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Acetyl
Terms modified by Acetyl Selected AbstractsEFFECTS OF A SINGLE, SHORT INTRAVENOUS DOSE OF ACETYL- l -CARNITINE ON PATTERN-REVERSAL VISUAL-EVOKED POTENTIALS IN CIRRHOTIC PATIENTS WITH HEPATIC ENCEPHALOPATHYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2006Massimo Siciliano SUMMARY 1In animals and in cultured neurons, l -carnitine and acetyl- l -carnitine (ALCAR) have been shown to counteract some of the toxic effects of ammonia. In order to detect similar properties in humans, we studied neuronal function after ALCAR administration in cirrhotics with hepatic encephalopathy (HE). 2Eighteen cirrhotic patients with persistent HE and hyperammonaemia were investigated in the present study and six subjects with a prior transient ischaemic attack were used as controls. 3The prominent positive component that occurs approximately 100 msec after the pattern reversal (P100) latencies of visual-evoked potentials were used to evaluate neuronal function. At first, the P100 latency was measured in six cirrhotic patients with HE and in the six controls before the administration of 0.5 g ALCAR in 50 mL isotonic saline (infusion rate 10 mL/min) and 15, 30, 60 and 90 min later. 4A significant reduction in P100 latencies was identified 30 min after ALCAR infusion in HE patients, whereas no differences were observed in controls. 5Thereafter, the P100 latency was evaluated in the 12 other cirrhotic patients with HE only before and 30 min after ALCAR infusion. The mean of the P100 latencies measured in these subjects was significantly shorter after ALCAR infusion compared with values obtained before ALCAR administration (mean (SD) 130.78 5.50 vs 136.08 6.45 msec, respectively; P = 0.0013). 6The present study suggests that a single intravenous dose of ALCAR may transiently improve neuronal function in cirrhotic patients with persistent HE and hyperammonaemia. [source] Acetyl- l -carnitine improves aged brain functionGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2010Satoru Kobayashi The effects of acetyl- l -carnitine (ALCAR), an acetyl derivative of l -carnitine, on memory and learning capacity and on brain synaptic functions of aged rats were examined. Male Fischer 344 rats were given ALCAR (100 mg/kg bodyweight) per os for 3 months and were subjected to the Hebb,Williams tasks and AKON-1 task to assess their learning capacity. Cholinergic activities were determined with synaptosomes isolated from brain cortices of the rats. Choline parameters, the high-affinity choline uptake, acetylcholine (ACh) synthesis and depolarization-evoked ACh release were all enhanced in the ALCAR group. An increment of depolarization-induced calcium ion influx into synaptosomes was also evident in rats given ALCAR. Electrophysiological studies using hippocampus slices indicated that the excitatory postsynaptic potential slope and population spike size were both increased in ALCAR-treated rats. These results indicate that ALCAR increases synaptic neurotransmission in the brain and consequently improves learning capacity in aging rats. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S99,S106. [source] Kinetic and mechanistic study on the thermal reactivity of stabilized phosphorus ylides, part 3: [(Acetyl)(arylcarbamoyl)methylene]triphenylphosphoranes and [(alkoxycarbonyl)(arylcarbamoyl)methylene]triphenylphosphoranes and their thiocarbamoyl analoguesINTERNATIONAL JOURNAL OF CHEMICAL KINETICS, Issue 1 2007R. Alan Aitken A series of five [(acetyl)(arylcarbabmoyl)methylene]triphenyl-phosphoranes 1a,e and their thiocarbamoyl analogues 2a,e, [(alkoxycarbonyl)(arylcarbamoyl)methylene]triphenylphosphoranes 3a,e and their thiocarbamoyl analogues 4a,e were prepared and fully characterized. All ylides are found under conditions of flash vacuum pyrolysis to fragment giving arylisocyanate or isothiocyanate and acetyl ylides or alkoxy ylides which undergo thermal extrusion of Ph3PO. A kinetic study shows that these reactions are unimolecular and are of first-order nature with no significant substituent effect. The thiocarbamoyl ylides 2 react from 4.6 to 42 times faster than their carbamoyl ylides 1, while the thiocarbamoyl ylides 4 react from 6.6 to 20.9 times faster than their carbamoyl ylides 3. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 39: 6,16, 2007 [source] Combined Application of Galactose Oxidase and ,- N -Acetylhexosaminidase in the Synthesis of Complex Immunoactive N -Acetyl- D -galactosaminidesADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 7-8 2005Pavla Fialová Abstract A high-yield preparatory procedure for the synthesis of p -nitrophenyl 2-acetamido-2-deoxy-,- D - galacto -hexodialdo-1,5-pyranoside (2) using the galactose oxidase from Dactylium dendroides in a batch reactor was developed. Enzymatic recognition of this aldehyde and the respective uronic acid 3 obtained by NaClO2 oxidation was studied using a set of 36 fungal ,- N -acetylhexosaminidases from Acremonium, Aspergillus, Penicillium and Talaromyces genera. The aldehyde 2 was readily hydrolysed by all tested ,- N -acetylhexosaminidases but neither the uronic acid 3 nor its methyl ester 4 were accepted. Molecular modelling with docking into the active centre of the ,- N -acetylhexosaminidase from Aspergillus oryzae revealed that the aldehyde 2 is processed as a C-6 geminal diol by the enzyme. The aldehyde 2 was tested for transglycosylation reactions using GlcNAc as an acceptor. The ,- N -acetylhexosaminidase from Talaromyces flavus gave the best yields (37%) of the transglycosylation product 2-acetamido-2-deoxy-,- D - galacto -hexodialdo-1,5-pyranosyl-(1,4)-2-acetamido- 2-deoxy- D -glucopyranose, which was oxidised in situ to yield the final product 2-acetamido-2-deoxy-,- D -galactopyranosyluronic acid-(1,4)-2-acetamido-2-deoxy- D -glucopyranose (6). Compounds 3 and 6 were shown to be high-affinity ligands for two natural killer cell activation receptors, NKR-P1A and CD69. For the latter receptor they turned out to be among the best ligands described so far. This increase was obviously due to the presence of a carboxy moiety. [source] Synthesis of N -Acetyl-,-aminobutyric Acid via Amidocarbonylation: A Case StudyADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 4 2003Dirk Gördes Abstract The synthesis of N -acetyl-,-aminobutyric acid by amidocarbonylation of propionaldehyde with acetamide in the presence of palladium catalysts is studied in detail. The influence of various reaction conditions and compositions (e.g., the co-catalysts acid and bromide) on the yield of N -acetyl-,-aminobutyric acid is shown. For the first time it is demonstrated that the palladium-catalyzed amidocarbonylations of aldehydes can be run with significantly lower halide concentrations (<30 mol,%) without a major yield decrease. While phosphine-free catalyst systems give best yields at low CO pressure, phosphine-ligated palladium catalysts lead to better yields at higher CO pressure. At low palladium loadings (<0.1 mol,%), unwanted condensation reactions of propionaldehyde become increasingly competitive. [source] Acetyl -l- carnitine protects yeast cells from apoptosis and aging and inhibits mitochondrial fissionAGING CELL, Issue 4 2010Vanessa Palermo Summary In this work we report that carnitines, in particular acetyl -l- carnitine (ALC), are able to prolong the chronological aging of yeast cells during the stationary phase. Lifespan extension is significantly reduced in yca1 mutants as well in rho0 strains, suggesting that the protective effects pass through the Yca1 caspase and mitochondrial functions. ALC can also prevent apoptosis in pro-apoptotic mutants, pointing to the importance of mitochondrial functions in regulating yeast apoptosis and aging. We also demonstrate that ALC attenuates mitochondrial fission in aged yeast cells, indicating a correlation between its protective effect and this process. Our findings suggest that ALC, used as therapeutic for stroke, myocardial infarction and neurodegenerative diseases, besides the well-known anti-oxidant effects, might exert protective effects also acting on mitochondrial morphology. [source] EPIGENETIK: Genomic Imprinting in SäugetierenBIOLOGIE IN UNSERER ZEIT (BIUZ), Issue 2 2007Article first published online: 11 APR 200 Die Epigenetik beschäftigt sich mit der Weitergabe von Eigenschaften auf die Nachkommen, die nicht auf Abweichungen in der DNA-Sequenz beruhen. Prominente Beispiele für epigenetische Modifikationen des Chromatins sind die Addition von Acetyl- oder Methylgruppen , auf unserem Titelbild symbolisiert durch den kleinen Turner in der Doppelhelix. Mehr zum Thema lesen Sie ab Seite 86. Bild: Linda Bucklin , FOTOLIA. [source] Fluorescence determination of N -acetylaspartic acid in the rat cerebrum homogenate using high-performance liquid chromatography with pre-column fluorescence derivatizationBIOMEDICAL CHROMATOGRAPHY, Issue 1 2008Takeshi Fukushima Abstract N -Acetyl- l -aspartic acid (NAA) is an endogenous compound, and its brain concentration is suggested to be altered in neurological disorders. In the present study, a fluorescence determination method for NAA was developed by employing reversed-phase high-performance liquid chromatography (HPLC) with pre-column fluorescence derivatization using 4- N,N -dimethylaminosulfonyl-7- N -(2-aminoethyl)amino-2,1,3-benzoxadiazole (DBD-ED). Using methylsuccinic acid as the internal standard, a linear calibration curve for NAA was constructed in the range 125,1000 µm (n = 3). The detection limit on the column was approximately 5.0 fmol (signal-to-noise ratio 3). The proposed HPLC method was applied to determine NAA in the rat cerebrum homogenate. Cerebrum NAA was successfully determined using 10 µL of the homogenate, and the validation data for the proposed HPLC method demonstrated satisfactory results. Intra- and inter-day precision and accuracy were within 1.1,7.0 and ,8.1,6.3%, respectively. The concentration of NAA in the male rat cerebrum (13 weeks old) was 84 ± 4.6 µmol/mg protein (n = 3). Copyright © 2007 John Wiley & Sons, Ltd. [source] Substitution of Acyl for Acetyl with N-Acylbenzotriazoles Catalyzed by Samarium Triiodide.CHEMINFORM, Issue 44 2007Xuefei Zou Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Ethanol Adsorption, Decomposition and Oxidation on Ir(111): A High Resolution XPS Study,CHEMPHYSCHEM, Issue 6 2007Cornelis J. Weststrate Dr. Abstract Ethanol (C2H5OH) adsorption, decomposition and oxidation is studied on Ir(111) using high-energy resolution, fast XPS and temperature-programmed desorption. During heating of an adsorbed ethanol layer a part of the C2H5OHad desorbs molecularly, and another part remains on the surface and decomposes around 200 K; these two decomposition pathways are identified, as via acetyl (H3CCO) and via COad+CH3ad, respectively. Acetyl and CH3ad decompose around 300 K into CHad (and COad). CHad decomposes forming Cx and H2 around 520 K. In the presence of Oad an acetate intermediate is formed around 180 K, as well as a small amount of CH3ad and COad. Acetate decomposes between 400,480 K into CO2, H2(/H2O) and CHad. [source] Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementiaACTA PSYCHIATRICA SCANDINAVICA, Issue 2 2010W. M. A. Verhoeven Verhoeven WMA, Csepán R, Marcelis CLM, Lefeber DJ, Egger JIM, Tuinier S. Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementia. Objective:, Sanfilippo B is a rare autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by a deficiency of N -acetyl-,-D-glucosaminidase (NAGLU). Method:, A mild mentally retarded elderly female patient is described with a slowly progressive dementia who had given birth to a daughter who developed normally. Results:, Metabolic screening revealed an enhanced concentration of heparan sulfate in urine. Enzymatic assay demonstrated deficiency of N -acetyl-,-D-glucosaminidase. Mutations in the NAGLU gene were found. One mentally retarded and hospitalized elder brother was also found to have MPS IIIB, whereas a second brother, who had died earlier, is suspected to have had the same metabolic disorder. Prior to the development of dementia, both the patient and her brother showed autistic like features, signs of ideomotor apraxia and weakness in verbal comprehension. Conclusion:, Screening for metabolic disorders, in particular MPSes, should always be considered in patients with a history of mental deficit and dementia or progressive functional decline. [source] Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazideDIABETES OBESITY & METABOLISM, Issue 2 2004J.-C. Mamputu Aim:, We have previously demonstrated that advanced glycation end products (AGEs) stimulate bovine retinal endothelial cell (BREC) proliferation through induction of vascular endothelial growth factor (VEGF) production by these cells. We have also shown that gliclazide, a sulfonylurea which decreases oxidative stress, inhibits this effect. The aim of the present study was to characterize the signalling pathways involved in AGE-induced BREC proliferation and VEGF production and mediating the inhibitory effect of gliclazide on these biological events. Methods:, BRECs were treated or not treated with AGEs in the presence or absence of gliclazide, antioxidants, protein kinase C (PKC), mitogen-activated protein kinase (MAPK) or nuclear factor-,B (NF-,B) inhibitors. BREC proliferation was assessed by measuring [3H]-thymidine incorporation into DNA. Activation of PKC, MAPK and NF-,B signal transduction pathways and determination of VEGF expression were assessed by Western blot analysis using specific antibodies. MAPK activity was also determined by an in vitro kinase assay. Results:, Treatment of BRECs with AGEs significantly increased cell proliferation and VEGF expression. AGEs induced PKC-, translocation, extracellular signal-regulated protein kinase 1/2 and NF-,B activation in these cells. Pharmacological inhibition of these signalling pathways abolished AGE effects on cell proliferation and VEGF expression. Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N -acetyl- l -cysteine resulted in a significant decrease in AGE-induced activation of PKC-, MAPK- and NF-,B-signalling pathways. Conclusions:, Our results demonstrate the involvement of PKC, MAPK and NF-,B in AGE-induced BREC proliferation and VEGF expression. Gliclazide inhibits BREC proliferation by interfering with these intracellular signal transduction pathways. [source] On-line sample preconcentration with chemical derivatization of bacterial biomarkers by capillary electrophoresis: A dual strategy for integrating sample pretreatment with chemical analysisELECTROPHORESIS, Issue 21 2005Adam S. Ptolemy Abstract Simple, selective yet sensitive methods to quantify low-abundance bacterial biomarkers derived from complex samples are required in clinical, biological, and environmental applications. In this report, a new strategy to integrate sample pretreatment with chemical analysis is investigated using on-line preconcentration with chemical derivatization by CE and UV detection. Single-step enantioselective analysis of muramic acid (MA) and diaminopimelic acid (DAP) was achieved by CE via sample enrichment by dynamic pH junction with ortho -phthalaldehyde/N -acetyl- L -cysteine labeling directly in-capillary. The optimized method resulted in up to a 100-fold enhancement in concentration sensitivity compared to conventional off-line derivatization procedures. The method was also applied toward the detection of micromolar levels of MA and DAP excreted in the extracellular medium of Escherichia coli bacterial cell cultures. On-line preconcentration with chemical derivatization by CE represents a unique approach for conducting rapid, sensitive, and high-throughput analyses of other classes of amino acid and amino sugar metabolites with reduced sample handling, where the capillary functions simultaneously as a concentrator, microreactor, and chiral selector. [source] Urinary L-FABP and anaemia: distinct roles of urinary markers in type 2 diabetesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2010M. Von Eynatten Eur J Clin Invest 2010; 40 (2): 95,102 Abstract Background, Urinary liver-type fatty acid binding protein (L-FABP) and kidney injury molecule (KIM)-1, novel urinary biomarkers of renal tubulointerstitial function, have previously been associated with acute ischaemic kidney injury. We studied the clinical significance of urinary L-FABP, KIM-1 and N -acetyl-,-glucosaminidase (NAG) as potential markers of renal function and chronic ischaemic injury in patients with diabetic nephropathy. Material and methods, A total of 130 type 2 diabetes patients with early diabetic nephropathy and 40 healthy controls were studied. Urinary L-FABP, KIM-1, NAG, albumin excretion rate (AER) and creatinine clearance were obtained from 24-h urine samples, and correlated with measures of red blood cell count, renal function and metabolic control. Results, Urinary L-FABP was significantly increased in diabetes patients compared with healthy controls [8·1 (interquartile 0·6,11·6) vs. 2·4 (0·5,3·6) ,g/g creatinine, P < 0·001] and correlated with AER (r = 0·276, P = 0·002), creatinine clearance (r = ,0·189, P = 0·033) and haemoglobin levels (r = ,0·190, P = 0·030). In multivariable linear regression analysis, haemoglobin (, = ,0·247, P = 0·015) and AER (, = 0·198, P = 0·046) were significant predictors of urinary L-FABP. Prevalent anaemia was independently associated with a 6-fold risk for increased tubulointerstitial kidney damage (upper vs. lower two L-FABP tertiles: OR, 6·06; 95% CI: 1·65,22·23; P = 0·007). Urinary KIM-1 was not significantly associated with kidney function, AER, or measures of red blood cell count while urinary NAG was associated with parameters of glucose control and renal function. Conclusions, Different urinary biomarkers may reflect distinct pathophysiological mechanisms of tubulointerstitial damage in early diabetic nephropathy: Urinary L-FABP could be a novel biomarker for chronic intrarenal ischaemia. [source] Polymerase,, is up-regulated during the T,cell-dependent immune response and its deficiency alters developmental dynamics of spleen centroblastsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005Daniel Lucas Abstract Mammalian DNA polymerase,, (Pol,), preferentially expressed in secondary lymphoid organs, is shown here to be up-regulated in germinal centers after immunization. Alternative splicing appears to be part of Pol, regulation during an immune response. We generated Pol,-deficient mice that are viable and show no anatomical malformation or serious alteration in lymphoid populations, with the exception of an underrepresentation of the B,cell compartment. Young and aged homozygous Pol,,/, mice generated similar immune responses after immunization with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken gammaglobulin (CGG), compared with their wild-type littermates. Nonetheless, the kinetics of development of the centroblast population showed significant differences. Hypermutation analysis of the rearranged heavy chain intron region in centroblasts isolated from NP-CGG-immunized Pol,,/, mice showed a similar quantitative and qualitative somatic mutation spectrum, but a lower representation of heavily mutated clones. These results suggest that although it is not a critical partner, Pol, modulates the in vivo somatic hypermutation process. [source] Palladium-Catalysed Direct C-H Activation/Arylation of Heteroaromatics: An Environmentally Attractive Access to Bi- or Polydentate LigandsEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 16 2008Fazia Derridj Abstract Bi- or polydentate ligands based on heterocycles can be easily prepared by palladium-catalysed C,H bond activation of heteroaromatics followed by heteroarylation with heteroaryl bromides. A variety of heteroaromatics such as furans, thiophenes, pyridines, thiazoles or oxazole derivatives have been employed and moderate to good yields were generally obtained using the air-stable complex [PdCl(dppb)(C3H5)] as catalyst. A range of functions such as acetyl, formyl, ester or nitrile on the heteroaromatics is tolerated.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] First (Peroxo)vanadium(V) Complex with Heteroligand Formed in Reaction System , Synthesis, Structure and Reactivity of K[VO(O2)(omeida)]·H2O {omeida = N -[2-(2-oxomorpholine-4-yl)ethyl]iminodiacetato(2,)}EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 11 2003Michal Sivák Abstract The crystalline peroxo complex of vanadium(V), K[VO(O2)(omeida)]·H2O, where omeida is a ,-lactone derivative, N -[2-(2-oxomorpholine-4-yl)ethyl]iminodiacetate(2,), has been obtained by reaction of vanadate with H2O2 and N -(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA) in acidic aqueous solution at pH = 3 and 278 K. X-ray analysis revealed a distorted pentagonal-bipyramidal coordination around the vanadium atom, with a typical cis arrangement of oxo and peroxo ligands in apical and equatorial positions, respectively. Two amino nitrogen atoms of the tetradentate omeida(2,)-N1,N2,O1,O2 ligand occupy the neighbouring equatorial positions of the pentagonal plane, and two oxygen atoms of carboxymethyl groups bound to the same N1 nitrogen atom are in equatorial and apical positions. The six-membered lactone ring in omeida was formed in the reaction solution from carboxy and hydroxy groups not involved in coordination with the vanadium atom. The 51V NMR spectra of K[VO(O2)(omeida)]·H2O, and of peroxovanadate/HEDTA/H2O and vanadate/HEDTA/H2O solutions, as well as the 1H NMR spectrum of HEDTA, proved that lactone ring closure proceeds only in peroxovanadate but not vanadate solutions. Spectroscopic investigation of the oxygen transfer reaction from the peroxo ligand in [VO(O2)(omeida)], to the thiolato sulfur atom in [Co(en)2{S(CH2)2NH2}]2+ or [Co(en)2(cyst)]+, and of the oxidation of N -acetyl- L -cysteine by K[VO(O2)(omeida)]·H2O, revealed much more complicated reaction mechanisms than those of other (amino-polycarboxylato)monoperoxo complexes of vanadium(V). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] A stress survival response in retinal cells mediated through inhibition of the serine,/,threonine phosphatase PP2AEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2010Sorcha Finnegan Abstract Cell survival signalling involving the PI3K/Akt survival pathway can be negatively regulated by several phosphatases including PP2A. When retinal-derived 661W cells were subjected to trophic factor deprivation this initiated a survival response through inhibition of the activity of PP2A and subsequent upregulation of the Erk and Akt survival pathways. We show this survival response via inhibition of PP2A activity was due in part to increased reactive oxygen species production when retinal cells were deprived of trophic factors. Inhibition of PP2A activity was mediated by a rapid and transient increase in phosphorylation at Tyr307, accompanied by an increase in demethylation and a decrease in the methylated form. Pre-treatment with N -acetyl- l -cysteine, which is involved in scavenging reactive oxygen species, prevented PP2A inhibition and subsequent upregulation of survival pathways. Pre-treatment with the Src family kinase inhibitor PP2 resulted in approximately 50% reduction in cellular levels of phospho-PP2A in trophic factor-deprived 661W cells, suggesting an Src tyrosine kinase had a role to play in this redox regulation of cell survival. We observed similar events in the rd10 mouse retina where there was an increased survival response prior to retinal cell death mediated through an increase in both phospho-PP2A and phospho-Gsk. Together, these results demonstrate that when retinal cells are stressed there is an initial struggle to survive, mediated through inhibition of PP2A and subsequent upregulation of survival pathways, and that these events occur simultaneously with production of reactive oxygen species, thus suggesting an important cell-signalling role for reactive oxygen species. [source] Negative cross-talk between presynaptic adenosine and acetylcholine receptorsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2006A. V. Shakirzyanova Abstract Functional interactions between presynaptic adenosine and acetylcholine (ACh) autoreceptors were studied at the frog neuromuscular junction by recording miniature end-plate potentials (MEPPs) during bath or local application of agonists. The frequency of MEPPs was reduced by adenosine acting on presynaptic adenosine A1 receptors (EC50 = 1.1 µm) or by carbachol acting on muscarinic M2 receptors (EC50 = 1.8 µm). However, carbachol did not produce the depressant effect when it was applied after the action of adenosine had reached its maximum. This phenomenon implied that the negative cross-talk (occlusion) had occurred between A1 and M2 receptors. Moreover, the occlusion was receptor-specific as ATP applied in the presence of adenosine continued to depress MEPP frequency. Muscarinic antagonists [atropine or 1-[[2-[(diethylamino)methyl)-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepine-6-one) (AFDX-116)] had no effect on the inhibitory action of adenosine and adenosine antagonists [8-(p -sulfophenyl)theophylline (8-SPT) or 1,3-dipropyl-8-cyclopentylxanthine (DPCPX)] had no effect on the action of carbachol. These data suggested that membrane,delimited interactions did not occur between A1 and M2 receptors. Both carbachol and adenosine similarly inhibited quantal release triggered by high potassium, ionomycin or sucrose. These results indicated a convergence of intracellular pathways activated by M2 and A1 receptors to a common presynaptic effector located downstream of Ca2+ influx. We propose that the negative cross-talk between two major autoreceptors could take place during intense synaptic activity and thereby attenuate the presynaptic inhibitory effects of ACh and adenosine. [source] Synthesis of Novel Macrolactam and Macroketone Analogues of Migrastatin from D -Glucal and Comparison with Macrolactone and Acyclic Analogues: A Dorrigocin A Congener Is a Potent Inhibitor of Gastric Cancer Cell MigrationEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 11 2008Guillaume Anquetin Abstract Novel macrolactam and macroketone analogues of the migrastatin macrolide core have been synthesised from tri- O -acetyl- D -glucal in order to facilitate structure-activity studies. The Horner olefination, followed by ring-closing metathesis were key steps in the synthesis of the macroketone. The ability of the macroketone and macrolactam derivatives to inhibit the migration of gastric tumour cells as determined using a transwell migration assay were compared with macrolactone analogues and dorrigocin A analogues. One dorrigocin A congener was the most potent inhibitor of gastric cancer cell migration.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Novel and Efficient Chemoenzymatic Synthesis of D -Glucose 6-Phosphate and Molecular Modeling Studies on the Selective BiocatalysisEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 17 2007Tatiana Rodríguez-Pérez Abstract A concise chemoenzymatic synthesis of glucose 6-phosphate is described. Candida rugosa lipase was found to be an efficient catalyst for both regio- and stereoselective deacetylation of the primary hydroxy group in the peracetylated D -glucose. In addition, we report an improved synthesis of 1,2,3,4,6-penta- O -acetyl-,- D -glucopyranose providing a large-scale procedure for the acetylation of ,- D -glucose without isomerization at the anomeric center. The high overall yield and the easy scalability makes this chemoenzymatic strategy attractive for industrial application. Furthermore, molecular modeling of phosphonate transition-state analog for the enzymatic hydrolysis step supports the substrate selectivity observed with Candida rugosa lipase.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] In the Search of Glycogen Phosphorylase Inhibitors: Synthesis of C- D -Glycopyranosylbenzo(hydro)quinones , Inhibition of and Binding to Glycogen Phosphorylase in the Crystal,EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 4 2007Li He Abstract Penta- O -acetyl-,- D -glycopyranoses and 1,4-dimethoxybenzene led selectively by electrophilic substitution to C-,- D -glycopyranosyl-1,4-dimethoxybenzenes which were converted by simple and efficient reactions (oxidation, reduction and deacetylation) to the corresponding C-glycosylhydro- and C-glycosylbenzoquinones, with either an acetylated or deprotected sugar moiety. C-,- D -Glucosylbenzoquinone 19 and C-,- D -Glucosylhydroquinone 23 were found to be competitive inhibitors of rabbit muscle glycogen phosphorylase b (GPb), with respect to the substrate ,- D -glucose-1-phosphate, with Ki values of 1.3 and 0.9 mM, respectively, whereas C-,- D -glucosylhydroquinone 17 was not effective up to a concentration of 8 mM. In order to elucidate the structural basis of inhibition, we determined the crystal structures of 19 and 23 in complex with GPb at a 2.03,2.05 Ĺ resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as ,- D -glucose and stabilise the transition state conformation of the 280s loop by making several favourable contacts to Asp283 and Asn284 of this loop. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Differential regulation of the nitric oxide,cGMP pathway exacerbates postischaemic heart injury in stroke-prone hypertensive ratsEXPERIMENTAL PHYSIOLOGY, Issue 1 2007Tetsuji Itoh Using a working perfused heart model, we investigated the hypothesis that alterations in the NO,cGMP pathway may exacerbate postischaemic mechanical dysfunction in the hypertrophied heart. Ischaemia for 25 min followed by reperfusion for 30 min produced marked cardiac mechanical dysfunction in both stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY). Exogenous treatment with S -nitroso- N -acetyl- dl -penicillamine (SNAP), a NO donor, had beneficial effects on the cardiac dysfunction induced by ischaemia,reperfusion (I/R) in the WKY heart, but the cardioprotective effect of SNAP was eliminated by guanylyl cyclase inhibitor. Cardiac cGMP levels were increased by SNAP or ischaemia in WKY. In contrast, in SHRSP hearts, SNAP could not alleviate the cardiac dysfunction caused by I/R. Pre-ischaemia, the cardiac cGMP level was significantly higher in SHRSP than in WKY; however, no significant difference was found after SNAP and ischaemia. The myocardial Ca2+ -dependent NO synthase (NOS) activity increased at the end of ischaemia in WKY. Conversely, the Ca2+ -independent NOS activity and protein levels were upregulated by I/R in the SHRSP myocardium. In the SHRSP hearts, non-selective NOS and selective Ca2+ -independent NOS inhibitors or antioxidant treatment alleviated cardiac dysfunction caused by I/R. Moreover, mRNA expression and Western blotting analysis of cGMP-dependent protein kinase type I showed more deterioration of SHRSP hearts compared with WKY. These results suggest that: (1) the NO-dependent cardioprotective effect is depressed; and (2) overproduction of NO derived from Ca2+ -independent NOS contributes to postischaemic heart injury in the hypertrophied heart of hypertensive status. [source] Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesisFEBS JOURNAL, Issue 18 2007Petra Ml, ochová Human glutamate carboxypeptidase II [GCPII (EC 3.4.17.21)] is recognized as a promising pharmacological target for the treatment and imaging of various pathologies, including neurological disorders and prostate cancer. Recently reported crystal structures of GCPII provide structural insight into the organization of the substrate binding cavity and highlight residues implicated in substrate/inhibitor binding in the S1, site of the enzyme. To complement and extend the structural studies, we constructed a model of GCPII in complex with its substrate, N -acetyl- l -aspartyl- l -glutamate, which enabled us to predict additional amino acid residues interacting with the bound substrate, and used site-directed mutagenesis to assess the contribution of individual residues for substrate/inhibitor binding and enzymatic activity of GCPII. We prepared and characterized 12 GCPII mutants targeting the amino acids in the vicinity of substrate/inhibitor binding pockets. The experimental results, together with the molecular modeling, suggest that the amino acid residues delineating the S1, pocket of the enzyme (namely Arg210) contribute primarily to the high affinity binding of GCPII substrates/inhibitors, whereas the residues forming the S1 pocket might be more important for the ,fine-tuning' of GCPII substrate specificity. [source] Structural studies of the capsular polysaccharide and lipopolysaccharide O-antigen of Aeromonas salmonicida strain 80204-1 produced under in vitro and in vivo growth conditionsFEBS JOURNAL, Issue 22 2004Zhan Wang Aeromonas salmonicida is a pathogenic aquatic bacterium and the causal agent of furunculosis in salmon. In the course of this study, it was found that when grown in vitro on tryptic soy agar, A. salmonicida strain 80204-1 produced a capsular polysaccharide with the identical structure to that of the lipopolysaccharide O-chain polysaccharide. A combination of 1D and 2D NMR methods, including a series of 1D analogues of 3D experiments, together with capillary electrophoresis-electrospray MS (CE-ES-MS), compositional and methylation analyses and specific modifications was used to determine the structure of these polysaccharides. Both polymers were shown to be composed of linear trisaccharide repeating units consisting of 2-acetamido-2-deoxy- d -galacturonic acid (GalNAcA), 3-[(N -acetyl-L-alanyl)amido]-3,6-dideoxy- d -glucose{3-[(N -acetyl- l -alanyl)amido]-3-deoxy- d -quinovose, Qui3NAlaNAc} and 2-acetamido-2,6-dideoxy- d -glucose (2-acetamido-2-deoxy- d -quinovose, QuiNAc) and having the following structure: [,3)- , - d -GalpNAcA-(1,3)- , - d -QuipNAc-(1,4)- , - d -Quip3NAlaNAc-(1-]n, where GalNAcA is partly presented as an amide and AlaNAc represents N -acetyl- l -alanyl group. CE-ES-MS analysis of CPS and O-chain polysaccharide confirmed that 40% of GalNAcA was present in the amide form. Direct CE-ES-MS/MS analysis of in vivo cultured cells confirmed the formation of a novel polysaccharide, a structure also formed in vitro, which was previously undetectable in bacterial cells grown within implants in fish, and in which GalNAcA was fully amidated. [source] Identification and characterization of a new gene from Variovorax paradoxus Iso1 encoding N -acyl- d -amino acid amidohydrolase responsible for d -amino acid productionFEBS JOURNAL, Issue 19 2002Pei-Hsun Lin An N -acyl- d -amino acid amidohydrolase (N -D-AAase) was identified in cell extracts of a strain, Iso1, isolated from an environment containing N -acetyl- d -methionine. The bacterium was classified as Variovorax paradoxus by phylogenetic analysis. The gene was cloned and sequenced. The gene consisted of a 1467-bp ORF encoding a polypeptide of 488 amino acids. The V. paradoxusN -D-AAase showed significant amino acid similarity to the N -acyl- d -amino acid amidohydrolases of the two eubacteria Alcaligenes xylosoxydans A-6 (44,56% identity), Alcaligenes facelis DA1 (54% identity) and the hyperthermophilic archaeon Pyrococcus abyssi (42% identity). After over-expression of the N -D-AAase protein in Escherichia coli, the enzyme was purified by multistep chromatography. The native molecular mass was 52.8 kDa, which agreed with the predicted molecular mass of 52 798 Da and the enzyme appeared to be a monomer protein by gel-filtration chromatography. A homogenous protein with a specific activity of 516 U·mg,1 was finally obtained. After peptide sequencing by LC/MS/MS, the results were in agreement with the deduced amino acid sequence of the N -D-AAase. The pI of the enzyme was 5.12 and it had an optimal pH and temperature of 7.5 and 50 °C, respectively. After 30 min heat treatment at 45 °C, between pH 6 and pH 8, 80% activity remained. The N -D-AAase had higher hydrolysing activity against N -acetyl- d -amino acid derivates containing d -methionine, d -leucine and d -alanine and against N -chloroacetyl- d -phenylalanine. Importantly, the enzyme does not act on the N -acetyl- l -amino acid derivatives. The enzyme was inhibited by chelating agents and certain metal ions, but was activated by 1 mm of Co2+ and Mg2+. Thus, the N -D-AAase from V. paradoxus can be considered a chiral specific and metal-dependent enzyme. [source] Comment to Sherr and Sherr (1999): "Is there any appropriate way to distinguish different ,- N -acetylhexosaminidase activities in aquatic environments?"FEMS MICROBIOLOGY ECOLOGY, Issue 1 2000Jaroslav Vrba Abstract The recent paper of Sherr and Sherr on detecting low-affinity ,-glucosaminidase activity in several marine microbes extends current knowledge about hydrolytic enzyme activities in natural aquatic systems. However, their conclusions regarding the whole-cell assay with MUF- N -acetyl-,- D -glucosaminide (MUF-[GlcNAc]) cannot be accepted. First, we explicitly demonstrate a strong correlation between extracellular activities of the high-affinity enzymes and grazing rates of bacterivorous protists. Therefore, the assay can still be recommended for the estimation of total protistan grazing on prokaryotic picoplankton. Second, the ability of many aquatic organisms to produce enzymes which cleave fluorogenic substrates, such as MUF-[GlcNAc] and/or MUF-,- D - N,N,,N,-triacetylchitotriose (MUF-[GlcNAc]3), has been well-documented during the last decade. Thus, neither of the two substrates may be considered as exclusively specific for targeting either lysozymes or ,- N -acetylhexosaminidases. [source] The ameliorative effect of cysteine prodrug l -2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2007B.H. Ali Abstract Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l -2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N -acetyl- , - d -glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent. [source] Acetyl- l -carnitine improves aged brain functionGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2010Satoru Kobayashi The effects of acetyl- l -carnitine (ALCAR), an acetyl derivative of l -carnitine, on memory and learning capacity and on brain synaptic functions of aged rats were examined. Male Fischer 344 rats were given ALCAR (100 mg/kg bodyweight) per os for 3 months and were subjected to the Hebb,Williams tasks and AKON-1 task to assess their learning capacity. Cholinergic activities were determined with synaptosomes isolated from brain cortices of the rats. Choline parameters, the high-affinity choline uptake, acetylcholine (ACh) synthesis and depolarization-evoked ACh release were all enhanced in the ALCAR group. An increment of depolarization-induced calcium ion influx into synaptosomes was also evident in rats given ALCAR. Electrophysiological studies using hippocampus slices indicated that the excitatory postsynaptic potential slope and population spike size were both increased in ALCAR-treated rats. These results indicate that ALCAR increases synaptic neurotransmission in the brain and consequently improves learning capacity in aging rats. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S99,S106. [source] Two New Cholestane Bisdesmosides from Reineckia carneaHELVETICA CHIMICA ACTA, Issue 3 2007Zhong-Quan Zhang Abstract Three cholestane bisdesmosides, together with the corresponding aglycone, were isolated from the whole plant of Reineckia carnea. By detailed analysis of the 1D- and 2D-NMR spectra, chemical methods, and comparison with spectral data of known compounds, the structures were determined to be (1,,3,,16,,22S)-cholest-5-ene-1,3,16,22-tetrol (1), (1,,3,,16,,22S)-cholest-5-ene-1,3,16,22-tetrol 1,16-di(, - D -glucopyranoside) (2), (1,,3,,16,,22S)-cholest-5-ene-1,3,16,22-tetrol 1-[O - , - L -rhamnopyranosyl-(1,2)- , - D -glucopyranoside] 16-(, - D -glucopyranoside) (3), (1,,3,,16,,22S)-cholest-5-ene-1,3,16,22-tetrol 1-(, - D -glucopyranoside) 16-(3- O -acetyl- , - D -glucopyranoside) (4). Compounds 3 and 4 appeared to be new compounds, while compound 1 was isolated for the first from a natural source. Compound 2 was isolated from the genus Reineckia for the first time. [source] | ||||||||||||||||||||||||||||||||||