有效缓解2g/L糠醛对酿酒酵母和嗜鞣管囊酵母产乙醇的抑制,乙醇

  8. The first Russian experience with the endothelin 1 receptor inhibitor traclir used in patients with pulmonary hypertension associated with systemic connective tissue diseases

    Directory of Open Access Journals (Sweden)

    Aleksandr Vitalyevich Volkov

    2011-01-01

    Full Text Available Objective: to study the efficacy and safety of the endothelin 1 receptor inhibitor traclir in patients with pulmonary hypertension (PH asso ciated with systemic connective tissue diseases. Subjects and methods. The study included 4 patients: 3 with scleroderma systematica and 1 with exanthematous lupus erythematosus. The diagnosis of PH was established on the basis of right heart catheterization data and after exclusion of all its other causes of HP. In addition to hemodynamic evaluation, the female patients underwent echocardiography (EchoCG, lung function tests, 6-minute walk test, and blood biochemical study (determination of uric acid levels. Traclir was given in a dose of 62.5 mg twice in the first 4 weeks of the study and then in a dose of 125 mg twice for the subsequent 12 weeks. Every 4 weeks, the levels of transaminases were monitored and a pregnancy test was carried out in patients of fertile age. Results. After 16-week intake of the drug, all the female patients were found to have obvious positive changes as a longer 6-min walk test distance and two female patients had improvement in the functional class of PH. Estimation of hemodynamic parameters suggested a posi tive effect in all the female patients, as confirmed primarily by an increase in cardiac index and a reduction in pulmonary vascular resist ance. According to EchoCG data, there was a substantial increase in tricuspid annular plane systolic excursion; other parameters had no informative value. During traclir therapy, there was also an increase in lung diffusion capacity and a reduction in uric acid levels. There were no adverse events throughout the trial. Conclusion. Thus, the experience with traclir used in patients with PH associated with systemic autoimmune diseases suggests its high effi cacy and safety.

  9. Pengaruh Ekstrak Daun Sambiloto (Andrographis paniculata terhadap Struktur Mikroanatomi Hepar dan Kadar Glutamat Piruvat Transaminase Serum Mencit (Mus musculus yang Terpapar Diazinon

    Directory of Open Access Journals (Sweden)

    TRI WULANDARI

    2007-11-01

    Full Text Available Diazinon is a pesticide which is often using by farmer to kill insect as theenemy of the plant. The over using of pesticide may result in the remaining of diazinon residue in farming product. This residue can cause the damage of body tissue, especially liver. The aim of research were to find out the effect of leaves sambiloto (Andrographis paniculata Ness. extract on microanatomic structure of liver and serum glutamate pyruvate transaminase (GPT level of mice (Mus musculus L. exposed to diazinon. The research used Compelete Random Design with five treatments. The treatment of each group were using CMC 1% (placebo control, diazinon solution 40 mg/Kg BW (negative ontrol and the leaves sambiloto extract 12,6; 25,2 and 37,8 mg /kg BW. Diazinon solution was given within 10 days and continued with extract of sambiloto leaves also within 10 days. Parameter observed was the microanatomic structure of liver and serum GPT level. The data was analyzed of Analysis of Varians (Anova and continued with DMRT at significance 5%. The result of the research showed that the giving of the extract of sambiloto leaves in some dose variation degree is significantly influential to repair the microanatomic structure of liver and to decrease the serum GPT level was 37,8 mg/Kg BW.

  10. 3-Bromopyruvic acid, a hexokinase II inhibitor, is an effective antitumor agent on the hepatoma cells : in vitro and in vivo findings.

    Science.gov (United States)

    Gong, Lei; Wei, Yuhua; Yu, Xin; Peng, Jirun; Leng, Xisheng

    2014-06-01

    Over-expressed in cancer cells, hexokinase II (HK II) forms a mitochondrial complex, which promotes cancer survival. 3- Bromopyruvic acid (3-BrPA) dissociates HK II from this complex, causing cell death, and thus, having an anti-tumor effect. The design of this study was to first analyze the expression of HK II in the hepatoma cell line, BEL-7402, then investigate the effects of 3-Br-PA on these cells, and finally, discuss its potential for clinical usage. HK II expression was detected in BEL-7402 cells by immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). In vitro treatment of cells with 3-BrPA significantly inhibited their growth, as evaluated by MTT assay and adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA). To analyze the in vivo function and safety of this drug, a tumor model was established by subcutaneously implanting hepatic cancer cells into nude mice. 3-BrPA treatment (50 mg/kg ip. daily, 6 days/week for three weeks) was effective in the animal model by attenuating tumor growth and causing tumor necrosis. Toxic signs were not observed. The acute toxicity study provided an LD50 of 191.7 mg/kg for 3-BrPA. Taken together, our in vitro and in vivo analyses suggest that 3-BrPA exerts anti-hepatoma effects, and may be an effective pharmacological agent for the treatment of hepatocellular carcinoma. PMID:24738957

  11. Corrosion inhibition in 2.0 M sulfuric acid solutions of high strength maraging steel by aminophenyl tetrazole as a corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Sherif, El-Sayed M., E-mail: emsherif@gmail.com [Center of Excellence for Research in Engineering Materials (CEREM), Advanced Manufacturing Institute, King Saud University, PO. Box 800, Al-Riyadh 11421 (Saudi Arabia); National Research Centre (NRC), Electrochemistry and Corrosion Laboratory, Department of Physical Chemistry, National Research Centre (NRC), Dokki, 12622 Cairo (Egypt)

    2014-02-15

    The corrosion of high strength maraging steel after varied immersion times in concentrated solution, 2.0 M, of sulfuric acid has been investigated. The work was also extended to study the effect of 5-(3-aminophenyl)-tetrazole (APTA) on the inhibition of the steel corrosion. The study has been carried out using electrochemical impedance spectroscopy (EIS), potentiodynamic polarization and scanning electron microscope (SEM) along with energy dispersive X-ray analyzer (EDX) investigations. EIS spectra showed that the corrosion and polarization resistances decrease with increasing the immersion time of the steel before measurement and increase in the presence of APTA and the increase of its concentration. Polarization data agreed with the EIS measurements and indicated that the increase of immersion time increases the corrosion of steel by increasing its corrosion current and corrosion rate and lowering its polarization resistance. On the other hand, the addition of APTA and the increase of its concentration minimized the corrosion of steel through decreasing the corrosion current and corrosion rate and increasing the polarization resistance at all exposure test periods. SEM and EDX investigations confirmed that the inhibition of the maraging steel in the 2.0 M H{sub 2}SO{sub 4} solutions is achieved via the adsorption of the APTA molecules onto the steel protecting its surface from being dissolved easily.

  12. USE OF ZOLEDRONIC ACID AND A RАNK LIGAND INHIBITOR IN THE PALLIATIVE TREATMENT OF CANCERS OF THE PROSTATE WITH BONE METASTASES

    Directory of Open Access Journals (Sweden)

    S. V. Mushigin

    2013-01-01

    Full Text Available In the metastatic patterns of the cancer, the tumor foci are located more frequently in the tubular bones and vertebral column, just less frequently in the bones of the pelvis, and even more rarely in those of the shoulder and skull. Bone pain is usually related to the involvement of the periosteum that has an extensive network of nociceptors. Auxiliary exposures that directly affect the intensity of pain syndrome and the strength of bone structures are used in addition to basic therapy options for cancer of the prostate. Among these agents there are bisphosphonates. Once ingested, bisphosphonates are transported by blood to the areas of active bone tissue rearrangement where they are tightly bound to the mineral matrix. Their administration causes a considerable reduction in pain syndrome, a decrease in the frequency of complications of bone metastases, and an increase in time before a first bone complication. Antiresorptive therapy including particularly zoledronic acid (resorba or denosumab is a necessary treatment option in the above category of patients with bone metastases.

  13. USE OF ZOLEDRONIC ACID AND A RАNK LIGAND INHIBITOR IN THE PALLIATIVE TREATMENT OF CANCERS OF THE PROSTATE WITH BONE METASTASES

    Directory of Open Access Journals (Sweden)

    S. V. Mushigin

    2014-07-01

    Full Text Available In the metastatic patterns of the cancer, the tumor foci are located more frequently in the tubular bones and vertebral column, just less frequently in the bones of the pelvis, and even more rarely in those of the shoulder and skull. Bone pain is usually related to the involvement of the periosteum that has an extensive network of nociceptors. Auxiliary exposures that directly affect the intensity of pain syndrome and the strength of bone structures are used in addition to basic therapy options for cancer of the prostate. Among these agents there are bisphosphonates. Once ingested, bisphosphonates are transported by blood to the areas of active bone tissue rearrangement where they are tightly bound to the mineral matrix. Their administration causes a considerable reduction in pain syndrome, a decrease in the frequency of complications of bone metastases, and an increase in time before a first bone complication. Antiresorptive therapy including particularly zoledronic acid (resorba or denosumab is a necessary treatment option in the above category of patients with bone metastases.

  14. Regulating Chondrogenesis of Human Mesenchymal Stromal Cells with a Retinoic Acid Receptor-Beta Inhibitor: Differential Sensitivity of Chondral Versus Osteochondral Development

    Directory of Open Access Journals (Sweden)

    Solvig Diederichs

    2014-05-01

    Full Text Available Aim: Main objective was to investigate whether the synthetic retinoic acid receptor (RAR-β antagonist LE135 is able to drive in vitro chondrogenesis of human mesenchymal stromal cells (MSCs or improve differentiation by suppressing hypertrophic chondrocyte development. Methods: Chondrogenesis of human bone marrow and adipose tissue-derived MSCs was induced in micromass pellet culture for six weeks. Effects of LE135 alone and in combinatorial treatment with TGF-β on deposition of cartilaginous matrix including collagen type II and glycosaminoglycans, on deposition of non-hyaline cartilage collagens type I and X, and on hypertrophy markers including alkaline phosphatase (ALP, indian hedghehog (IHH and matrix metalloproteinase (MMP-13 were assessed. Results: LE135 was no inducer of chondrogenesis and failed to stimulate deposition of collagen type II and glycosaminoglycans. Moreover, addition of LE135 to TGF-β-treated pellets inhibited cartilaginous matrix deposition and gene expression of COL2A1. In contrast, non-hyaline cartilage collagens were less sensitive to LE135 and hypertrophy markers remained unaffected. Conclusion: This demonstrates a differential sensitivity of chondral versus endochondral differentiation pathways to RARβ signaling; however, opposite to the desired direction. The relevance of trans-activating versus trans-repressing RAR signaling, including effects on activator protein (AP-1 is discussed and implications for overcoming current limits of hMSC chondrogenesis are considered.

  15. Valproic acid, a histone deacetylase inhibitor, decreases proliferation of and induces specific neurogenic differentiation of canine adipose tissue-derived stem cells.

    Science.gov (United States)

    Kurihara, Yasuhiro; Suzuki, Takehito; Sakaue, Motoharu; Murayama, Ohoshi; Miyazaki, Yoko; Onuki, Atsushi; Aoki, Takuma; Saito, Miyoko; Fujii, Yoko; Hisasue, Masaharu; Tanaka, Kazuaki; Takizawa, Tatsuya

    2014-01-01

    Adipose tissue-derived stem cells (ADSCs) isolated from adult tissue have pluripotent differentiation and self-renewal capability. The tissue source of ADSCs can be obtained in large quantities and with low risks, thus highlighting the advantages of ADSCs in clinical applications. Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to affect ADSC differentiation in mice and rats; however, few studies have been performed on dogs. We aimed to examine the in vitro effect of VPA on canine ADSCs. Three days of pretreatment with VPA decreased the proliferation of ADSCs in a dose-dependent manner; VPA concentrations of 4 mM and above inhibited the proliferation of ADSCs. In parallel, VPA increased p16 and p21 mRNA expression, suggesting that VPA attenuated the proliferative activity of ADSCs by activating p16 and p21. Furthermore, the effects of VPA on adipogenic, osteogenic or neurogenic differentiation were investigated morphologically. VPA pretreatment markedly promoted neurogenic differentiation, but suppressed the accumulation of lipid droplets and calcium depositions. These modifications of ADSCs by VPA were associated with a particular gene expression profile, viz., an increase in neuronal markers, that is, NSE, TUBB3 and MAP2, a decrease in the adipogenic marker, LPL, but no changes in osteogenic markers, as estimated by reverse transcription-PCR analysis. These results suggested that VPA is a specific inducer of neurogenic differentiation of canine ADSCs and is a useful tool for studying the interaction between chromatin structure and cell fate determination.

  16. 玉米秸秆稀酸预处理条件对糠醛类抑制物产生的影响%Research on the factors brought by furfural inhibitor during acid -pretreatment of corn stover

    Institute of Scientific and Technical Information of China (English)

    张莎莎; 张坤; 陈晓晓; 王晓俊; 左小明; 薛冬桦

    2015-01-01

    To explore the factors that affect the generation of furfural inhibitor during the process,corn stover was pretreated using diluted sulfuric acid.The correlation between pretreatment conditions and re-ducing sugar and furfural was analysed by partial correlation.The analysis showed that the main factor af-fecting furfural generation was the concentration of the sulfuric acid.There was a positive correlation be-tween the concentration of furfural and sulfuric acid.Pretreatment temperature and time were associated with the furfural concentration significantly;however the solid liquid ratio was not associated with the generation of furfural.The results showed that the optimal results were achieved by using 1% sulfuric acid to pretreat the corn stover at 120 ℃ for 90 minutes and ratio of solid to liquid 1∶10,as results,the furfural concentration was measured as 0.99 mg/mL with reducing sugar at 27.6 mg/mL.%以玉米秸秆为原料,探讨稀硫酸预处理玉米秸秆过程中影响糠醛类抑制物产生的因素,运用偏相关性分析法分析不同预处理条件与还原糖、糠醛的相关性。分析得知,影响预处理液中糠醛类抑制物产生的主要因素是硫酸浓度,二者呈正相关。预处理温度和时间与糠醛浓度显著相关,而固液比对糠醛类抑制物的产生没有显著影响。实验结果表明,当硫酸浓度为1%、预处理温度120℃、时间90 min,固液比1∶10时预处理液中糠醛浓度为0.99 mg/mL,还原糖浓度为27.6 mg/mL。

  17. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  18. Behaviour of tetramine inhibitors during pickling of hot rolled steels

    Energy Technology Data Exchange (ETDEWEB)

    Cornu, Marie-José, E-mail: marie-jose.cornu@arcelormittal.com [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Koltsov, Alexey, E-mail: alexey.koltsov@arcelormittal.com [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Nicolas, Sabrina, E-mail: sabrina_nicolas@live.fr [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Laboratoire de Chimie Physique et Microbiologie pour l’Environnement (LCPME) – UMR 7564 CNRS – Université de Lorraine, 405 rue de Vandoeuvre, 54602 Villers-lès-Nancy (France); Colom, Lydia, E-mail: Lydia.colom@sfr.fr [ArcelorMittal Maizières Research, Voie Romaine, 57280 Maizières-lès-Metz (France); Dossot, Manuel, E-mail: manuel.dossot@univ-lorraine.fr [Laboratoire de Chimie Physique et Microbiologie pour l’Environnement (LCPME) – UMR 7564 CNRS – Université de Lorraine, 405 rue de Vandoeuvre, 54602 Villers-lès-Nancy (France)

    2014-02-28

    To avoid the dissolution of steel in industrial pickling process, tetramine inhibitors are added to the pickling bath. This study is devoted to the understanding of the action mechanism of these inhibitors in hydrochloric and sulphuric baths on non-alloyed and alloyed steels. Pickling experiments and characterization with XPS, Raman and infrared spectroscopies have shown that inhibitors work only in acid media and leached out from the steel surfaces during the rinsing operation just after pickling. The effectiveness of inhibitors depends on the acid media and the temperature. Experimental data are consistent with a surface mechanism, i.e., the so-called “outer-sphere” adsorption.

  19. Behaviour of tetramine inhibitors during pickling of hot rolled steels

    International Nuclear Information System (INIS)

    To avoid the dissolution of steel in industrial pickling process, tetramine inhibitors are added to the pickling bath. This study is devoted to the understanding of the action mechanism of these inhibitors in hydrochloric and sulphuric baths on non-alloyed and alloyed steels. Pickling experiments and characterization with XPS, Raman and infrared spectroscopies have shown that inhibitors work only in acid media and leached out from the steel surfaces during the rinsing operation just after pickling. The effectiveness of inhibitors depends on the acid media and the temperature. Experimental data are consistent with a surface mechanism, i.e., the so-called “outer-sphere” adsorption.

  20. Behaviour of tetramine inhibitors during pickling of hot rolled steels

    Science.gov (United States)

    Cornu, Marie-José; Koltsov, Alexey; Nicolas, Sabrina; Colom, Lydia; Dossot, Manuel

    2014-02-01

    To avoid the dissolution of steel in industrial pickling process, tetramine inhibitors are added to the pickling bath. This study is devoted to the understanding of the action mechanism of these inhibitors in hydrochloric and sulphuric baths on non-alloyed and alloyed steels. Pickling experiments and characterization with XPS, Raman and infrared spectroscopies have shown that inhibitors work only in acid media and leached out from the steel surfaces during the rinsing operation just after pickling. The effectiveness of inhibitors depends on the acid media and the temperature. Experimental data are consistent with a surface mechanism, i.e., the so-called "outer-sphere" adsorption.