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Showing 1681–1700 of 2058 publications.
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Rolph, Michael S.; Kaufmann, Stefan Hugo ErnstConventional vaccination strategies have failed for numerous pathogens, and the development of novel approaches to vaccine development is a major public health priority. Killed or subunit vaccines represent an attractive approach due to their safety, but they suffer from low immunogenicity and generally require adjuvants. In this study, the possibility of harnessing CD40 signaling for enhancing the immunogenicity of killed vaccines was investigated. Intravenous immunization of C57BL/6 mice with heat-killed Listeria monocytogenes (HKL) induced minimal immunity, but HKL administered together with an agonistic anti-CD40 mAb induced high levels of both CD4+ and CD8+ T cells capable of producing IFN-? following in vitro HKL stimulation. HKL/anti-CD40 vaccination elicited robust protection against subsequent Listeria challenge. Approximately 1000-fold fewer bacteria were detected in the liver and spleen of vaccinated mice, and vaccinated mice were also able to resist a normally lethal Listeria challenge. CD40-mediated adjuvant activity required endogenous IL-12 at the time of vaccination, and protection was mediated by both CD8+ and CD4+ T cells. Thus, CD40 signaling can deliver potent adjuvant activity for vaccination against intracellular pathogens and is particularly effective for pathogens requiring both CD4+ and CD8+ T cells for effective control.
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Sader, Mark A.; Griffiths, Kaye A.; McCredie, Robyn J.; Handelsman, David J.; Celermajer, David S.OBJECTIVES: The study examined arterial and cardiac structure and function in bodybuilders using androgenic anabolic steroids (AAS), compared to non-steroid-using bodybuilder controls. BACKGROUND: Adverse cardiovascular events have been reported in bodybuilders taking anabolic steroids. The cardiovascular effects of AAS, however, have not been investigated in detail. METHODS: We recruited 20 male bodybuilders (aged 35 3 years), 10 actively using AAS and 10 who denied ever using steroids. Serum lipid and hormone levels, carotid intima-media thickness (IMT), arterial reactivity, and left ventricular (LV) dimensions were measured. Vessel diameter was measured by ultrasound at rest, during reactive hyperemia (an endothelium-dependent response, leading to flow-mediated dilation, FMD), and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Arterial reactivity was also measured in 10 age-matched non-bodybuilding sedentary controls. RESULTS: Use of AAS was associated with significant decreases in high density lipoprotein cholesterol, sex hormone binding globulin, testosterone and gonadotrophin levels, and significant increases in LV mass and self-reported physical strength (p < 0.05). Carotid IMT (0.60 0.04 mm vs. 0.63 0.07 mm), arterial FMD (4.7 1.4% vs. 4.1 0.7%) and GTN responses (11.0 1.9% vs. 14.4 1.7%) were similar in both bodybuilding groups (p > 0.2). The GTN responses were significantly lower and carotid IMT significantly higher in both bodybuilding groups, however, compared with the non-bodybuilding sedentary controls (p = 0.01). CONCLUSIONS: Although high-level bodybuilding is associated with impaired vascular reactivity and increased arterial thickening, the use of AAS per se is not associated with significant abnormalities of arterial structure or function. 2001 by the American College of Cardiology.
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Watts, Ralph Neal; Richardson, Des RaymondNitrogen monoxide (NO) affects cellular iron metabolism due to its high affinity for this metal ion. Indeed, NO has been shown to increase the mRNA binding activity of the iron-regulatory protein 1, which is a major regulator of iron homeostasis. Recently, we have shown that NO generators increase 59Fe efflux from cells prelabeled with 59Fe-transferrin (Wardrop, S. L., Watts, R. N., and Richardson, D. R. (2000) Biochemistry 39, 2748-2758). The mechanism involved in this process remains unknown, and in this investigation we demonstrate that it is potentiated upon adding D-glucose (D-Glc) to the reincubation medium. In D-Glc-free or D-Glc-containing media, 5. 6 and 16.5% of cellular 59Fe was released, respectively, in the presence of S-nitrosoglutathione. This difference in 59Fe release was observed with a variety of NO generators and cell types and was not due to a change in cell viability. Kinetic studies showed that D-Glc had no effect on the rate of NO production by NO generators. Moreover, only the metabolizable monosaccharides D-Glc and D-mannose could stimulate NO-mediated 59Fe mobilization, whereas other sugars not easily metabolized by fibroblasts had no effect. Hence, metabolism of the monosaccharides was essential to increase NO-mediated 59Fe release. Incubation of cells with the citric acid cycle intermediates, citrate and pyruvate, did not enhance NO-mediated 59Fe release. Significantly, preincubation with the GSH-depleting agents, L-buthionine-[S,R]-sulfoximine or diethyl maleate, prevented NO-mediated 59Fe mobilization. This effect was reversed by incubating cells with N-acetyl-L-cysteine that reconstitutes GSH. These results indicate that GSH levels are essential for NO-mediated 59Fe efflux. Hence, D-Glc metabolism via the hexose monophosphate shunt resulting in the generation of GSH may be essential for NO-mediated 59Fe release. These results have important implications for intracellular signaling by NO and also NO-mediated cytotoxicity of activated macrophages that is due, in part, to iron release from tumor target cells.
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Becker, Erika M.; Richardson, Des RaymondFriedreich's ataxia (FA) is a severe neurodegenerative condition with an incidence of 1:50 000 in the European population. In 97% of patients this disease is due to an intronic GAA triplet repeat expansion in the FRDA gene resulting in a marked decrease in its expression. The protein encoded by this gene is known as frataxin which is found within the mitochondrion. Upon deletion of the homologous gene (YFH1) in the yeast, there was an accumulation of iron (Fe) within the mitochondrion. When the YFH1 gene was reintroduced back into the yeast cell Fe was exported out of the mitochondrion and into the cytosol. Evidence that human frataxin is also involved in mitochondrial Fe-overload comes from studies in FA patients that have shown an accumulation of Fe within the heart. While the precise role of human frataxin remains to be determined, the molecule appears to be involved indirectly in regulating the export and/or import of mitochondrial Fe. The finding of mitochondrial Fe-overload suggests that the use of specific Fe chelators which can permeate the mitochondrion may have potential in the treatment of this disease. 2001 Elsevier Science Ltd.
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Lyons, Malcolm A.; Brown, Andrew J.Cholesterol oxidation products (oxysterols) have been implicated in atherogenesis due to their presence in atherosclerotic tissue and their potent effects in vitro. One of the major oxysterols currently of interest is 7-ketocholesterol (7K) and it has been suggested that the diet is an important source of this oxysterol. This investigation tested the hypothesis that 7K, delivered in a physiologically relevant vehicle, chylomicron remnant-like emulsion (CMR), would be metabolised and excreted by mice in a similar manner and to a similar extent as previously observed in rats when delivered in a chemically modified lipoprotein, acetylated low-density lipoprotein (acLDL). Indeed, the metabolism of 14C-7K delivered in CMR mirrored that of acLDL and was much more rapid than 3H-cholesterol delivered simultaneously. The 7K-derived 14C was cleared from the liver, appeared in the intestine and was excreted in the faeces. A substantial proportion of the 7K-derived 14C in the intestine and faeces was aqueous-soluble, indicating metabolism to polar products, presumably bile acids. Moreover, while cholesterol-derived 3H increased in the aorta, 14C appeared transiently and there was no observable accumulation within 24 h. The data confirm our previous findings of rapid hepatic metabolism of 7K when delivered in acLDL and demonstrate that 7K delivered in a vehicle of dietary significance is similarly metabolised and excreted. Indeed, the data encourage further investigation into the contribution that dietary oxysterols may or may not make to atherogenesis. 2001 Elsevier Science B.V.
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Carr, Anitra C.; Hawkins, Clare L.; Thomas, Shane R.; Stocker, Roland; Frei, Balz B.Hypochlorous acid (HOCl), the major strong oxidant produced by the phagocyte enzyme myeloperoxidase, reacts readily with free amino groups to form N-chloramines. Since different N-chloramines have different stabilities and reactivities depending on their structures, we investigated the relative reactivities of three model N-chloramines and HOCl with human plasma constituents. The N-chloramines studied were N?-acetyl-lysine chloramine (LysCA, a model of protein-associated N-chloramines), taurine chloramine (TaurCA, the primary N-chloramine produced by activated neutrophils), and monochloramine (MonoCA, a lipophilic N-chloramine). Addition of these chlorine species (100-1000 ?M each) to plasma resulted in rapid loss of thiols, with the extent of thiol oxidation decreasing in the order TaurCA = LysCA > MonoCA = HOCl. The single reduced thiol of albumin was the major target. Loss of plasma ascorbate also occurred, with the extent decreasing in the order HOCl > LysCA > TaurCA > MonoCA. Experiments comparing equimolar albumin thiols and ascorbate showed that while HOCl caused equivalent loss of thiols and ascorbate, the N-chloramines reacted preferentially with thiols. The chlorine species also inactivated ?<inf>1</inf>-antiproteinase, implicating oxidation of methionine residues, and ascorbate provided variable protection depending on the chlorine species involved. Together, our data indicate that in biological fluids N-chloramines react more readily with protein thiols than with methionine residues or ascorbate, and thus may cause biologically relevant, selective loss of thiol groups. 2001 Elsevier Science Inc.
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Sader, Mark A.; McCredie, Robyn J.; Griffiths, Kaye A.; Wishart, Susan M.; Handelsman, David J.; Celermajer, David S.OBJECTIVE: To assess prospectively the effects of low dose oestradiol on arterial endothelial and smooth muscle function in healthy men. Oestrogen use is associated with reduced cardiovascular disease in oestrogen-deficient women, however, the vascular effects of low-dose oestradiol in healthy men have not been investigated previously. PATIENTS and DESIGN: Twenty-three men (aged 32 8 years) were randomized to receive depot implants of testosterone (T) alone (group 1, n = 10), or T with either 10 mg (group 2, n = 7) or 20 mg (group 3, n = 6) of oestradiol (E). MEASUREMENTS: Hormone levels, lipids and vascular reactivity were measured before, 1 month and 6 months after hormone implantation. Using highresolution ultrasound, brachial artery diameter was measured at rest, during reactive hyperaemia (leading to flow-mediated dilatation, FMD, which is endothelium-dependent) and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). RESULTS: Oestradiol produced a dose-dependent increase in plasma oestradiol (at 1 month 96 7, 149 6, 192 23 pmol/I in the 3 groups, respectively, P < 0.001 by ANOVA for trend). Minor side-effects (gynaecomastia, nipple tenderness) indicated that 20 mg oestradiol was the maximum tolerated dose. There was also a dose-dependent increase in FMD with oestradiol dose: at 1 month, -0.2, + 0.2 and + 1.8% for groups 1-3, respectively (P = 0.31 by ANOVA for trend); and at 6 months, -0.8, + 0.4 and +2.2% (P = 0.02). The rise in oestradiol levels following treatment correlated with the improvement in FMD (P = 0.01). GTN responses were similar in the 3 groups throughout the study. CONCLUSION: In healthy young men, oestradiol supplementation is associated with enhanced arterial endothelial function, a key marker of vascular health.
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Richardson, Des Raymond; Dean, Roger T.[No abstract available]
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Hawkins, Clare L.; Davies, Michael J.The oxidation of proteins by free radicals is thought to play a major role in many oxidative processes within cells and is implicated in a number of human diseases as well as ageing. This review summarises information on the formation of radicals on peptides and proteins and how radical damage may be propagated and transferred within protein structures. The emphasis of this article is primarily on the deleterious actions of radicals generated on proteins, and their mechanisms of action, rather than on enzymatic systems where radicals are deliberately formed as transient intermediates. The final section of this review examines the control of protein oxidation and how such damage might be limited by antioxidants. 2001 Elsevier Science B.V.
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Burnett, John R.; Moses, Esther A.; Croft, Kevin D.; Brown, Andrew J.; Grainger, Keith; Vasikaran, Samuel; Leitersdorf, Eran; Watts, Gerald F.Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease characterised clinically by juvenile bilateral cataracts, progressive neurological dysfunction, and formation of tendon xanthomata. We describe the clinical and biochemical features, molecular diagnosis and long-term management of the first reported Australasian case of CTX. Molecular analysis confirmed the diagnosis of CTX and demonstrated that the patient was homozygous for a G ? A transition in the splice donor site of intron 4 of the sterol 27-hydroxylase gene. Serum cholestanol concentrations were decreased with the HMG-CoA reductase inhibitor simvastatin alone and greater reductions were achieved after the addition of the bile acid chenodeoxycholic acid; suggesting a synergistic effect of this combination. Despite serum cholestanol concentrations remaining within the low-normal range, there has been no significant improvement in mental and physical abilities or in EEG abnormalities with 5 years of treatment. Metabolism of radiolabeled 7-ketocholesterol to aqueous soluble products was absent in CTX-derived macrophages. Consistent with this finding, plasma 7?-hydroxycholesterol, 7?-hydroxycholesterol, and 7-ketocholesterol concentrations were increased in the CTX subject compared with controls. 2001 Elsevier Science B.V.
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Gaus, Katharina; Justin Gooding, J. Justin; Dean, Roger T.; Kritharides, Leonard; Jessup, Wendy K.The kinetics (0 to 3 h) of cholesterol efflux to delipidated apolipoprotein A-1 were investigated, and the experimental data were best fitted to a mathematical model that involves two independent pathways of cholesterol efflux. The first pathway with a rate constant of 4.6 h-1 is fast but removes only 3-5% of total cholesterol. After preconditioning apoA-1, it was found that this pathway remains, and hence it is a property of the cholesterol-loaded cells rather than due to modification on the apolipoprotein. This fast initial efflux does not seem to contribute to cholesterol efflux at later stages (> 1 h) where a second pathway predominates. However, the fast initial efflux pool can be restored if apoA-1 is withdrawn. The second slower pathway (?<inf>membrane-media</inf> = 0.79 h-1) is associated with cholesterol ester hydrolysis whose rate constant could be experimentally verified (?<inf>cal</inf> = 0.43, ?<inf>exp</inf> = 0.38 0.05). The model suggests that two different plasma membrane domains are involved in the two pathways. Loading of the cells with an oxysterol, 7-ketocholesterol (7K), inhibits efflux from both pathways. The model predicts that 7K decreases the initial efflux by decreasing the available cholesterol (by possibly affecting lipid packing), while all rate constants in the second pathway are decreased. In conclusion, the kinetic model suggests that cholesterol efflux to apoA-1 is a two-step process. In the first step, some of the plasma membrane cholesterol contributes to a fast initial efflux (possibly from lipid rafts) and leads to a second pathway that mobilizes intracellular cholesterol mobilization.
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Richardson, Des RaymondPreviously we showed that preincubation of cells with ferric ammonium citrate (FAC) resulted in a marked increase in Fe uptake from both 59Fe-transferrin (Tf) and 59Fe-citrate (D.R. Richardson, E. Baker, J. Biol. Chem. 267 (1992) 13972-13979; D.R. Richardson, P. Ponka, Biochim. Biophys. Acta 1269 (1995) 105-114). This Fe uptake process was independent of the transferrin receptor and appeared to be activated by free radicals generated via the iron-catalysed Haber-Weiss reaction. To further understand this process, the present investigation was performed. In these experiments, cells were preincubated for 3 h at 37C with FAC or metal ion solutions and then labelled for 3 h at 37C with 59Fe-Tf. Exposure of cells to FAC resulted in Fe uptake from 59Fe-citrate that became saturated at an Fe concentration of 2.5 ?M, while FAC-activated Fe uptake from Tf was not saturable up to 25 ?M. In addition, the extent of FAC-activated Fe uptake from citrate was far greater than that from Tf. These results suggest a mechanism where FAC-activated Fe uptake from citrate may result from direct interaction with the transporter, while Fe uptake from Tf appears indirect and less efficient. Preincubation of cells with FAC at 4C instead of 37C prevented its effect at stimulating 59Fe uptake from 59Fe-Tf, suggesting that an active process was involved. Previous studies by others have shown that FAC can increase ferrireductase activity that may enhance 59Fe uptake from 59Fe-Tf. However, there was no difference in the ability of FAC-treated cells compared to controls to reduce ferricyanide to ferrocyanide, suggesting no change in oxidoreductase activity. To examine if activation of this Fe uptake mechanism could occur by incubation with a range of metal ions, cells were preincubated with either FAC, ferric chloride, ferrous sulphate, ferrous ammonium sulphate, gallium nitrate, copper chloride, zinc chloride, or cobalt chloride. Stimulation of 59Fe uptake from Tf was shown (in order of potency) with ferric chloride, ferrous sulphate, ferrous ammonium sulphate, and gallium nitrate. The other metal ions examined decreased 59Fe uptake from Tf. The fact that redox-active Cu(II) ion did not stimulate Fe uptake while redox-inactive Ga(III) did, suggests a mechanism of transporter activation not solely dependent on free radical generation. Indeed, the activation of Fe uptake appears dependent on the presence of the Fe atom itself or a metal ion with atomic similarities to Fe (e.g. Ga). 2001 Elsevier Science B.V.
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Stocker, Roland[No abstract available]
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Richardson, Des Raymond[No abstract available]
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Thomas, Shane R.; Salahifar, Houta; Mashima, Ryuichi; Hunt, Nicholas H.; Richardson, Des Raymond; Stocker, RolandInduction of the heme-containing indoleamine 2,3-dioxygenase (IDO) by IFN-? is implicated in anti-microbial and pro-inflammatory activities of human macrophages. Antioxidants can modulate the expression of immune and inflammatory genes, and pyrrolidine dithiocarbamate (PDTC) is a frequently used antioxidant to inhibit the transcription factor NF-?B. Here we show that IFN-? treatment of human monocyte-derived macrophages (hMDMs) increased the proportion of oxidized glutathione. PDTC attenuated this increase and inhibited IDO activity, although it increased IDO protein expression and did not affect IDO mRNA expression and enzyme activity directly. Other antioxidants, 2-ME, ebselen, and t-butyl hydroquinone, inhibited IDO protein expression. Similar to PDTC, the heme biosynthesis inhibitor succinylacetone (SA) and the iron-chelator pyridoxal isonicotinoyl hydrazone inhibited cellular IDO activity without affecting protein expression, whereas addition of hemin or the heme precursor ?-aminolevulinic acid increased IDO activity. Also, incubation of IFN-?-activated hMDM with ?-[14C]-aminolevulinic acid resulted in the incorporation of label into immunoprecipitated IDO, a process inhibited by PDTC and SA. Furthermore, supplementation of lysates from PDTC- or SA-treated hMDM with hemin fully restored IDO activity to control levels, and hemin also reversed the inhibitory action of SA but not PDTC in intact cells. Together these results establish a requirement for de novo heme synthesis for IDO activity in IFN-?-activated hMDM. They show that, similar to other pro-inflammatory proteins, the activity of IDO is modulated by antioxidants though in the case of PDTC this takes place posttranslationally, in part by limiting the availability of heme for the formation of holo-IDO.
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Richardson, Des Raymond; Mouralian, C.; Po?ka, Prem; Becker, Erika M.Friedreich's ataxia (FA) is a crippling neurodegenerative disease that is due to iron (Fe) overload within the mitochondrion. One therapeutic intervention may be the development of a chelator that could remove mitochondrial Fe. We have implemented the only well characterized model of mammalian mitochondrial Fe overload to examine the Fe chelation efficacy of novel chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) class. In this model we utilize reticulocytes treated with the haem synthesis inhibitor succinylacetone which results in mitochondrial Fe-loading. Our experiments demonstrate that in contrast to desferrioxamine, several of the PCIH analogues show very high activity at mobilizing 59Fe from 59Fe-loaded reticulocytes. Further studies on these ligands in animals are clearly warranted considering their potential to treat FA. 2001 Elsevier Science B.V.
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Pattison, David I.; Davies, Michael J.; Levina, Aviva; Dixon, Nicholas E.; Lay, Peter AndrewCatechols are found extensively in nature both as essential biomolecules and as the byproducts of normal oxidative damage of amino acids and proteins. They are also present in cigarette smoke and other atmospheric pollutants. Here, the interactions of reactive species generated in Cr(VI)/catechol(amine) mixtures with plasmid DNA have been investigated to model a potential route to Cr(VI)-induced genotoxicity. Reduction of Cr(VI) by 3,4-dihydroxyphenylalanine (DOPA) (1), dopamine (2), or adrenaline (3) produces species that cause extensive DNA damage, but the products of similar reactions with catechol (4) or 4-tert-butylcatechol (5) do not damage DNA. The Cr(VI)/catechol(amine) reactions have been studied at low added H<inf>2</inf>O<inf>2</inf> concentrations, which lead to enhanced DNA cleavage with I and induce DNA cleavage with 4. The Cr(V) and organic intermediates generated by the reactions of Cr(VI) with I or 4 in the presence of H<inf>2</inf>O<inf>2</inf> were characterized by EPR spectroscopy. The detected signals were assigned to Cr(V)-catechol, Cr(V)-peroxo, and mixed Cr(V)-catechol-peroxo complexes. Oxygen consumption during the reactions of Cr(VI) with 1, 2, 4, and 5 was studied, and H<inf>2</inf>O<inf>2</inf> production was quantified. Reactions of Cr(VI) with 1 and 2, but not 4 and 5, consume considerable amounts of dissolved O<inf>2</inf>, and give extensive H<inf>2</inf>O<inf>2</inf> production. Extents of oxygen consumption and H<inf>2</inf>O<inf>2</inf> production during the reaction of Cr(VI) with enzymatically generated 1 and N-acetyl-DOPA (from the reaction of Tyr and N-acetyl-Tyr with tyrosinase, respectively) were correlated with the DNA cleaving abilities of the products of these reactions. The reaction of Cr(VI) with enzymatically generated 1 produced significant amounts of H<inf>2</inf>O<inf>2</inf> and caused significant DNA damage, but the N-acetyl-DOPA did not. The extent of in vitro DNA damage is reduced considerably by treatment of the Cr(VI)/catechol(amine) mixtures with catalase, which shows that the DNA damage is H<inf>2</inf>O<inf>2</inf>-dependent and that the major reactive intermediates are likely to be Cr(V)-peroxo and mixed Cr(V)-catechol-peroxo complexes, rather than Cr(V)-catechol intermediates.
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Baoutina, Anna; Dean, Roger T.; Jessup, Wendy K.Oxidative modification of low-density lipoprotein (LDL) has been implicated in atherosclerosis. Intensive scientific efforts over the last two decades have focused on the elucidation of the mechanisms by which LDL is oxidized in vivo. A wealth of in vitro studies has demonstrated that the cell types present in atherosclerotic lesions, including monocyte/macrophages, quantitatively one of the most important cell types in plaque development, promote LDL oxidation. The mechanisms of cellular prooxidant activities have been extensively investigated. Fewer studies have addressed possible protective properties of the cells in LDL oxidation. This review summarizes recent observations of antioxidant, and potentially antiatherogenic, activities of macrophages toward LDL, including macrophage-mediated detoxification of lipid and protein hydroperoxides, metal sequestration and the generation of compounds with antioxidant properties. These activities could contribute to the net effect of macrophages on deleterious LDL oxidation and to the complex role of these cells in lesion development. Copyright 2001 Elsevier Science Inc.
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Gao, Jin; Richardson, Des RaymondSome chelators of the pyridoxal isonicotinoyl hydrazone class have antiproliferative activity that is far greater than desferrioxamine (DFO). In this study, DFO was compared with one of the most active chelators (311) on the expression of molecules that play key roles in cell-cycle control. This was vital for understanding the role of iron (Fe) in cell-cycle progression and for designing chelators to treat cancer. Incubating cells with DFO, and especially 311, resulted in a decrease in the hyperphosphorylated form of the retinoblastoma susceptibility gene product (pRb). Chelators also decreased cyclins D1, D2, and D3, which bind with cyclin-dependent kinase 4 (cdk4) to phosphorylate pRb. The levels of cdk2 also decreased after incubation with DFO, and especially 311, which may be important for explaining the decrease in hyperphosphorylated pRb. Cyclins A and B1 were also decreased after incubation with 311 and, to a lesser extent, DFO. In contrast, cyclin E levels increased. These effects were prevented by presaturating the chelators with Fe. In contrast to DFO and 311, the ribonucleotide reductase inhibitor hydroxyurea increased the expression of all cyclins. Hence, the effect of chelators on cyclin expression was not due to their ability to inhibit ribonucleotide reductase. Although chelators induced a marked increase in WAF1 and GADD45 mRNA transcripts, there was no appreciable increase in their protein levels. Failure to translate these cell-cycle inhibitors may contribute to dysregulation of the cell cycle after exposure to chelators. 2001 by The American Society of Hematology.
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Mashima, Ryuichi; Witting, Paul Kenneth; Stocker, RolandThe oxidative theory suggests that LDL oxidation contributes to atherogenesis, implying that attenuation of this process by antioxidants should decrease atherosclerosis. However, a causative link between LDL oxidation and atherogenesis is not firmly established. It requires the identification of the oxidants that are responsible for the initiation of LDL oxidation, and an understanding of the modified moieties that are responsible for the proatherogenic activities of oxidized LDL. The present review summarizes recent data on potential biological oxidants for LDL in the vessel wall, and discusses the antiatherogenic role(s) of selected antioxidants. 2001 Lippincott Williams & Wilkins.
