Kegg Pathway: Butanoate metabolism

Riv Biol. 2008 Jan-Apr; 101(1): 67-80
Ding D, Ding Y, Cai Y, Chen S, Xu W

The objective of this article is to obtain a more detailed insight into poly-beta-hydroxybutyrate (PHB) metabolism through network-based metabolic pathway analysis. We employ extreme pathways to perform this study, because calculating and interpreting extreme pathways is a promising way for pathway analysis and metabolic engineering. After giving an in silico model of Butanoate metabolism of Bacillus thuringiensis 97-27 (btk), extreme pathways were calculated and classified. Furthermore, the type I and II extreme pathways were further classified and analyzed in detail based on their structure and functional capabilities. Besides "historical" biochemical pathways, the results also suggest that there are some novel pathways.

Mol Microbiol. 2008 Apr; 68(1): 152-72
Zuther K, Mayser P, Hettwer U, Wu W, Spiteller P, Kindler BL, Karlovsky P, Basse CW, Schirawski J

Tryptophan is a precursor for many biologically active secondary metabolites. We have investigated the origin of indole pigments first described in the pityriasis versicolor-associated fungus Malassezia furfur. Some of the identified indole pigments have properties potentially explaining characteristics of the disease. As M. furfur is not amenable to genetic manipulation, we used Ustilago maydis to investigate the pathway leading to pigment production from tryptophan. We show by high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance analysis that the compounds produced by U. maydis include those putatively involved in the etiology of pityriasis versicolor. Using a reverse genetics approach, we demonstrate that the tryptophan aminotransferase Tam1 catalyses pigment biosynthesis by conversion of tryptophan into indolepyruvate. A forward genetics approach led to the identification of mutants incapable of producing the pigments. These mutants were affected in the sir1 gene, presumably encoding a sulphite reductase. In vitro experiments with purified Tam1 showed that 2-oxo 4-methylthio Butanoate serves as a substrate linking tryptophan deamination to sulphur metabolism. We provide the first direct evidence that these indole pigments form spontaneously from indolepyruvate and tryptophan without any enzymatic activity. This suggests that compounds with a proposed function in M. furfur-associated disease consist of indolepyruvate-derived spontaneously generated metabolic by-products.

J Agric Food Chem. 2008 Mar 12; 56(5): 1611-8
Andersen CM, Andersen LT, Hansen AM, Skibsted LH, Petersen MA

Degradation of the potential photosensitizers, riboflavin, chlorophyll, and porphyrin, in Danbo cheese by monochromatic light of wavelength 366, 436, or 546 nm was studied. Three cheeses were investigated, two conventional (16% fat and 25% fat) and one "organic" (25% fat). The effect of illumination was measured by fluorescence spectroscopy and analyzed using multiway and multivariate data analysis. Riboflavin was found to degrade only by 436 nm light, whereas chlorophylls and porphyrins also were influenced by 436 and 546 nm light. The organic cheese had the largest chlorophyll content both before and after similar light exposure, and no change in chlorophyll of this cheese was observed for any of the illumination wavelengths. Upon light exposure of the cheeses, volatile compounds were formed, as analyzed by gas chromatography-mass spectrometry (GC-MS). The relative concentrations of methyl Butanoate, 1-pentanol, benzaldehyde, 2-butanone, 2-heptanone, and butyl acetate were found to weakly correlate with the surface fluorescence intensity. 1-Pentanol and the ketones are secondary lipid oxidation products, consistent with a chemical coupling between photosensitizer degradation and formation of volatile lipid oxidation products.

Oncol Rep. 2008 Jan; 19(1): 245-51
Gmeiner WH, Hellmann GM, Shen P

The goal of this study was to identify systematic alterations in key cell signaling and metabolic pathways that occur during colon cancer carcinogenesis and metastasis. Understanding gene expression changes in the context of specific pathways may increase our understanding of carcinogenesis and help guide treatment. Ten cases, with matched controls, were profiled for expression of >18,000 human transcripts using Affymetrix U133A chips. Data were filtered using GeneSifter. Gene expression levels for primary colon samples were compared to a normal colon while metastatic tissues were compared to the primary colon. Differentially regulated genes were associated using the Kyoto encyclopedia of genes and genome pathways to identify cell signaling and metabolic pathways altered during carcinogenesis and metastasis. Primary colon samples displayed high positive z-scores (indicating a gene ontology term that occurs more frequently than expected) for genes involved in Wnt-signaling (4.11), nitrogen metabolism (7.30) and inositol phosphate metabolism (2.47). Expression level changes for individual genes in each cluster were statistically significant (e.g. p=0.017 for cyclin D1 in the Wnt-signaling cluster). Metastatic tissue from the liver and omentum, but not the lung, displayed a decreased expression of genes important for oxidative phosphorylation. The metastatic tissue from all sites displayed a substantially decreased expression for genes involved in Butanoate and propanoate metabolism and valine, leucine and isoleucine degradation. Our results demonstrate that systematic changes in gene expression occur for proteins involved in key cell signaling and metabolic pathways during the course of carcinogenesis and metastasis. These expression level changes complement the spectrum of mutations that characterize the progression of colorectal cancer.

Molecules. 2006; 11(1): 72-80
Sapijanskaite B, Mickevicius Y, Mikulskiene G

The reactions in benzene of 9-alkyl-3-aminocarbazoles with ethyl-3-oxoButanoate yielded ethyl-3-[(9-alkyl-9H-carbazol-3-yl)amino]but-2-enoate condensation products or N-(9-ethyl-9H-carbazol-3-yl)-3-oxobutanamide acylation products. The condensation products were cyclized to the corresponding 4,7-dihydro-pyrido[2,3-c]-carbazol-1-ones upon heating in mineral oil at 240-250 degrees C. The structures of the synthesized compounds were investigated by IR, mass spectrometry, (1)H- and (13)C-NMR spectroscopy and MM2 molecular mechanics and AM1 semi-empirical quantum mechanical methods.

Food Addit Contam. 2007 Nov; 24(11): 1306-17
Ducruet V, Vitrac O, Saillard P, Guichard E, Feigenbaum A, Fournier N

The sorption of 14 aroma compounds into PET and PVC was monitored during storage of a strawberry syrup for 1 year. Concentrations in the syrup and in the polymer were determined during storage and compared with previously published results obtained with glass bottles. Apparent partition coefficients between the polymer and the syrup (noted K app) were estimated from experimental kinetics without reaching equilibrium K app values and optimally identified from the kinetic data obtained between 30 and 90 days. They exhibited a similar behaviour for both polymers with values were between 2 x 10(-5) and 2 x 10(-3), 4 x 10(-5) and 3 x 10(-2), respectively, for PET and PVC. The variation of K app values in PET was mainly correlated to the polarity of tested compounds as assessed by their log P values. By contrast, the variations in K app values for PVC were mainly related to their chain lengths. Due to slightly higher partition coefficients and diffusion coefficients in PVC compared with PET, the amount of absorbed aroma was four times higher in PVC than in PET; however, the amount of absorbed aroma compounds was less than 0.1% of the initial amount present into the syrup, except for octyl Butanoate. The variation in concentration in the syrup was interpreted as a combination of a degradation process and a transport process into the packaging material. Both effects were particularly noticeable for both PET and unstable aroma compounds.

Bioorg Med Chem. 2007 Sep 15; 15(18): 6037-42
Wimmer Z, Floro AJ, Zarevúcka M, Wimmerová M, Sello G, Orsini F

During the investigation of ester derivatives (juvenogens, biochemically activated insect hormonogenic compounds) of biologically active alcohols with potential application in insect pest control, a need for availability of all existing stereoisomers of ethyl N-{2-[4-(2-butanoyloxycyclohexyl)methyl]phenoxy}ethyl carbamate occurred. They were synthesized from their chiral precursors, the corresponding stereoisomers of 2-(4-methoxybenzyl)cyclohexyl Butanoate, by removing their protecting group (methyl), and by subsequent condensation of the aromatic hydroxyl moiety with ethyl N-(2-bromoethyl) carbamate. The requested enantiomers of 2-(4-methoxybenzyl)cyclohexyl Butanoate were obtained by a Candida antarctica lipase-mediated transesterification and chiral resolution of the respective racemic cis- and trans-isomers of 2-(4-methoxybenzyl)cyclohexanol either directly or after a subsequent chemical esterification of the chiral precursor. In this synthesis, two convenient butanoic acid activating esters, vinyl Butanoate and 2,2,2-trifluoroethyl Butanoate, were employed, and the chiral precursors in the synthesis of the target molecules were obtained in 41-48% yields (i.e., 82-96% conversion), and with enantiomeric purity ee=96-98%, respectively. The enantiomeric purity of the products was determined by chiral HPLC analysis, and their absolute configuration was assigned on the basis of analyzing the (1)H and (19)F NMR spectra of their diastereoisomeric Mosher acid (3,3,3-trifluoromethyl-2-methoxy-2-phenylpropanoic acid) esters.

Org Biomol Chem. 2007 May 21; 5(10): 1615-20
Komoda T, Sugiyama Y, Hirota A

The biosynthesis of tetrapetalones (tetrapetalones A, B, C, and D) in Streptomyces sp. USF-4727 was studied by feeding experiments with [1-13C] sodium propanoate, [1-13C] sodium Butanoate, [carbonyl-13C] 3-amino-5-hydroxybenzoic acid (AHBA) hydrochloride, and [1-13C] glucose, followed by analysis of the 13C-NMR spectra. These feeding experiments revealed that the four tetrapetalones were polyketide compounds constructed from propanoate, Butanoate, AHBA, and glucose. The tetrapetalone biosynthetic pathway was also suggested in this study. In this pathway, tetrapetalone A (1) is synthesized by polyketide synthase (PKS) using AHBA as a starter unit, then the side chain of 1 is subjected to acetoxylation to produce tetrapetalone B (2). Additionally, 1 is oxidized and transformed into tetrapetalone C (3). In a similar way, 2 is converted to tetrapetalone D (4). Therefore, the biosynthetic relationship of the four tetrapetalones was indicated.

Appl Microbiol Biotechnol. 2007 Jul; 75(6): 1249-56
Itoh N, Nakamura M, Inoue K, Makino Y

An asymmetric hydrogen-transfer biocatalyst consisting of mutated Rhodococcus phenylacetaldehyde reductase (PAR) or Leifsonia alcohol dehydrogenase (LSADH) was applied for some water-soluble ketone substrates. Among them, 4-hydroxy-2-butanone was reduced to (S)/(R)-1,3-butanediol, a useful intermediate for pharmaceuticals, with a high yield and stereoselectivity. Intact Escherichia coli cells overexpressing mutated PAR (Sar268) or LSADH were directly immobilized with polyethyleneimine or 1,6-diaminehexane and glutaraldehyde and evaluated in a batch reaction. This system produced (S)-1,3-butanediol [87% enantiomeric excess (e.e.)] with a space time yield (STY) of 12.5 mg h(-1) ml(-1) catalyst or (R)-1,3-butanediol (99% e.e.) with an STY of 60.3 mg h(-1) ml(-1) catalyst, respectively. The immobilized cells in a packed bed reactor continuously produced (R)-1,3-butanediol with a yield of 99% (about 49.5 g/l) from 5% (w/v) 4-hydroxy-2-Butanoate over 500 h.

Protein Pept Lett. 2007; 14(2): 165-9
Farias T, Mandrich L, Rossi M, Manco G

Previously we characterized an acetyl-esterase from Escherichia coli, formally Aes, from a thermodynamic point of view in comparative studies with thermophilic homologs. Since the enzyme appeared unusually resistant to the thermal denaturation we analysed the kinetic behaviour with respect to the temperature. The enzyme displays a surprising optimal temperature at 65 degrees C, showing a specific activity of 250 U/mg using pNP-Butanoate as substrate, but a low kinetic stability at the same temperature (t(1/2) of inactivation=5 min). By a random mutagenesis approach we searched for mutated versions of Aes with increased thermostability. We found the mutant T74A, which shows the same specific activity of wild type but a t(1/2) of inactivation of 30 min at 65 degrees C.

J Control Release. 2006 Nov 28; 116(2): 227-37
Doody AM, Korley JN, Dang KP, Zawaneh PN, Putnam D

Polyethylenimine is a popular DNA transfection reagent, and many approaches have been explored to further enhance its transfection efficiency. Substitution of branched polyethylenimine's primary amine groups is an attractive approach because it is amenable to a variety of chemistries and is also implicated as a primary factor in its cytotoxicity. The purpose of this work was to serially substitute saturated hydrocarbons to branched polyethylenimine and determine what structure/function relationships exist between the hydrocarbon length and its degree of substitution, relative to transfection efficiency in multiple cell lines. Specifically, acetate, Butanoate and hexanoate were conjugated to branched polyethylenimine (M(w) = 25,000) using an aqueous condensation protocol. Transfections were performed in culture using HeLa, NIH/3T3 and Clone 9 cell lines. Biophysical characteristics of the polyelectrolyte complexes were also measured (hydrodynamic diameter, relative binding affinity) and correlated to transfection efficiency. The results show that substitution of the primary amines generally increases transfection efficiency relative to unconjugated polyethylenimine, but increasing the degree of substitution beyond approximately 25 mol% generally decreases transfection efficiency from the optimum. Additionally, increasing hydrocarbon length generally decreased transfection efficiency. There was little correlation between particle size and binding efficiency to transfection efficiency.

J Med Chem. 2006 Jul 13; 49(14): 4055-8
Cheng JF, Huang Y, Penuliar R, Nishimoto M, Liu L, Arrhenius T, Yang G, O'leary E, Barbosa M, Barr R, Dyck JR, Lopaschuk GD, Nadzan AM

Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-3-carboxamido)Butanoate (5, CBM-301940) exhibited excellent potency and in vivo PK/ADME properties. It is the most powerful stimulant of glucose oxidation reported to date in isolated working rat hearts. Compound 5 improved the cardiac efficiency and function in a rat heart global ischemia/reperfusion model, suggesting MCD inhibitors may be useful for the treatment of ischemic heart diseases.

J Agric Food Chem. 2006 Jan 25; 54(2): 382-9
Avila M, Garde S, Fernández-García E, Medina M, Nuñez M

The effect on the volatile compounds and on the odor and aroma of Hispánico cheese of a high-pressure (HP) treatment (400 MPa for 5 min at 10 degrees C, applied to 15-day-old cheeses), by itself or combined with the addition of a bacteriocin-producing (BP) culture to milk, was investigated. HP-treated cheeses showed higher levels of hexanal, 3-hydroxy-2-pentanone, 2-hydroxy-3-pentanone, and hexane and lower levels of ethanal, ethanol, 1-propanol, ethyl acetate, ethyl Butanoate, ethyl hexanoate, 2-pentanone, and butanoic acid than untreated cheeses. HP cheeses received higher "milky" odor descriptor scores and lower scores for odor quality and intensity and for "buttery", "yogurt-like", and "caramel" odor descriptors. Addition of the BP culture enhanced the formation of three aldehydes, three alcohols, three ethyl esters, and three ketones but decreased the levels of seven ketones and butanoic acid. BP cheeses received higher scores for aroma intensity and for "yogurt-like" and "cheesy" aroma descriptors. Principal component analysis showed the correlation between diketones and aroma descriptors "caramel", "buttery", and "milky" and between 3-methylbutanal and the odor and aroma intensity scores and aroma descriptors "sheepy" and "meat broth".

J Agric Food Chem. 2005 Dec 14; 53(25): 9781-9
Rizzolo A, Cambiaghi P, Grassi M, Zerbini PE

Conference pears (Pyrus communis L.) were treated with 25 and 50 nL L(-1) 1-methylcyclopropene (1-MCP) at -0.5 degrees C for 24 h, then stored for up to 22 weeks in air (NA) and controlled atmosphere (CA). After 7 and 14 weeks of storage, fruits were retreated with 1-MCP. After 7, 14, and 22 weeks of storage, fruits were kept for up to 7 days at 20 degrees C in air for poststorage ripening. The effects of 1-MCP treatment declined with duration of storage in both storage atmospheres, indicating that retreatments had little additional effects on subsequent ripening. Ethylene production was lower and firmness was higher in 50 nL L(-1) fruits, while the 25 nL L(-1) dose was not very different from the control. Development of superficial scald was not prevented by 1-MCP treatments, but the severity of the symptoms was influenced. The 1-MCP effects were perceivable on texture (juiciness) and flavor. Control fruit and 25 nL L(-1) fruit reached their best sensory quality after 14 weeks of storage, while 50 nL L(-1) fruit reached the same sensory quality later, keeping a fresh flavor when the quality of control fruit declined and became watery or grainy. The fresh flavor in 50 nL L(-1) fruit was probably due to the presence below the odor detection threshold concentrations of the volatile compounds responsible for the "ripe pear" aroma, mainly of butanol and ethyl Butanoate. CA prolonged or enhanced the effects of 1-MCP; 1-MCP cannot substitute for CA but can reinforce the CA effects.

Indian J Exp Biol. 2005 Nov; 43(11): 1042-7
Lohiya NK, Manivannan B, Bhande SS, Panneerdoss S, Garg S

Apart from condoms and vasectomy, which have several limitations of their own, no other methods of contraception are available to men. Various chemical, hormonal, vas based and herbal contraceptives have been examined and few of them have reached the stage of clinical testing. Promising leads have been obtained from testosterone buciclate/undecanoate, alone or in combination with levonorgestrel Butanoate or cyproterone acetate, RISUG, an injectable intravasal contraceptive and a few herbal products, particularly the seed products of Carica papaya. It is feasible that an ideal male contraceptive, that meets out all the essential criteria will be made available to the community in the near future.

Mol Pharmacol. 2006 Mar; 69(3): 680-90
Foucaud M, Tikhonova IG, Langer I, Escrieut C, Dufresne M, Seva C, Maigret B, Fourmy D

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2-methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]}-Butanoate N-methyl-D-glucamine (PD135,158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2-oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1-(2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoyl-methyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation.

Biopolymers. 2006 Mar; 81(4): 235-48
Shrake A, Frazier D, Schwarz FP

A comprehensive study of the thermal stabilization of defatted human albumin monomer by n-alkyl fatty acid anions (FAAs), formate through n-decanoate, was carried out by differential scanning calorimetry (DSC). The concentration of each ligand affording maximum thermal stabilization was determined; n-nonanoate provides the greatest stabilization but is only marginally better than n-octanoate and n-decanoate. The use of reversible thermodynamics and a two-state denaturation model for albumin has been validated. Standard free energies of binding, calculated from increases in free energy of denaturation, for n-Butanoate and longer FAAs, are linear with n-alkyl chain length whereas those for formate, acetate, and n-propionate deviate from linearity; those for acetate and n-propionate are even greater than that of n-Butanoate, thereby suggesting, in addition to the common class of sites available to all such ligands, the presence of an additional class of lower affinity binding sites available only to these shortest ligands. Competition experiments involving acetate and n-octanoate and involving n-pentanoate and n-octanoate confirmed the binding of acetate to lower affinity sites unavailable to n-octanoate and n-pentanoate. Furthermore, an equation is provided, allowing computation of the transition temperature as a function of the free energy for any reversible process causing a change in thermal stability of a protein undergoing reversible, two-state denaturation. With this equation, modeling the competition experiments by using the binding parameters determined by DSC provides additional support for the class of lower affinity sites, which play a significant role in thermal stabilization of albumin at higher concentrations of these shortest FAAs.

Eur J Pharm Biopharm. 2006 Jan; 62(1): 32-8
Wang SN, Deng YH, Xu H, Wu HB, Qiu YK, Chen DW

This paper described the synthesis of a novel galactosylated lipid with mono-galactoside moiety, (5-Cholesten-3beta-yl) 4-oxo-4-[2-(lactobionyl amido) ethylamido] Butanoate (CHS-ED-LA), and the targetability of doxorubicin (DOX), a model drug, in liposomes containing 10% mol/mol CHS-ED-LA (galactosylated liposomes, GalL) to the liver was studied. The weighted-average overall drug targeting efficiency (Te(*)) was used to evaluate the liver targetability of GalL DOX. The results showed that GalL DOX gave a relatively high (Te(*))(liver) value of 64.6%, while DOX in conventional liposome (CL DOX) only gave a (Te(*))(liver) value of 21.8%. In the liver, the GalL DOX was mainly taken up by parenchymal cells (88% of the total hepatic uptake). Moreover, preinjection of asialofetuin significantly inhibited the liver uptake of GalL DOX (from 70 to 12% of the total injected dose). It was suggested that liposomes containing such novel galactosylated lipid, CHS-ED-LA, had a great potential as drug delivery carriers for hepatocyte-selective targeting.

J Pharmacol Exp Ther. 2006 Jan; 316(1): 466-75
Yaksh TL, Kokotos G, Svensson CI, Stephens D, Kokotos CG, Fitzsimmons B, Hadjipavlou-Litina D, Hua XY, Dennis EA

Phospholipase A(2) (PLA(2)) forms are expressed in spinal cord, and inhibiting spinal PLA(2) induces a potent antihyperalgesia. Here, we examined the antihyperalgesic effects after systemic and i.t. delivery of four compounds constructed with a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four-carbon tether. These molecules were characterized for their ability to block group IVA calcium-dependent PLA(2) (cPLA(2)) and group VIA calcium-independent PLA(2) (iPLA(2)) in inhibition assays using human recombinant enzyme. The rank ordering of potency in blocking group IVA cPLA(2) was AX048 (ethyl 4-[(2-oxohexadecanoyl)amino]Butanoate), AX006 (4-[(2-oxohexadecanoyl)amino]butanoic acid), and AX057 (tert-butyl 4-[(2-oxohexadecanoyl)amino]Butanoate) > AX010 (methyl 4-[(2-oxohexadecanoyl)amino]Butanoate) and for inhibiting group VIA iPLA(2) was AX048, AX057 > AX006, and AX010. No agent altered recombinant cyclooxygenase activity. In vivo, i.t. (30 mug) and systemic (0.2-3 mg/kg i.p.) AX048 blocked carrageenan hyperalgesia and after systemic delivery in a model of spinally mediated hyperalgesia induced by i.t. substance P (SP). The other agents were without activity. In rats prepared with lumbar i.t. loop dialysis catheters, SP evoked spinal prostaglandin E(2) (PGE(2)) release. AX048 alone inhibited PGE(2) release. Intrathecal SR141617, a cannabinoid CB1 inhibitor at doses that blocked the effects of i.t. anandamide had no effect upon i.t. AX048. These results suggest that AX048 is the first systemically bioavailable compound with a significant affinity for group IVA cPLA(2), which produces a potent antihyperalgesia. The other agents, although demonstrating enzymatic activity in cell-free assays, appear unable to gain access to the intracellular PLA(2) toward which their action is targeted.

J Agric Food Chem. 2005 Oct 5; 53(20): 7931-8
Fan W, Qian MC

The aroma compounds of young and aged Chinese "Yanghe Daqu" liquor samples were extracted by solid phase microextraction (SPME) and analyzed by gas chromatography (GC)-olfactometry dilution analysis. The original liquor samples were diluted with deionized water to give a final alcohol content of 14% (v/v). The samples were stepwise diluted (1:1) with 14% (by volume) ethanol-water solution and then extracted by headspace SPME. The samples were preequilibrated at 50 degrees C for 15 min and extracted with stirring at the same temperature for 30 min prior to injection into GC. The aroma compounds were identified by both GC-MS and GC-olfactometry using DB-Wax and DB-5 columns. The results suggested that esters were the major contributors to Yanghe Daqu liquor aroma. Ethyl hexanoate, ethyl Butanoate, and ethyl pentanoate had very high flavor dilution values in both young and aged liquors (FD > 8192). Methyl hexanoate, ethyl heptanoate, ethyl benzoate, and butyl hexanoate could also be very important because of their high flavor dilution values (FD > or = 256). Moreover, two acetals, 1,1-diethoxyethane and 1,1-diethoxy-3-methylbutane, also were shown high flavor dilution values in Yanghe Daqu liquors (FD > or = 256). Other aroma compounds having moderate flavor dilution values included acetaldehyde, 3-methylbutanol, and 2-pentanol (FD > or = 32). Comparing young and aged liquors, the aroma profiles were similar, but the aroma compounds in the aged sample had higher flavor dilution values than in the young ones.