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Biomedical subjects

E Schreiner

Publications and source records attributed to E Schreiner.

At least 19 recordsLinked to original sources
PubMed2004

Polymorphic microsatellite markers in the outbred CFW and ICR stocks for the generation of speed congenic mice on C57BL/6 background.

Reliable definition of the phenotype of particular alleles is carried out in the genetic background of inbred strains. Appearance of mutations in outbred mice therefore requires the generation of congenic mice. The aim of this study was the establishment of a list of polymorphic microsatellite markers which can be used in a polymerase chain reaction (PCR)-based marker-assisted selection protocol (MASP) to allow the use of the two common outbred stocks, CFW and ICR, as donor animals for the fast generation of congenic C57BL/6 mice. The selection of informative microsatellite markers was carried out to provide a simple evaluation of the PCR products by conventional agarose gel electrophoresis. Outbred mice from three suppliers were examined. In total, 153 microsatellite loci were analysed. Here we present 76 and 70 microsatellite markers polymorphic for the outbred ICR and CFW stocks compared to C57BL/6. At least three microsatellite loci per chromosome were chosen as informative markers for the autosomal genome, giving rise to a maximum marker distance of 58 cM. Thus, additional individual markers have to be selected for the respective outbred mouse which is chosen as a donor animal.

Animals↗
PubMed2002

Current drugs and future hopes in the treatment of Alzheimer's disease.

In spite of several years of experience with the use of cholinesterase inhibitors for treatment of symptoms of Alzheimer's disease their influence on disease progression remains still unclear. New cholinesterase inhibitors should provide an additional neuroprotective activity, because only substances which stop neuronal death can influence disease progression. New treatment strategies are focusing on amyloid processing, preventing the occurrence of toxic A beta(1-42) peptide. These procedures include the vaccination trials, but their clinical usefulness has to be proven. Also strategies focussing on neurofibrillary pathologies should be explored in detail. Drug development for Alzheimer's disease should include all pathological events associated with neurodegeneration, like oxidative stress, neuroinflammation or disturbances in growth factor signaling. Abnormal protein aggregation as a common feature of different neurodegenerative diseases might also be a promising drug target. Beside beta sheet breakers directed against beta-amyloid deposition the endogenous protein beta-synuclein or derivatives of it might be able to counteract aggregation of alpha-synuclein as well as of amyloid beta protein. Interaction with alpha-synuclein deserves special attention because it might be an early step of synaptic degeneration. Due to the complexity of the disease combination of different drugs might be the most promising way to go. The parallel development of early biological markers should enable intervention in pre-symptomatic disease stages.

Aged↗
PubMed1994

Inhibitors of HIV-1 proteinase containing 2-heterosubstituted 4-amino-3-hydroxy-5-phenylpentanoic acid: synthesis, enzyme inhibition, and antiviral activity.

A convenient procedure for the synthesis of 2-heterosubstituted statine derivatives as novel building blocks in HIV-protease inhibitors has been developed. The synthesis starts with protected L-phenylalaninols, which were converted to gamma-amino alpha, beta-unsaturated esters in a one-pot procedure. A highly diastereoselective epoxidation of the N-protected (E)-enoates, followed by regioselective ring opening of the corresponding 2,3-epoxy esters with a variety of heteronucleophiles, resulted in 2-heterosubstituted statine derivatives. The overall stereo-chemical outcome of the transformations meets the required configuration of HIV-protease inhibitors. The short, synthetically flexible, and highly diastereoselective synthesis of 2-heterosubstituted statines has enabled a broad derivation, covering the S3, S2, and S1'-S3' sites of the enzyme. In a series of 46 derivatives, several potent inhibitors were obtained with Ki values as low as 3.4 nM and antiviral activity in the lower nanomolar-range. The structural parameters of the compounds which determine the potency of inhibition and selectivity for the viral enzyme are discussed.

Amino Acid Sequence↗
PubMed1992

Use of sialic acid analogues to define functional groups involved in binding to the influenza virus hemagglutinin.

The initial step of influenza infection is binding of the virus particles via their hemagglutinin to cell-surface sialic acids. This study was initiated to elucidate the functional groups of the nine-carbon sialic acid molecule which interact with the hemagglutinin and contribute to the affinity of this sugar to the protein. In order to address this question, synthetic sialic acid analogues were tested in a virus adsorption inhibition assay for their inhibitory potency. Modifications in three regions of the sialic acid molecule were evaluated: the glycerol side chain (C7-C9), the N-acetyl group at C5, and the carboxy group (C1). In the glycerol side chain, the hydroxy groups at C7 and C8 appear to be important for binding through hydrogen bonds, whereas the hydroxyl at C9 does not appear to be involved. The N-acetyl group is critical for the interaction of sialic acid with the hemagglutinin. The results suggest that its contribution is mediated through hydrophobic interactions of the methyl group. Finally, the orientation of the carboxy group is essential for the binding of sialic acid to the hemagglutinin. The information gained in this study will be useful in developing novel compounds which bind more avidly to the influenza virus hemagglutinin. Such a strategy may contribute to the design of new anti-influenza drugs.

Binding Sites↗
PubMed1992

Elucidation of the topological parameters of N-acetylneuraminic acid and some analogues involved in their interaction with the N-acetylneuraminate lyase from Clostridium perfringens.

A series of neuraminic acid derivatives modified in the side chain or at C-3, C-4 or C-5 were tested as substrates of inhibitors of N-acetylneuraminate lyase (EC 4.1.3.3) from Clostridium perfringens. The results, together with Km and Ki values reported previously, indicate that the region most important for the binding of sialic acids is an equatorial zone reaching from C-8 via the ring oxygen atom to C-4 of the sugar molecule, whereas the substituents at C-9 and C-5 may be varied to a higher extent without significantly disturbing enzyme action. It is shown that stereo-electronic factors are responsible for the immediate heterolytic fragmentation of the cyclic sialic acid into pyruvic acid and 2-acetamidomannose or a related C-6 sugar.

Clostridium perfringens↗
PubMed1991

2,3-Didehydro-2-deoxysialic acids structurally varied at C-5 and their behaviour towards the sialidase from Vibrio cholerae.

2,3-Didehydro-2-deoxy-N-trifluoroacetylneuraminic acid (5-trifluoroacetyl-Neu2en) (3) has been synthesised from Neu5Ac2en (1) by hydrazinolysis, to give Neu2en (2), followed by N-trifluoroacetylation. 2,3-Didehydro-2,3-dideoxy-D-glycero-D-galacto-2-nonulopyranoson ic acid (Kdn2en, 8) and 5-azido-2,3-didehydro-2,3,5-trideoxy-D-glycero-D-galacto-2-nonu lopyranosonic acid (5-azido-5-deoxy-Kdn2en, 9) have been prepared from the acetylated methyl esters of Kdn (4) and 5-azido-5-deoxy-Kdn (5) via Zemplén saponification. The behaviour of the above 2,3-didehydro-2-deoxysialic acids towards Vibrio cholerae sialidase has been investigated.

Kinetics↗
PubMed1989

The side-chain conformations of N-acetyl-7-,8-,9-deoxy-, and -4,7-dideoxy-neuraminic acid and their effect on the activation of CTP:N-acylneuraminic acid cytidylyltransferase.

The conformations of the deoxy side-chain analogs of N-acetylneuraminic acid and of N-acetyl-4-deoxyneuraminic acid have been studied by n.m.r. spectroscopy, which allowed us to distinguish between local minima conformations suggested by hard-sphere calculations. The conformations were correlated with the activity with CTP: N-acetylneuraminic acid cytidylyltransferase (CMPsialate synthase; EC 2.7.7.43).

Carbohydrate Conformation↗
PubMed1987

[Iatrogenesis].

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Cross Infection↗
PubMed1987

Stability of isolated hepatic aldehyde dehydrogenases from rats in vitro.

Aldehyde dehydrogenases (ALDH) isolated from livers of adult female SPF Sprague-Dawley rats were rapidly (within hours) inactivated by oxygen (7.8 ppm, from air) and simultaneous exposure to light energy (subdued daylight, 5000 lx; direct sunlight, 66,000 lx) at 22 degrees C. Oxygen withdrawal (e.g. by treatment with nitrogen) and darkness prevented the inactivation. An addition of glutathione, dithiothreitol, nicotinic acid-amide-adenine-dinucleotide (NAD) or its reduced form (NADH) to the ALDH preparations preserved the enzyme activity; the above SH-reagents regenerated an already occurred loss of activity rapidly (within minutes) and almost completely. It is concluded that the hepatic ALDH from rats posses in the active centre two SH-groups in close vicinity which can be oxidized slightly to the intramolecular disulfide and reduced again. The protection against inactivation by NAD (oxidized or reduced) may be afforded by occupation of the cosubstrate binding site of the enzyme.

Aldehyde Dehydrogenase↗
PubMed1986

Non-competitive inhibition of the alcohol dehydrogenase activity in rat liver by latamoxef, cefamandole or cefoperazone.

High concentrations of 1 or 10 mmol/l latamoxef (LMOX), cefamandole (CMD) or cefoperazone (CPZ) in vitro non-competitively inhibit to a small extent the alcohol dehydrogenase isolated from rat liver in the presence of ethanol as a substrate, as is shown by enzyme-kinetic data evaluated in a Lineweaver-Burk diagram. This observation may serve as an approach to partially explain a possible delay of ethanol elimination from the blood after pretreatment with these beta-lactam antibiotics.

Alcohol Oxidoreductases↗
PubMed1985

Activities of hepatic epoxide hydrolase and glutathione S-transferase in rats under the influence of tetramethyl thiuramdisulfide, tetramethyl thiurammonosulfide or dimethyl dithiocarbamate.

The epoxide hydrolase (EH) activity in the liver of adult female Wistar rats significantly increased 18 h after the administration by gavage of tetramethyl thiuramdisulfide (TMTD, 1 mmol/kg) or tetramethyl thiurammonosulfide (TMTM, 2 mmol/kg). No increase was observed 5 h after administration of Na-dimethyl dithiocarbamate (Na-DMDTC, 4 mmol/kg). The glutathione S-transferase (GST) activity in the cytosol and microsomes of the liver was slightly enhanced after oral (gavage) administration of TMTD, TMTM or Na-DMDTC (doses up to 4 mmol/kg). In vitro, TMTD, TMTM, and Na-DMDTC significantly enhanced the hepatic activity of EH prepared from adult female Wistar rats. Cytosolic and microsomal GST activities from the liver were significantly raised in vitro by Na-DMDTC. The results have a bearing on the evaluation of the risk to health of these chemicals in the workplace.

Administration, Oral↗
PubMed1977

Electrophysiological changes in the canine atrium and ventricle during progressive hyperkalaemia: electrocardiographical correlates and the in vivo validation of in vitro predictions.

The electrophysiological response to hyperkalaemia was reinvestigated in the whole dog for several reasons including: the paucity of comparative electrophysiological and electrocardiographical studies in which atrial and ventricular tissues were simultaneously investigated; the contrast between the clarity of findings in previous in vitro studies as compared with the rather conflicting results in earlier in vivo investigations; and the difficulty in validating the extrapolation from in vitro results and theory to the in vivo situation because of deficiences in the literature. Biphasic alterations in atrial and ventricular conduction times as well as excitability in response to progressively increasing hyperkalaemia were documented. The alterations in conduction times were reflected quite accurately by relevant electrocardiographical changes. Experiments in the whole animal were designed to test predictions based on membrane theory: the results offering strong support for the validity of extrapolating from the in vitro to the in vivo situation. The results of this study should help clarify and render interpretable many of the seemingly conflicting results in the literature.

Animals↗