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Biomedical subjects

C Smith

Publications and source records attributed to C Smith.

At least 19 recordsLinked to original sources
PubMed1992

Acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors. 1. 2-(Alkylthio)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT.

A potent, bioavailable ACAT inhibitor may have beneficial effects in the treatment of atherosclerosis by (i) reducing the absorption of dietary cholesterol, (ii) reducing the secretion of very low density lipoproteins into plasma from the liver, and (iii) preventing the transformation of arterial macrophages into foam cells. We have found that a mevalonate derivative 2, which contains a 4,5-diphenyl-1H-imidazol-2-yl moiety, inhibits rat hepatic microsomal ACAT in vitro and produces a significant hypocholesterolemic effect in the cholesterol-fed rat. Structure-activity relationships for analogues of 2 demonstrate that the 4,5-diphenyl-1H-imidazole moiety is a pharmacophore for inhibition of rat microsomal ACAT.

Animals↗
PubMed1992

Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite.

Superoxide dismutase and Fe3+EDTA catalyzed the nitration by peroxynitrite (ONOO-) of a wide range of phenolics including tyrosine in proteins. Nitration was not mediated by a free radical mechanism because hydroxyl radical scavengers did not reduce either superoxide dismutase or Fe3+EDTA-catalyzed nitration and nitrogen dioxide was not a significant product from either catalyst. Rather, metal ions appear to catalyze the heterolytic cleavage of peroxynitrite to form a nitronium-like species (NO2+). The calculated energy for separating peroxynitrous acid into hydroxide ion and nitronium ion is 13 kcal.mol-1 at pH 7.0. Fe3+EDTA catalyzed nitration with an activation energy of 12 kcal.mol-1 at a rate of 5700 M-1.s-1 at 37 degrees C and pH 7.5. The reaction rate of peroxynitrite with bovine Cu,Zn superoxide dismutase was 10(5) M-1.s-1 at low superoxide dismutase concentrations, but the rate of nitration became independent of superoxide dismutase concentration above 10 microM with only 9% of added peroxynitrite yielding nitrophenol. We propose that peroxynitrite anion is more stable in the cis conformation, whereas only a higher energy species in the trans conformation can fit in the active site of Cu,Zn superoxide dismutase. At high superoxide dismutase concentrations, phenolic nitration may be limited by the rate of isomerization from the cis to trans conformations of peroxynitrite as well as by competing pathways for peroxynitrite decomposition. In contrast, Fe3+EDTA appears to react directly with the cis anion, resulting in greater nitration yields.

Animals↗
PubMed1992

Effect of cocaine, ethanol or nicotine on ornithine decarboxylase activity in early chick embryo brain.

Fetal drug exposure causes multiple deficits in the developing child. For both humans and animal models, the single most common drug-related problem is fetal growth suppression. This defect is associated with significant perinatal morbidity and mortality and may also be related to significant behavioral problems appearing later in life. Studies focussed on the molecular mechanism of fetal drug effects in placental models are complicated by multiple interactions of the drug with mother, placenta and fetus. Using early (76-168 h) chick embryos as a non-placental model, and three common drugs of abuse (nicotine, ethanol and cocaine) it was found that each drug suppressed the peak in fetal brain ornithine decarboxylase (ODC) activity that normally occurs at 120 h of development. For each drug, the decrease in ODC activity at 120 h was followed by a small but significant increase in ODC. Thus, although the drug-treated embryos were smaller in size, they appeared to be undergoing compensatory growth and, in fact, became equal in weight to the vehicle-treated animals, if allowed to hatch.

Animals↗
PubMed1992

Stimulation of lipid peroxidation and hydroxyl-radical generation by the contents of human atherosclerotic lesions.

Lipid peroxidation within human arterial lesions is thought to play an important role in the development of atherosclerosis. Peroxidation can be accelerated by the presence of 'catalytic' iron or copper ions. Gruel samples from advanced atherosclerotic lesions in the abdominal aortae of human cadavers were tested for pro-oxidant properties. All samples contained bleomycin-detectable iron and phenanthroline-detectable copper. Almost all gruel samples stimulated peroxidation of rat liver microsomes, and this was usually inhibited by the iron-ion chelator desferrioxamine. Some samples stimulated formation of hydroxyl radicals from H2O2 in the presence of ascorbate, a reaction again inhibited by desferrioxamine. We conclude that the interior of human advanced atherosclerotic lesions is a highly pro-oxidant environment, and that the use of copper or iron ions to promote peroxidation of low-density lipoproteins in vitro may be a valid model for events in the arterial wall.

Animals↗
PubMed1992

Droloxifene (3-hydroxytamoxifen) has membrane antioxidant ability: potential relevance to its mechanism of therapeutic action in breast cancer.

Droloxifene (3-hydroxytamoxifen), is a triphenylethylene derivative recently developed for the treatment of breast cancer. Droloxifene was found to exhibit a membrane antioxidant ability in that it inhibited Fe(III)-ascorbate dependent lipid peroxidation in rat liver microsomes and ox-brain phospholipid liposomes. It also inhibited microsomal lipid peroxidation induced by Fe(III)-ADP/NADPH. Droloxifene was a better inhibitor of lipid peroxidation than tamoxifen, but was less effective than 17 beta-oestradiol in the two microsomal systems and in the preformed liposomal system. When introduced into ox-brain phospholipid liposomes, droloxifene inhibited Fe(III)-ascorbate induced lipid peroxidation to approximately the same extent as similarly introduced cholesterol and tamoxifen, although to a lesser extent than 17 beta-oestradiol. This inhibition of lipid peroxidation by droloxifene may result from a membrane stabilization that could be associated in cancer cells with decreased plasma membrane fluidity. This mechanism may be related to the clinically important antiproliferative action of droloxifene on cancer cells.

Animals↗
PubMed1992

Genomic organization of the halophilic archaeon Haloferax mediterranei: physical map of the chromosome.

Pulsed field gel electrophoresis (PFG) has been used to study the genomic organization of the halophilic archaeon Haloferax mediterranei. Analysis of the different genomic elements as well as the restriction patterns obtained with several endonucleases revealed that this microorganism has a circular chromosome of 2.9 Mb and, at least, three extrachromosomal elements of 490, 320 and 130 kb respectively. The complete physical map of the chromosome for the endonucleases PacI and BamHI has been constructed, and several BcII, BgIII and DraI restriction fragments have been aligned on these maps. The localization of heterologous and homologous genes on the physical map, including those for rRNA, lay the ground work for the construction of a genetic map.

Chromosomes, Bacterial↗
PubMed1992

The clinical significance of Haemophilus influenzae and H. parainfluenzae isolated from the sputum of adult patients at an urban general hospital.

Fifty-seven patients, from whose sputum Haemophilus influenzae (49 cases) or Haemophilus parainfluenzae (8 cases) was isolated during a 7-month period, were studied. In the majority of cases there were well-defined predisposing factors to respiratory tract colonisation or infection with the isolates, in particular bronchiectasis and chronic obstructive airways disease. Colonisation of the airways, bronchopneumonia in patients with underlying lung disease, acute lobar pneumonia, and postoperative chest infections were the commonest clinical diagnoses. Primary acute lobar pneumonia with these organisms alone was uncommon. All of the H. influenzae isolates were nontypeable, and there was a wide range of biotypes of both organisms. Three H. influenzae isolates produced beta-lactamase, and there was, in general, a low incidence of resistance to a wide range of antimicrobial agents on disc susceptibility testing.

Adult↗
PubMed1992

Mutagenic activity of a series of synthetic and naturally occurring heterocyclic amines in Salmonella.

26 synthetic and naturally occurring heterocyclic amines were tested in the Salmonella/microsome assay (Ames test) using tester strains TA98 and TA100 in the presence of an Aroclor-induced rat-liver S9 fraction. 9 of the compounds were protein-pyrolysis products which had previously been shown to be mutagenic. Mutagenic potencies similar to previously reported values were demonstrated for these compounds with the exception that Trp-P-1 was only mutagenic in strain TA98 in our study, although it had previously been reported to be weakly mutagenic in strain TA100. 17 structurally diverse heterocyclic amines were synthesized and tested for mutagenicity. The structural diversity of these synthetic heterocyclic amines will enhance the sensitivity of future quantitative structure-activity relationship (QSAR) studies by demonstrating the structural characteristics essential for mutagenicity. The results of this study provide a large data base for the mutagenicity of this important class of compounds.

Amines↗
PubMed1992

Characterization of Caramel Colour IV.

A large number of commercial Caramel Colour IV samples were characterized in order to assess the uniformity of the class and to provide data to be used in specifications development. Owing to the chemical and physical complexity of caramel colour it was not feasible to perform detailed analysis of all constituents for assessment of uniformity. Instead, selected parameters were evaluated and judgements were made with respect to compositional uniformity based on the similarities of these parameters among the various samples. As Caramel Colour IV is required by the food industry in a range of colour intensities, there must be a range of properties that differ from sample to sample, but that are sufficiently similar for the material to still be considered as part of the Caramel Colour IV class. Fractions as well as whole caramel were analysed using selected spectrophotometric, chromatographic and chemical techniques. Samples were fractionated based on molecular weight and polarity. The data presented here provide evidence for the uniformity in composition of Caramel Colour IV with respect to molecular weight distribution, to nitrogen and sulphur content and their distribution throughout the fractions, to absorbance properties and to specific low molecular weight compounds. Thus, it can be concluded that Caramel Colour IV exhibits compositional uniformity within the range of colour intensity required by the food industry worldwide.

Candy↗
PubMed1992

Characterization of Caramel Colours I, II and III.

Groups of representative samples of Caramel Colours I, II, and III were characterized in order to assess the compositional uniformity within each class and to determine differences between each class. Compositional uniformity within each class was demonstrated by fractionation of the caramel samples and analysis by UV and visible absorbance, HPLC and chemical analysis. Although there was overlap between certain parameters of one or more caramel colour classes, the overall 'fingerprint' for each class, based on several different parameters, was distinctly unique. Such parameters included net ionic charge, absorbance properties, nitrogen and sulphur content, specific low molecular weight compounds and HPLC profiles. HPLC analysis revealed unique profiles within each class and distinct differences between classes. The data presented here for Caramel Colours I, II, and III, and elsewhere for Caramel Colour IV, indicate that each of the four classes can be considered as separate and that, throughout each class, the samples characterized constitute a homologous series of mixtures in terms of chemical composition.

Candy↗
PubMed1992

Development of specifications for caramel colours.

Specifications have been developed to define each of the four classes of caramel colour. The specifications were based on analysis of a large database generated during the course of characterization studies of each of the classes. A series of simple and practical tests was developed for the analysis of caramel colour samples to ensure conformity to the specifications.

Candy↗
PubMed1992

Protection by albumin against the pro-oxidant actions of phenolic dietary components.

Synthetic and natural phenolic compounds are increasingly used in food preservation. Carnosol and carnosic acid (active components of rosemary extract), flavonoids (morin, quercetin, fisetin, myricetin), other plant phenolics (gossypol) and propyl gallate may protect lipids against oxidative damage but have the potential to increase damage to non-lipid constituents of foods, such as carbohydrates and DNA. Thus, in the presence of ferric EDTA and H2O2, they can form highly reactive hydroxyl radicals that can degrade the sugar deoxyribose and/or accelerate DNA degradation by means of a ferric-bleomycin complex. Human and bovine serum albumin afford considerable protection against damage to deoxyribose and DNA mediated by the above reactions. It is suggested that, given the fortification of foods with iron and EDTA and the use of phenolic substances as 'antioxidant' food additives, the addition of albumin might afford some protection.

Abietanes↗
PubMed1992

Chromosomal mapping of the human annexin IV (ANX4) gene.

Annexin IV (placental anticoagulant protein II) is a member of the annexin or lipocortin family of calcium-dependent phospholipid-binding proteins. A cDNA for human annexin IV was isolated from a placental library that is 675 bases longer in the 3' untranslated region than previously reported, indicating the existence of alternative mRNA processing for this gene. Genomic Southern blotting with a cDNA probe indicated a gene size of 18-56 kb. Primers developed for polymerase chain reaction (PCR) allowed amplification of a 1.6-kb portion of the ANX4 gene. DNA sequence analysis showed that this PCR product contained a single intron with exon-intron boundaries in exactly the same position as in the mouse annexin I and annexin II genes. PCR analysis of a somatic cell hybrid panel mapped the ANX4 gene to chromosome 2, and in situ hybridization with a cDNA probe showed a unique locus for ANX4 at 2p13. This study provides further evidence that genes for the annexins are dispersed throughout the genome but are similar in size and exon-intron organization.

Amino Acid Sequence↗