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Metabolic Conversion (metabolic + conversion)
Selected AbstractsMicroglia express functional 11,-hydroxysteroid dehydrogenase type 1,GLIA, Issue 10 2010Andres Gottfried-Blackmore Abstract Glucocorticoids are potent regulators of inflammation exerting permissive, stimulatory, and suppressive effects. Glucocorticoid access to intracellular receptors is regulated by the activity of two distinct enzymes known as 11,-hydroxysteroid dehydrogenase (11,HSD) Type 1 and Type 2, which catalyze the activation or deactivation of glucocorticoids. Although expression of these enzymes in major organ systems and their roles in the metabolic effects of glucocorticoids have been described, their role in the inflammatory response has only recently started to be addressed. In this report, we have studied the expression and activity of 11,HSD Type 1 and Type 2 in microglia cells. Microglia, the brain's resident macrophages, initiate and orchestrate CNS inflammatory responses. Importantly, activated microglia are implicated in most neurodegenerative conditions, making them key subjects of study. We found that microglia expressed 11,HSD-1, but not 11,HSD-2, both in ex vivo FACS-sorted adult cells and in vitro primary cultures. 11,HSD-1 expression was increased in LPS-activated microglia. Moreover, 11,HSD-1 catalyzed the metabolic conversion of 11-dehydro-corticosterone into corticosterone (CORT), which potently reduced cytokine production in activated microglia. We propose that 11,HSD-1 may provide microglia with an intrinsic mechanism to autoregulate and inhibit proinflammatory mediator production through CORT formation. © 2010 Wiley-Liss, Inc. [source] Fluorescence and coloration of grey hairINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 5 2009S. Daly Synopsis Grey hair samples were collected from 11 individuals and separated into un-pigmented and pigmented fibres (International Hair Importers). Fluorescence measurements were obtained by using a double-grating fluorescence spectrophotometer and a bifurcated fibre optics accessory to measure the spectra directly from the surface of hair at various distances from the fibre root. Colour measurements were carried out by using a Hunter colorimeter. The fluorescence spectra of un-pigmented hair obtained by the excitation at 290 nm show a peak at 356 nm [tryptophan (Trp)], and multi-peak emissions in the range from 395 to 500 nm. A significant variation in the Trp emission intensity at 356 nm vs. the intensity of emission in the 395,500 nm range was observed for hair collected from various individuals with yellow coloured hair producing stronger relative emission in 395,500 nm range. Quantitative measurements of coloration and the calculation of the Yellowness Index (YI) showed linear correlation between YI and the ratio of fluorescence intensities I440/I356 The spectra obtained by excitation at 320 nm showed the emission peaks at 395 nm (unidentified), 420 nm (N -formylkynurenine), 460 nm (kynurenine), and 495 nm (3-hydroxykynurenine), which are the products of oxidative or metabolic conversion of tryptophan. Un-pigmented, yellow hair showed a build-up of the fluorescence band corresponding to 3-hydroxykynurenine at 495 nm. The data also showed the fluorescence quenching effect of melanin resulting in the lowering of the fluorescence intensity of pigmented hair. The spectra obtained at various positions along the fibres demonstrated gradual photo-decomposition of hair chromophores during their lifetimes. This was indicated by a decrease of Trp fluorescence intensity, which was relatively fast (8·10,4,1.5·10,3 [day,1] as calculated for hair obtained from various individuals) for un-pigmented hair and slower for pigmented hair. A decrease in Trp emission was accompanied by an increase in the yellow coloration toward the ends of un-pigmented fibres. Resume Des échantillons de cheveux gris ont été collectés chez onze personnes et triés entre fibres non pigmentés et fibres pigmentés (International Hair Importers). Les mesures de fluorescence ont été réalisées à l'aide d'un spectrophotomètre de fluorescence double grille et d'un accessoire constitué d'une fibre optique bifurquée. Ce dispositif permet la mesure du spectre directement depuis la surface d'un cheveu à diverses distances de sa racine. Les mesures de couleur ont été réalisées à l'aide d'un colorimètre HUNTER. Le spectre de fluorescence d'un cheveu non pigmenté obtenu par excitation à 290 nm montre un pic à 356 nm (tryptophane : Trp) et des émissions multi pics dans l'intervalle 395 à 500 nm. On observe une variation significative de l'intensité du Trp à 356 nm par rapport à l'intensité d'émission dans l'intervalle 395,500 nm sur les cheveux prélevés sur diverses personnes, les cheveux colorés en jaune produisant une émission relative plus forte dans l'intervalle 395,500 nm. Les mesures quantitatives de la couleur et le calcul de l'indice de jaunissement (YI) montrent une corrélation linéaire entre YI et le rapport des intensités de fluorescence I 440/I356. Le spectre obtenu par excitation à 320 nm montre des pics d'émission à 395 nm (non identifiés), 420 nm (N-formylkynurenine), 460 nm (kynurenine), 495 nm (3-hydroxy kinurenine) propres aux produits d'oxydation ou de conversion métabolique du Tryptophane. Les cheveux jaunes non pigmentés présentent une saturation de la bande de fluorescence correspondant à la 3-hydroxykynurenine à 495 nm. Ces données montrent également l'effet de quenching de la mélanine entraînant un affaiblissement de l'intensité de la fluorescence des cheveux pigmentés. Le spectre obtenu en divers endroits le long des fibres indique une photodécomposition graduelle des chromophores des cheveux durant leur temps de vie. Ceci se traduit par une diminution de l'intensité de fluorescence du Trp qui est relativement rapide pour les cheveux non pigmentés (8,10,4,1,5,10,3 [jour , 1], conformément aux calculs effectués sur des cheveux prélevés sur différents individus) et par une diminution plus lente pour les cheveux pigmentés. Une diminution de l'émission du Trp s'accompagne d'une augmentation de la coloration jaune de l'extrémité des cheveux, détectable sur des cheveux non pigmentés. [source] Straight-chain naltrexone ester prodrugs: Diffusion and concurrent esterase biotransformation in human skinJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2002Audra L. Stinchcomb Abstract Naltrexone (NTX) is an opioid antagonist used for treatment of narcotic dependence and alcoholism. Transdermal naltrexone delivery is desirable to help improve patient compliance. The purpose of this study was to increase the delivery rate of NTX across human skin by using lipophilic alkyl ester prodrugs. Straight-chain naltrexone-3-alkyl ester prodrugs of 2,7 carbons in chain length were synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The melting points, solubilities, and skin disposition of the drugs were determined. The prodrugs were almost completely hydrolyzed on passing through the skin and appeared as NTX in the receiver compartment. The mean NTX flux from the prodrug-saturated solutions exceeded the flux of NTX base by ,2,7-fold. The amount of drug detected in the skin was significantly greater after treatment with the prodrug solutions compared with treatment with NTX base. The extent of parent drug (NTX) regeneration in the intact skin ranged from 28 to 91%. Higher NTX regeneration percentages in skin appeared to correlate with increased drug delivery rates. Definitively, the highly oil-soluble prodrugs provide a higher NTX flux across human skin in vitro and undergo significant metabolic conversion in the skin. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2571,2578, 2002 [source] Role of Dopamine D1 Receptors and Extracellular Signal Regulated Kinase in the Motivational Properties of Acetaldehyde as Assessed by Place Preference ConditioningALCOHOLISM, Issue 4 2010Liliana Spina Background:, The role of dopamine D1 receptors and Extracellular signal Regulated Kinase (ERK) in the motivational properties of drugs can be studied by place-conditioning. Recent advances have shown that the motivational properties of ethanol, determined by place-conditioning, are mediated by its metabolic conversion into acetaldehyde. To date, the role of D1 receptors and ERK activation in acetaldehyde-elicited place preference has not been determined. The aim of this study was to assess the role of D1 receptors blockade and MEK inhibition in the acquisition of acetaldehyde-elicited conditioned place preference. Methods:, Male Sprague,Dawley rats were subjected to repeated pairings with 1 compartment of the conditioning apparatus immediately following acetaldehyde (20 mg/kg i.g.) or ethanol (1 g/kg i.g.) administration. The D1 receptor antagonist, SCH 39166 (50 ,g/kg s.c.), was administered 10 minutes before acetaldehyde or ethanol administration. In order to study the role of activated ERK in the acetaldehyde-elicited place preference, rats were administered the MEK inhibitor, PD98059 (1, 30, and 90 ,g i.c.v.), 10 or 30 minutes before acetaldehyde. To verify the specificity of these effects, we also studied whether PD98059 pretreatment could affect morphine (1 mg/kg s.c.)-elicited place preference. Results:, Both acetaldehyde and ethanol elicited significant place preferences and these were prevented by pretreatment with SCH 39166. In addition, pretreatment with PD98059, dose (30 and 90 but not 1 ,g i.c.v.) and time (10 but not 30 minutes before) dependently, prevented the acquisition of acetaldehyde- and significantly reduced the acquisition of morphine-elicited conditioned place preference. Conclusions:, These results confirm that acetaldehyde and ethanol elicit conditioned place preference and demonstrate that D1 receptors are critically involved in these effects. Furthermore, the finding that PD98059 prevents the acquisition of acetaldehyde-elicited conditioned place preference highlights the importance of the D1 receptor,ERK pathway in its motivational effects. [source] Polycapillary-optics-based micro-XANES and micro-EXAFS at a third-generation bending-magnet beamlineJOURNAL OF SYNCHROTRON RADIATION, Issue 2 2009Geert Silversmit A focusing system based on a polycapillary half-lens optic has been successfully tested for transmission and fluorescence µ-X-ray absorption spectroscopy at a third-generation bending-magnet beamline equipped with a non-fixed-exit Si(111) monochromator. The vertical positional variations of the X-ray beam owing to the use of a non-fixed-exit monochromator were shown to pose only a limited problem by using the polycapillary optic. The expected height variation for an EXAFS scan around the Fe K -edge is approximately 200,µm on the lens input side and this was reduced to ,1,µm for the focused beam. Beam sizes (FWHM) of 12,16,µm, transmission efficiencies of 25,45% and intensity gain factors, compared with the non-focused beam, of about 2000 were obtained in the 7,14,keV energy range for an incoming beam of 0.5 × 2,mm (vertical × horizontal). As a practical application, an As K -edge µ-XANES study of cucumber root and hypocotyl was performed to determine the As oxidation state in the different plant parts and to identify a possible metabolic conversion by the plant. [source] Effects of anthocyanins and other phenolics of boysenberry and blackcurrant as inhibitors of oxidative stress and damage to cellular DNA in SH-SY5Y and HL-60 cellsJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 5 2006Dilip Ghosh Abstract There is growing interest both from consumers and researchers in the role that berries play in human health. The objective of this study was to investigate whether anthocyanins and other phenolics present in boysenberries and blackcurrants are effective in protecting cells against the oxidative damage induced by hydrogen peroxide (H2O2). The concentrations of polyphenols used were within the human physiological range. The data showed that SH-SY5Y human neuroblastoma cells were protected against H2O2 -induced toxicity by the anthocyanins and phenolic fractions. The concurrent addition of either fractions of these berries with H2O2 significantly inhibited the increase in intracellular reactive oxygen species (ROS) production. Pre-incubation of cells with the same concentrations had no effect on the ROS level,a result that may be due to the metabolic conversion to inactive compounds. Anthocyanins and phenolic fractions of blackcurrant were better at protecting DNA of HL-60 human promyelocytic cells from damage than similar fractions from boysenberry. The phenolic extract of blackcurrant demonstrated the highest protective effect against H2O2 -induced neurotoxicity, oxidative stress and DNA damage and may be a good candidate for inclusion into a processed functional food. Copyright © 2006 Society of Chemical Industry [source] Moxidectin and ivermectin metabolic stability in sheep ruminal and abomasal contentsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005A. LIFSCHITZ The oral administration of macrocyclic lactones to sheep leads to poorer efficacy and shorter persistence of the antiparasitic activity compared to the subcutaneous treatment. Gastrointestinal biotransformation occurring after oral treatment to ruminant species has been considered as a possible cause of the differences observed between routes of administration. The current work was addressed to evaluate on a comparative basis the in vitro metabolism of moxidectin (MXD) and ivermectin (IVM) in sheep ruminal and abomasal contents. Both compounds were incubated under anaerobic conditions during 2, 6 and 24 h in ruminal and abomasal contents collected from untreated adult sheep. Drug concentrations were measured by high-performance liquid chromatography with fluorescence detection after sample clean up and solid phase extraction. Neither MXD nor IVM suffered metabolic conversion and/or chemical degradation after 24-h incubation in ruminal and abomasal contents collected from adult sheep. Unchanged MXD and IVM parent compounds represented between 95.5 and 100% of the total drug recovered in the ruminal and abomasal incubation mixtures compared with those measured in inactive control incubations. The partition of both molecules between the solid and fluid phases of both sheep digestive contents was assessed. MXD and IVM were extensively bound (>90%) to the solid material of both ruminal and abomasal contents collected from sheep fed on lucerne hay. The results reported here confirm the extensive degree of association to the solid digestive material and demonstrates a high chemical stability without evident metabolism and/or degradation for both MXD and IVM in ruminal and abomasal contents. [source] Cell-free expression and selective isotope labelling in protein NMRMAGNETIC RESONANCE IN CHEMISTRY, Issue S1 2006David Staunton Abstract Isotope labelling is a very powerful tool in NMR studies of proteins and has been employed in various ways for over 40 years. 15N and 13C incorporation, using recombinant expression systems, is now commonplace because heteronuclear experiments assist with the fundamental problems of peak resolution and assignment. The use of selective labelling for peak assignment has been restricted by the scrambling of isotope label through metabolic pathways within the expression host organism. The availability of efficient cell-free expression systems with low levels of metabolic conversion allow the increasing use of selective isotope labelling as a tool in protein NMR. We describe two examples, one where a selective labelling scheme can identify backbone amide peaks from unassigned 1H15N HSQC and HNCO spectra of a 84 residue protein, and another where a specific backbone amide in a 198 residue construct of the ninth and tenth Type III repeats from human fibronectin can be labelled and rapidly identified using a simple HSQC experiment. Copyright © 2006 John Wiley & Sons, Ltd. [source] | |||||||||||||