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Biomedical subjects

C J Morris

Publications and source records attributed to C J Morris.

At least 55 records · Page 3Linked to original sources
PubMed1993

High field proton NMR investigations of the metabolic profiles of multidrug-sensitive and -resistant leukaemic cell lines: evidence for diminished taurine levels in multidrug-resistant cells.

High field proton (1H) nuclear magnetic resonance (NMR) spectroscopy has for the first time been employed to investigate and compare the metabolic profiles of vinblastine-sensitive and -resistant T-lymphoid leukaemic cell lines (CCRF-CEM and CEM/VLB100 respectively) and evidence is presented for a significantly lower taurine content in the CEM/VLB100 resistant subline when expressed relative to that of its drug-sensitive parental counterpart. These data suggest differences in the nature and relative involvements of taurine biosynthetic pathways between the two cell lines, a phenomenon that may be related to their differing sensitivities towards chemotherapeutic agents such as adriamycin which promote the generation of cytotoxic reactive oxygen species (ROS) in vivo. However, the 1H NMR data obtained provided no evidence for an increased metabolic consumption of hypotaurine (a metabolic precursor of taurine with powerful .OH radical scavenging properties) in CCRF-CEM cells since differences observed in the hypotaurine: taurine concentration ratio between the drug-sensitive and -resistant cell lines were not statistically significant. Furthermore, hypotaurine is unlikely to compete with alternative endogenous .OH radical scavengers present such as lactate since its level in either of the two cell lines investigated (ca. 6.0 x 10(-8) mol./10(8) cells) is insufficient for it to act as an antioxidant in this context. The biochemical and therapeutic significance of these results are discussed.

Antineoplastic Agents↗
PubMed1993

An imaginative approach to synovitis--the role of hypoxic reperfusion damage in arthritis.

The rheumatoid joint is hypoxic. The loss of the physiologic defense mechanism, reflex muscle inhibition, allows the generation of high intraarticular pressures, particularly during exercise. Hypoxia alters the biochemistry of the synovium and encourages the production of reactive oxygen species (ROS) on reperfusion of blood. In excess, ROS damage tissues, and the products of oxidative damage are detectable in rheumatoid synovial fluid. In addition to damaging proteins, carbohydrates and lipids, cellular and structural damage also occurs.

Arthritis↗
PubMed1992

Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice.

The metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), a heterocyclic amine carcinogen detected in cooked meats, was investigated in mice. In 3-methylcholanthrene-induced mice administered 0.1, 1.0 and 10 mg/kg [14C]PhIP (i.p.), urinary and fecal excretion over 24 h accounted for 16% and 42-56% of the dose respectively. Urinary excretion of unchanged parent compound accounted for only 0.5-0.8% of the administered dose. At all doses, the major urinary metabolite was identified as 4'-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate and this metabolite comprised approximately 5% of the dose. Uninduced mice excreted greater than 13% of a 10 mg/kg dose as the sulfate conjugate. Urinary excretion of both 2-amino-1-methyl-6-(4'-hydroxy)-phenylimidazo[4,5-b]pyridine (4'-hydroxy-PhIP) and a glucuronide conjugate of 2-hydroxyamino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (N-hydroxy-PhIP) was also higher (4-fold) in uninduced versus induced mice. The decreased urinary excretion of P450-derived metabolites via induction contrasted with increased metabolite formation by hepatic microsomal preparations. 4'-Hydroxy-PhIP and N-hydroxy-PhIP were produced in amounts nearly 7- and 3-fold higher respectively by induced versus uninduced microsomal incubations at 50 microM [3H]PhIP. At concentrations less than 10 microM, PhIP was almost exclusively converted by the induced preparations to an unidentified metabolite that was not retained by the C18 column. This metabolite, which also was formed in incubations with either 4'-hydroxy-PhIP or N-hydroxy-PhIP, was produced by microsomes from uninduced animals at a much slower rate. Covalent binding to microsomal protein in incubations with [3H]PhIP was concentration-dependent and 2- to 4-fold higher in induced than uninduced preparations. Covalent binding in liver and kidney of induced mice administered [14C]PhIP was dose dependent. At 10 mg/kg PhIP, adducts were produced at 1.7-fold higher levels in livers of induced versus uninduced mice, but renal binding was higher in uninduced animals. These studies indicate the importance of cytochrome P450 and other xenobiotic enzymes in the metabolism, disposition and activation of PhIP.

Animals↗
PubMed1992

Skin inflammation: reactive oxygen species and the role of iron.

Superoxide and hydrogen peroxide are reactive oxygen species (ROS) primarily produced by phagocytic cells as a consequence of the process of phagocytosis. This defensive role, may, however, become one of attack when production of ROS is excessive and overwhelms cellular scavenging systems. This happens in situations such as acute inflammation and results in host cell membrane damage, which is particularly prevalent in the presence of transition metal catalysts such as iron and copper. The skin is uniquely vulnerable to this attack being rich in polyunsaturated fatty acids and exposed to high oxygen tensions and ultraviolet light, both of which promote production of ROS. Additionally, the respiratory burst of infiltrating polymorphonuclear leukocytes and macrophages in inflamed skin will produce high local levels of superoxide that can release "catalytic iron" from storage proteins such as ferritin. The role of iron and ROS in the pathogenesis of inflammatory skin disease is discussed as is the possibility of novel therapeutic strategies based on their removal.

Dermatitis↗
PubMed1992

The role of iron in an acute model of skin inflammation induced by reactive oxygen species (ROS).

The effect of iron was studied in rats in a ROS-initiated model of acute skin inflammation. Iron dextran was administered i.v. 24 h before the induction of the inflammatory response by intradermal injection of glucose oxidase attached to polyethylene glycol (GOD-PEG). Iron exacerbated the response at 24 and 48 h (P greater than 0.001). Histologically, a similar picture was seen to that without iron except for an increase in tissue oedema and matrix destruction including the skin glands. Associated with iron loading was an increase in Perls stainable iron in the skin (P greater than 0.025) and liver (P greater than 0.001). However, skin inflammation without iron loading also increased skin iron levels (P greater than 0.025). Total serum iron was decreased in iron-loaded and GOD-PEG animals (P greater than 0.01) and the unbound iron binding capacity (UIBC) increased (P greater than 0.01).

Animals↗
PubMed1992

Cloning of a methanol-inducible moxF promoter and its analysis in moxB mutants of Methylobacterium extorquens AM1rif.

In Methylobacterium extorquens AM1, gene encoding methanol dehydrogenase polypeptides are transcriptionally regulated in response to C1 compounds, including methanol (M. E. Lidstrom and D. I. Stirling, Annu. Rev. Microbiol. 44:27-57, 1990). In order to study this regulation, a transcriptional fusion has been constructed between a beta-galactosidase reporter gene and a 1.55-kb XhoI-SalI fragment of M. extorquens AM1rif DNA encoding the N terminus of the methanol dehydrogenase large subunit (moxF) and 1,289 bp of upstream DNA. The fusion exhibited orientation-specific promoter activity in M. extorquens AM1rif but was expressed constitutively when the transcriptional fusion was located on the plasmid. However, correct regulation was restored when the construction was inserted in the M. extorquens AM1rif chromosome. This DNA fragment was shown to contain both the moxFJGI promoter and the sequences necessary in cis for its transcriptional regulation by methanol. Transcription from this promoter was studied in the M. extorquens AM1rif moxB mutant strains UV4rif and UV25rif, which have a pleiotropic phenotype with regard to the components of methanol oxidation. In these mutants, beta-galactosidase activity from the fusion was reduced to a level equal to that of the vector background when the fusion was present in both plasmid and chromosomal locations. Since both constitutive and methanol-inducible promoter activities were lost in the mutants, moxB appears to be required for transcription of the genes encoding the methanol dehydrogenase polypeptides.

Alcohol Oxidoreductases↗
PubMed1992

Effect of intravenous iron-dextran (Imferon) infusion on antigen induced monarticular arthritis in rabbits.

The effect of intravenously infused iron-dextran (Imferon) on the progression of antigen induced monarticular arthritis in rabbits was studied. A rapid deposition of iron and apoferritin in the synovia of arthritis joints occurred after infusion of iron-dextran during either the acute or chronic phases of the disease. This coincided with the appearance of catalytic (bleomycin reactive) iron in the synovial fluid. There was no evidence, however, for an exacerbation of the antigen induced arthritis as a result of the iron-dextran, and synovial and bleomycin reactive iron concentrations decreased with time after administration, indicating a redistribution of the synovial iron load. Thus although intravenously infused iron-dextran appears to 'prime' the rabbit arthritic joint transiently with the potential for iron stimulated oxygen free radical damage, other factors may determine its occurrence.

Animals↗
PubMed1992

Effect of iron complexes on adjuvant arthritis in rats.

When a total dose infusion of iron dextran is given to anaemic rheumatoid patients an exacerbation of inflammatory synovitis in previously affected joints is observed. The adjuvant arthritis model of inflammation in rats has been used to investigate the mechanism of iron promoted synovitis. Either iron dextran (5 mg injected intravenously) with a dextran C control, or iron sorbitol (7.5 mg injected intramuscularly) with a sorbitol citrate complex control was given at the onset of clinical joint inflammation. Iron dextran significantly increased joint inflammation (assessed by joint scoring) at days 12, 13, 14, and 16 after injection. Similarly, iron sorbitol produced a significant increase in the joint score at days 17, 18, 19, and 21. In addition, extensive osteoporosis was observed in the rats treated with iron sorbitol. These pro-inflammatory effects of iron coincide with the presence of positive results for synovial iron (III) using Perl's test and neutrophil infiltration. The results of this study suggest that the iron induced increase in synovitis in adjuvant arthritis is a result of iron promoted oxidative damage and is not likely to be due to the dextran C or the sorbitol citric acid components. It is suggested that a similar mechanism may occur in rheumatoid patients given iron supplements.

Animals↗
PubMed1991

Oxidation of thiol in the vimentin cytoskeleton.

Sublethal doses of H2O2, which induces oxidative stress, cause substantial alteration to the vimentin cytoskeleton in various cell types. We have used a thiol-blot assay to assess thiol status in individual proteins from cell extracts. Vimentin thiol is oxidized in preference to other cytoskeleton proteins. Immunoblot analysis also demonstrated a loss of reactivity to an anti-vimentin monoclonal antibody under non-reducing conditions, possibly due to thiol-group oxidation. During induced oxidative stress a number of proteins become associated with the cytoskeleton extracts.

Cells, Cultured↗
PubMed1991

Skin inflammation induced by reactive oxygen species (ROS): an in-vivo model.

A model of skin inflammation induced by reactive oxygen species has been established using the hydrogen-peroxide-producing enzyme glucose oxidase. As a means of increasing the half-life of the enzyme and tissue retention polyethylene glycol (PEG) was attached. A rapid inflammatory response occurred consisting of an oedematous, non-erythemic swelling lasting at least 48 h. Histologically, there was an infiltration of the dermis by monocytes and neutrophils, collagen matrix breakdown and damage to the vascular endothelium. This response was significantly inhibited by both catalase and superoxide dismutase attached to PEG (PEG-CAT and PEG-SOD, respectively). PEG alone produced no effects. PEG-CAT was able to sustain an inhibitory effect for at least 12 h, whereas PEG-SOD significantly reduced inflammation for up to 6 h. PEG-SOD may have an exacerbatory effect over longer periods.

Animals↗
PubMed1991

Drug-induced pleural effusions.

Systematic analysis of pleural fluid, in conjunction with the patient's clinical presentation, should allow the clinician to arrive at the correct diagnosis in approximately 90% of cases. An awareness that some commonly used pharmaceutical agents can cause pleural effusion may help the clinician recognize the pathogenesis of some effusions whose cause is less obvious.

Humans↗
PubMed1990

Influence of respiratory substrate on the cytochrome content of Shewanella putrefaciens.

Shewanella putrefaciens can use trimethylamine oxide (TMAO) as electron acceptor under anoxic conditions. The associated cytochromes induced during growth under various respiratory conditions have been separated by liquid chromatography (DEAE Sepharose CL6b) and SDS-PAGE and characterized spectrophotometrically and by redox potentiometry. Two major low potential cytochromes and at least three minor low potential cytochromes, likely to be involved in TMAO reduction, were found. No cytochrome specific for TMAO reductase was found.

Chromatography, High Pressure Liquid↗
PubMed1990

Nucleotide sequence of the Methylobacterium extorquens AM1 moxF and moxJ genes involved in methanol oxidation.

The nucleotide sequence has been determined for two genes involved in methanol oxidation in the facultative methylotroph, Methylobacterium extorquens AM1. The two genes are moxF, encoding the 66-kDa subunit of the methanol dehydrogenase and moxJ, located immediately downstream from moxF, which encodes a 30-kDa protein with unknown function. This information completes the sequence of the 5.86-kb XhoI-SalI fragment containing the moxFJGI region in M. extorquens AM1, and the structure of this gene cluster is presented. Evidence is presented that moxJ is also present in Paracoccus denitrificans. The aa sequence of MoxJ has provided little information concerning its function, but it does appear to contain a signal sequence suggesting a periplasmic location.

Alcohol Oxidoreductases↗
PubMed1990

A model for desferrioxamine-induced retinopathy using the albino rat.

We describe a rat model of the ocular toxicity induced in patients by the iron chelator desferrioxamine (DFX). The functional integrity of the rat photoreceptor membrane is assessed by measurement of the electroretinogram b wave amplitude. Following single bolus doses of DFX (50, 100 and 150 mg), rats develop dose-related suppression of b wave amplitude within 48 h. Recovery takes place over the subsequent 14 days. This ocular damage is exacerbated by exposure to increased levels of white light and oxygen. Studies in this model also show that darkness and, in particular, red light protect the eye against DFX toxicity. This is of potential use in patient management during DFX therapy.

Animals↗
PubMed1990

Wegener's granulomatosis presenting as subglottic stenosis.

One of the rarest diseases associated with upper airway obstruction in adults is subglottic stenosis from the necrotizing vasculitis of Wegener's granulomatosis. Early recognition and treatment of this potentially fatal syndrome is necessary to insure long-term survival.

Adolescent↗