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Showing 1741–1760 of 2058 publications.
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Richardson, Des Raymond[No abstract available]
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Dean, Roger T.[No abstract available]
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Rossi, Enrico; McQuillan, Brendan M.; Hung, Joseph C.; Thompson, Peter Lindsay; Kuek, Conchita; Beilby, John P.Background and Purpose - Serum ferritin and heterozygosity for the C282Y mutation of the hemochromatosis gene have both been associated with an increased risk of cardiovascular events. The purpose of the study was to test whether either is a risk predictor for asymptomatic carotid atherosclerosis. Methods - We assessed carotid intima-media wall thickness (IMT) and focal plaque formation by high-resolution B-mode ultrasound, conventional risk factors, serum ferritin levels, and the C282Y mutation of the hemochromatosis gene in a randomly selected community population of 1098 subjects (545 women and 553 men) aged 27 to 77 years. Results - After adjustment for conventional risk factors, serum ferritin was not associated with carotid mean IMT. Women with ferritin values over the first quartile (>34 ?g/L) had an adjusted odds ratio of 2.1 (95% CI, 1.3 to 3.4; P=0.0016) for carotid plaque compared with the first quartile. Ferritin was not associated with carotid plaque in men. Subjects who were heterozygous for the C282Y mutation constituted 11.4% of the population, and there was no independent association of this genotype with either carotid IMT or focal plaque formation. Conclusions - We conclude that in our community population, C282Y genotype status was not a risk predictor for either carotid mean IMT or plaque formation. Serum ferritin values in women were independently associated with carotid plaque.
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Rodgers, Kenneth John; Dean, Roger T.Protein-bound 3,4-dihydroxyphenylalanine (DOPA) can be generated in mammalian cells by both controlled enzymatic pathways, and by uncontrolled radical reactions. Protein-bound DOPA (PB-DOPA) has reducing activity and the capacity to inflict secondary damage on other important biomolecules such as DNA. This may be mediated through replenishment of transition metals or from catechol-quinone-catechol redox cycles in the presence of cellular components such as ascorbate or cysteine, resulting in amplification of radical damaging events. The generation of PB-DOPA confers on protein the ability to chelate transition metals generating protein 'oxychelates'; this may be amongst the factors, which localise such damage. Tissue levels of PB-DOPA are increased in a number of age-related pathologies such as atherosclerosis and cataract formation. We discuss the detoxification, and the subsequent proteolysis and excretion of components of PB-DOPA. We contrast the fact that in marine organisms, and particularly in extracellular proteins, PB-DOPA and other DOPA-polymers can play important functional roles in adhesion and the provision of tensile properties. (C) 2000 Elsevier Science Ltd.
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Witting, Paul Kenneth; Stocker, Roland; Letters, Jacinta M.Oxidation of low-density lipoprotein (LDL) lipid is implicated in atherogenesis and certain antioxidants inhibit atherosclerosis. Ubiquinol-10 (CoQ<inf>10</inf>H<inf>2</inf>) inhibits LDL lipid peroxidation in vitro although it is not known whether such activity occurs in vivo, and, if so, whether this is anti- atherogenic. We therefore tested the effect of ubiquinone-10 (CoQ<inf>10</inf>) supplemented at 1% (w/w) on aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. Hydroperoxides of cholesteryl esters and triacylglycerols (together referred to as LOOH) and their corresponding alcohols were used as the marker for lipoprotein lipid oxidation. Atherosclerosis was assessed by morphometry at the aortic root, proximal and distal arch, and the descending thoracic and abdominal aorta. Compared to controls, CoQ<inf>10</inf>-treatment increased plasma coenzyme Q, ascorbate, and the CoQ<inf>10</inf>H<inf>2</inf> : CoQ<inf>10</inf> + CoQ<inf>10</inf>H<inf>2</inf> ratio, decreased plasma ?-tocopherol (?-TOH), and had no effect on cholesterol and cholesterylester alcohols (CE-OH). Plasma from CoQ<inf>10</inf>-supplemented mice was more resistant to ex vivo lipid peroxidation. CoQ<inf>10</inf> treatment increased aortic coenzyme Q and ?-TOH and decreased the absolute concentration of LOOH, whereas tissue cholesterol, cholesteryl esters, CE-OH, and LOOH expressed per bisallylic hydrogen-containing lipids were not significantly different. CoQ<inf>10</inf>-treatment significantly decreased lesion size in the aortic root and the ascending and the descending aorta. Together these data show that CoQ<inf>10</inf> decreases the absolute concentration of aortic LOOH and atherosclerosis in apoE-/- mice. (C) 2000 Elsevier Science Inc.
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France, M. P.; Sundberg, John P.; Martinic, GaryLarge solitary cysts in the superficial tissues of the ventral neck are described in five laboratory mice of two inbred strains and one outbred line. The cysts were lined by cuboidal to columnar epithelium similar to that in branchial cysts reported in other animal species but distinct from the stratified squamous epithelium with prominent lymphoid tissue typical of branchial cysts in man. These findings suggest that the lesion referred to as a branchial cyst in animals differs slightly from the lesion of the same name in man. (C) 2000 Harcourt Publishers Ltd.
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Wright, Adam; Hawkins, Clare L.; Davies, Michael J.[No abstract available]
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Pattison, David I.; Lay, Peter Andrew; Davies, Michael J.[No abstract available]
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Dass, Crispin R.; Jessup, Wendy K.Several studies have revealed that high-density lipoprotein (HDL) is the most reliable predictor for susceptibility to cardiovascular disease. Since apolipoprotein A-I (apoA-I) is the major protein of HDL, it is worthwhile evaluating the potential of this protein to reduce the lipid burden of lesions observed in the clinic. Indeed, apoA-I is used extensively in cell culture to induce cholesterol efflux. However, while there is a large body of data emanating from in-vitro and cell-culture studies with apoA-I, little animal data and scant clinical trials examining the potential of this apolipoprotein to induce cholesterol (and other lipid) efflux exists. Importantly, the effects of oxysterols, such as 7-ketocholesterol (7KC), on cholesterol and other lipid efflux by apoA-I needs to be investigated in any attempt to utilise apoA-I as an agent to stimulate efflux of lipids. Lessons may be learnt from studies with other lipid acceptors such as cyclodextrins and phospholipid vesicles (PLVs, liposomes), by combination with other effluxing agents, by remodelling the protein structure of the apolipoprotein, or by altering the composition of the lipoprotein intended for administration in-vivo. Akin to any other drug, the usage of this apolipoprotein in a therapeutic context has to follow the traditional sequence of events, namely an evaluation of the biodistribution, safety and dose-response of the protein in animal trials in advance of clinical trials. Mass production of the apolipoprotein is now a simple process due to the advent of recombinant DNA technology. This review also considers the potential of cyclodextrins and PLVs for use in inducing reverse cholesterol transport in-vivo. Finally, the potential of cyclodextrins as delivery agents for nucleic acid-based constructs such as oligonucleotides and plasmids is discussed.
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Lau, Antony K.; Witting, Paul Kenneth; Chaufour, Xavier; Celermajer, David S.; Pettersson, Knut S.; Stocker, Roland[No abstract available]
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Garner, Brett; Davies, Michael J.; Truscott, Roger John WillisRecent studies have identified specific hydroxylated amino acid oxidation products which strongly suggest the presence of hydroxyl radical (HO)-damaged proteins in human cataractous lenses. In the present study, the ability of early stage (type II) and advanced (type IV) nuclear cataractous lens homogenates to catalyse HO production in the presence of H<inf>2</inf>O<inf>2</inf> was investigated using electron paramagnetic resonance (EPR) spectroscopy with the free radical trap, 5.5-dimethyl-1-pyrroline-N-oxide (DMPO). Cataractous lens homogenates incubated with 1 mM H<inf>2</inf>O<inf>2</inf> generated a distinct HO signal, which was significantly more intense in the nuclear region of the type IV compared to the type II lenses. The ability of individual lens nuclei and cortices to stimulate HO production was positively correlated. The DMPO-HO signal was competitively inhibited by ethanol, confirming that the DMPO-HO signal was due to HO formation and not DMPO-OOH degradation. The metal ion chelator, diethylene- triaminepentaacetic acid, also inhibited HO formation, indicating that lenticular metal ions play a key role in HO formation. Cataractous lens homogenates also stimulated ascorbyl radical production, further suggesting the presence of redox-active metal ions in the tissue. Analysis of lenses for total Fe and Cu (using atomic absorption spectrometry) showed that the more advanced type IV lenses tended to have higher Fe, but similar Cu, levels compared to the type II lenses. The levels of both metals were lower in non- cataractous lenses. These data support the hypothesis that transition metal- mediated HO production may play a role in the aetiology of age-related nuclear cataract.
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Brown, Andrew J.; Mander, Erin L.; Gelissen, Ingrid C.; Kritharides, Leonard; Dean, Roger T.; Jessup, Wendy K.Cholesterol- and cholesteryl ester-rich macrophage foam cells, characteristic of atherosclerotic lesions, are often generated in vitro using oxidized low density lipoprotein (OxLDL). However, relatively little is known of the nature and extent of sterol deposition in these cells or of its relationship to the foam cells formed in atherosclerotic lesions. The purpose of this study was to examine the content and cellular processing of sterols in OxLDL-loaded macrophages, and to compare this with macrophages loaded with acetylated LDL (AcLDL; cholesteryl ester-loaded cells containing no oxidized lipids) or 7-ketocholesterol-enriched acetylated LDL (7KCAcLDL; cholesteryl ester-loaded cells selectively supplemented with 7-ketocholesterol (7KC), the major oxysterol present in OxLDL). Both cholesterol and 7KC and their esters were measured in macrophages after uptake of these modified lipoproteins. Oxysterols comprised up to 50% of total sterol content of OxLDL-loaded cells. Unesterified 7KC and cholesterol partitioned into cell membranes, with no evidence of retention of either free sterol within lysosomes. The cells also contained cytosolic, ACAT-derived, cholesteryl and 7-ketocholesteryl esters. The proportion of free cholesterol and 7KC esterified by ACAT was 10-fold less in OxLDL-loaded cells than in AcLDL or 7KCAcLDL-loaded cells. This poor esterification rate in OxLDL-loaded cells was partly caused by fatty acid limitation. OxLDL-loaded macrophages also contained large (~40-50% total cell sterol content) pools of oxidized esters, containing cholesterol or 7KC esterified to oxidized fatty acids. These were insensitive to ACAT inhibition, very stable and located in lysosomes, indicating resistance to lysosomal esterases. Macrophages loaded with OxLDL do not accumulate free sterols in their lysosomal compartment, but do accumulate lysosomal deposits of OxLDL-derived cholesterol and 7-ketocholesterol esterified to oxidized fatty acids. The presence of similar deposits in lesion foam cells would represent a pool of sterols that is particularly resistant to removal.
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Lovejoy, David B.; Richardson, Des RaymondThe metal complexes of a variety of ligands show diverse pharmacological properties. The potential of these compounds as antineoplastic agents is underlined by the success of the clinically used platinum complex cisplatin (cis-[(NH<inf>3</inf>)<inf>2</inf>PtCl<inf>2</inf>]). In the current review, specific examples of gallium, copper, ruthenium and titanium complexes are discussed with special relevance to their use in the treatment of cancer. Some of these complexes have demonstrated marked activity in a number of animal models and for some compounds, clinical trials are anticipated or have already begun. Collectively, the results in the literature indicate that the study of metal complexes as antineoplastic agents deserves continued intensive investigation.
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Richardson, Des RaymondDevelopment of oral iron (Fe) chelation therapy remains an important goal for the treatment of Fe-overload disease and perhaps other conditions. For many years, the major problem with Fe chelation therapy has been that the drug in clinical use, desferrioxamine (DFO), requires long sc. infusions (12-24 h/day, 5-6 days per week). In addition, DFO is not orally effective, is highly expensive and does not easily permeate cell membranes to bind intracellular Fe pools. Obviously, the development of an orally effective and economical drug is vital. The recent 10th International Conference on Oral Iron Chelators (ICOC) discussed the latest findings in this challenging field. The conference was particularly focused to discuss recent investigations with the orally effective chelator, deferiprone (also known as L1, DMHP or 1,2-dimethylhydroxypyridone).
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Hawkins, Clare L.; Davies, Michael J.[No abstract available]
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Larkin, L.; Khachigian, Levon M.; Jessup, Wendy K.Apolipoprotein E (apo E), a 34 kDa component of lipoproteins produced by the liver and in circulating macrophages, plays a critical role in the reverse transport of cholesterol to the liver via the circulation. Cholesterol-rich macrophages (macrophage foam cells) are a major cell type in human atherosclerotic lesions. Apo E deficiency in mice leads to the formation of atherosclerotic lesions. Conversely, macrophage-specific expression of apo E in these deficient mice can reduce the extent of atherosclerosis. These observations, together with the anti-inflammatory and anti-proliferative properties of Apo E, demonstrate an atheroprotective role for the apolipoprotein. Agents that regulate macrophage metabolism are also able to modulate apo E expression. Sterol loading, for example, enhances apo E synthesis and secretion. Additionally, exposure of macrophage foam cells to cholesterol acceptors such as apo A-1, the protein component of high density lipoprotein, further enhance apo E secretion. Cytokines can have a negative regulatory effect on apo E production in macrophages. Apo E expression is controlled at the transcriptional, post-transcriptional and post-translational level. Here, we review the cellular and molecular mechanisms modulating apo E synthesis and secretion in macrophages.
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McCrohon, Jane A.; Nakhla, Shirley; Jessup, Wendy K.; Stanley, Keith K.; Celermajer, David S.Background - Males have an earlier onset and greater prevalence of clinical atherosclerosis than age-matched females, which is consistent with an atheroprotective effect of the female sex steroids, estrogen and progesterone. We therefore examined the effects of estrogen and progesterone on human foam cell formation, a key early event in atherogenesis. Methods and Results - Monocytes from healthy female and male donors were obtained from white cell concentrates and allowed to differentiate into macrophages over 10 days. These human monocyte-derived macrophages (MDMs) were exposed to either control (0.1% vol/vol ethanol) or estrogen or progesterone treatment on days 3 through 10. Lipid loading was achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the MDMs was then extracted for analysis of cholesteryl ester (CE) content. 17?-Estradiol at both physiological (2 nmol/L) and supraphysiological (20 and 200 nmol/L) concentrations produced a significant reduction in macrophage CE content (883%, 882%, and 854%, respectively; P<0.02 compared with control). Physiological and supraphysiological levels of progesterone (2, 10, and 200 nmol/L) produced an even more dramatic reduction in CE content (749%, 5610%, and 658%, respectively; P<0.002 compared with control). This effect could be abrogated by coincubation with the progesterone receptor antagonist RU486. Neither estrogen nor progesterone produced a reduction in lipid loading in male- donor-derived MDMs. Detailed lipid trafficking studies demonstrated that both estrogen and progesterone altered macrophage uptake and/or processing of modified LDL. Conclusions - Physiological levels of estrogen and progesterone are associated with a female-sex-specific reduction in human macrophage lipid loading, which is consistent with an atheroprotective effect.
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Davies, Michael J.; Fu, Shanlin; Wang, Hongjie; Dean, Roger T.The mechanisms of formation and the nature of the altered amino acid side chains formed on proteins subjected to oxidant attack are reviewed. The use of stable products of protein side chain oxidation as potential markers for assessing oxidative damage in vivo in humans is discussed. The methods developed in the authors laboratories are outlined, and the advantages and disadvantages of these techniques compared with other methodologies for assessing oxidative damage to proteins and other macromolecules. Evidence is presented to show that protein oxidation products are sensitive markers of oxidative damage, that the pattern of products detected may yield information as to the nature of the original oxidative insult, and that the levels of oxidized side-chains can, in certain circumstances, be much higher than those of other markers of oxidation such as lipid hydroperoxides. Copyright (C) 1999 Elsevier Science Inc.
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Stocker, RolandAntioxidants that inhibit LDL oxidation are thought to be potential anti-atherogenic compounds. The results of major human randomized trials with antioxidants have, however, been disappointing, except for probucol, which consistently inhibits restenosis. Similarly, animal intervention studies show that antioxidants do not generally inhibit atherosclerosis, although some compounds provide protection. Direct evidence for the oxidation of LDL causing atherosclerosis is needed. This article summarizes results from antioxidant intervention studies, and highlights some of the key issues that need to be addressed to link biochemical changes in the arterial wall more directly to the oxidation theory of atherosclerosis. (C) 1999 Lippincott Williams and Wilkins.
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Witting, Paul Kenneth; Willhite, Celeste A.; Davies, Michael J.; Stocker, RolandMetmyoglobin metMb) and H<inf>2</inf>O<inf>2</inf> can oxidize low-density lipoprotein (LDL) in vitro, and oxidized LDL may be atherogenic. The role of ?-tocopherol (?- TOH) in LDL oxidation by peroxidases such as metMb is unclear. Herein, we show that during metMb/H<inf>2</inf>O<inf>2</inf>-induced oxidation of native LDL, ?- tocopheroxyl radical (?-TO.) and hydroperoxides and alcohols of cholesteryl esters [CE-O(O)H] and phosphatidylcholine [PC-O(O)H] accumulate concomitantly with ?-TOH consumption. The ratio of accumulating CE-O(O)H to PC-O(O)H remains constant as long as ?-TOH is present. Accumulation of CE-O(O)H is dependent on, and correlates with, LDL's ?-TOH content, yet does not require preformed lipid hydroperoxides or H<inf>2</inf>O<inf>2</inf>. This indicates that in native LDL ?-TOH can act as a phase-transfer agent and ?-TO as a chain-transfer agent propagating LDL lipid peroxidation via tocopherol-mediated peroxidation (TMP). After ?-TOH depletion, CE-O(O)H continues to accumulate, albeit at a slower rate than in the presence of ?-TOH. This second phase of LDL oxidation is accompanied by depletion of PCOOH, a rapid increase in the CE- O(O)H/PC-O(O)H ratio, formation of lipid-derived alkoxyl radicals and phosphatidylcholine hydroxides (PC-OH), and accumulation of a second organic radical, characterized by a broad singlet EPR signal. The latter persists for several hours at 37 C. We conclude that metMb/H<inf>2</inf>O<inf>2</inf>-induced peroxidation of LDL lipids occurs initially via TMP. After ?-TOH depletion, cholesteryl esters peroxidize at higher fractional rates than surface phospholipids, and this appears to be mediated at least in part via reactions involving alkoxyl radicals derived from the peroxidatic activity of metMb on PC-OOH.
