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Showing 1341–1360 of 2058 publications.
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Chan, Sharon L.; Kim, Woojin Scott; Kwok, John B.J.; Hill, Andrew F.; Cappai, Roberto; Rye, Kerry Anne; Garner, BrettATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and, like its closest homolog ABCA1, belongs to the ABCA subfamily of full-length ABC transporters. ABCA1 promotes cellular cholesterol efflux to lipid-free apolipoprotein acceptors and also inhibits the production of neurotoxic p-amyloid (Ap) peptides in vitro. The potential functions of ABCA7 in the brain are unknown. This study investigated the ability of ABCA7 to regulate cholesterol efflux to extracellular apolipoprotein acceptors and to modulate A? production. The transient expression of ABCA7 in human embryonic kidney cells significantly stimulated cholesterol efflux (fourfold) to apolipoprotein E (apoE) discoidal lipid complexes but not to lipid-free apoE orapoA-I. ABCA7 also significantly inhibited A? secretion from Chinese hamster ovary cells stably expressing human amyloid precursor protein (APP) or APP containing the Swedish K670M671 ? N670L671 mutations when compared with mock-transfected cells. Studies with fluorogenic substrates indicated that ABCA7 had no impact on ?-, ?-, or ?- secretase activities. Live cell imaging of Chinese hamster ovary cells expressing APP-GFP indicated an apparent retention of APP in a perinuclear location in ABCA7 co-transfected cells. These studies indicate that ABCA7 has the capacity to stimulate cellular cholesterol efflux to apoE discs and regulate APP processing resulting in an inhibition of Ap production. 2008 International Society for Neurochemistry.
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Cohn, Jeffrey S.[No abstract available]
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McCaskie, Pamela A.; Beilby, John P.; Hung, Joseph C.; Chapman, Caroline L.; McQuillan, Brendan M.; Powell, Brenda L.; Thompson, Peter Lindsay; Palmer, Lyle J.The major underlying cause of CHD is atherosclerosis, and oxidised LDL is known to play an important role in its development. We examined the role of three single nucleotide polymorphisms (SNPs) in the 15-lipoxygenase gene (ALOX15), in atherosclerosis. We genotyped three SNPs in the ALOX15 promoter in two Western Australian samples - 1,111 community-based individuals and 556 with CHD. SNPs and haplotypes were tested for an association with carotid plaque, intima-media thickness and risk of CHD. The -611GG genotype was associated with increased likelihood of carotid plaque in CHD patients (OR = 4.01, 95%CI = 1.39-11.53, P = 0.005) and the C alleles of the G-220C and G-189C SNPs were associated with decreased likelihood of plaque among cases (OR = 0.66, 95%CI = 0.43-0.99, P = 0.05 and OR = 0.51, 95%CI = 0.34-0.78, P = 0.002 respectively). The GGG haplotype was associated with increased risk of carotid plaque in CHD patients (OR = 5.77, 95%CI = 1.82-18.29, P = 0.0007) and in community-based individuals under 53 years (OR = 4.15, 95%CI = 1.23-14.08, P = 0.02). No association was observed between ALOX15 SNPs or haplotypes and intima-media thickness. This study is novel as it is the first to examine the association between 15-lipoxygenase polymorphisms and atherosclerotic indicators. These findings suggest a possible role of ALOX15 polymorphisms in focal plaque formation. Springer-Verlag 2008.
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Lambert, Gilles; Ancellin, Nicolas; Charlton, Francesca; Comas, Daniel; Pilot, Julia; Keech, Anthony C.; Patel, Sanjay; Sullivan, David R.; Cohn, Jeffrey S.; Rye, Kerry Anne; Barter, Philip J.BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment. METHODS: We developed a sandwich ELISA using recombinant human PCSK9 protein and 2 affinity-purified polyclonal antibodies directed against human PCSK9. We measured circulating PCSK9 concentrations in 115 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study before and after fenofibrate treatment. RESULTS: We found that plasma PCSK9 concentrations correlate with total (r=0.45, P=0.006) and LDL (r= 0.54, P = 0.001) cholesterol but not with triglycerides or HDL cholesterol concentrations in that cohort. After 6 weeks of treatment with comicronized fenofibrate (200 mg/day), plasma PCSK9 concentrations decreased by 8.5% (P = 0.041 vs pretreatment). This decrease correlated with the efficacy of fenofibrate, as judged by a parallel reduction in plasma triglycerides (r = 0.31, P = 0.015) and LDL cholesterol concentrations (r = 0.27, P = 0.048). CONCLUSIONS: We conclude that this decrease in PCSK9 explains at least in part the LDL cholesterol-lowering effects of fenofibrate. Fenofibrate might be of interest to further reduce cardiovascular risk in patients already treated with a statin. 2008 American Association for Clinical Chemistry.
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Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatmentKastelein, Johannes Jacob Pieter; van der Steeg, Wim A.; Holme, Ingar Morten K.; Gaffney, Michael; Cater, Nilo B.; Barter, Philip J.; Deedwania, Prakash ?.; Olsson, Anders G.; Boekholdt, S. M.; DeMicco, David A.; Szarek, Michael J.; LaRosa, John C.; Pedersen, Terje R.; Grundy, Scott M.Background - Low-density lipoprotein (LDL) cholesterol is the principal target of lipid-lowering therapy, but recent evidence has suggested more appropriate targets. We compared the relationships of on-treatment levels of LDL cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B, as well as ratios of total/HDL cholesterol, LDL/HDL cholesterol, and apolipoprotein B/A-I, with the occurrence of cardiovascular events in patients receiving statin therapy. Methods and results - A post hoc analysis was performed that combined data from 2 prospective, randomized clinical trials in which 10 001 ("Treating to New Targets") and 8888 ("Incremental Decrease in End Points through Aggressive Lipid Lowering") patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment. In models with LDL cholesterol, non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome, whereas a positive relationship with LDL cholesterol was lost. In a model that contained non-HDL cholesterol and apolipoprotein B, neither was significant owing to collinearity. Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters. Conclusions - In patients receiving statin therapy, on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol. Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships. These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy. Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I, it seems premature to consider the ratio variables as clinically useful. 2008 American Heart Association. All rights reserved.
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Rees, Martin D.; Kennett, Eleanor C.; Whitelock, John; Davies, Michael J.The extracellular compartments of most biological tissues are significantly less well protected against oxidative damage than intracellular sites and there is considerable evidence for such compartments being subject to a greater oxidative stress and an altered redox balance. However, with some notable exceptions (e.g., plasma and lung lining fluid) oxidative damage within these compartments has been relatively neglected and is poorly understood. In particular information on the nature and consequences of damage to extracellular matrix is lacking despite the growing realization that changes in matrix structure can play a key role in the regulation of cellular adhesion, proliferation, migration, and cell signaling. Furthermore, the extracellular matrix is widely recognized as being a key site of cytokine and growth factor binding, and modification of matrix structure might be expected to alter such behavior. In this paper we review the potential sources of oxidative matrix damage, the changes that occur in matrix structure, and how this may affect cellular behavior. The role of such damage in the development and progression of inflammatory diseases is discussed. 2008 Elsevier Inc. All rights reserved.
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Davies, Michael J.; Hawkins, Clare L.; Pattison, David I.; Rees, Martin D.A marked increase in interest has occurred over the last few years in the role that mammalian heme peroxidase enzymes, primarily myeloperoxidase, eosinophil peroxidase, and lactoperoxidase, may play in both disease prevention and human pathologies. This increased interest has been sparked by developments in our understanding of polymorphisms that control the levels of these enzymes, a greater understanding of the basic chemistry and biochemistry of the oxidants formed by these species, the development of specific biomarkers that can be used in vivo to detect damage induced by these oxidants, the detection of active forms of these peroxidases at most, if not all, sites of inflammation, and a correlation between the levels of these enzymes and a number of major human pathologies. This article reviews recent developments in our understanding of the enzymology, chemistry, biochemistry and biologic roles of mammalian peroxidases and the oxidants that they generate, the potential role of these oxidants in human disease, and the use of the levels of these enzymes in disease prognosis. 2008 Mary Ann Liebert, Inc.
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Martinic, GaryThe author describes a method of intragastric gavage in rabbits using a pediatric feeding tube. Researchers used this technique to administer radiolabeled cholesterol in a pilot study of cholesterol efflux. The author discusses specific considerations for gavaging rabbits, emphasizing occupational safety and rabbit welfare.
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Hooper, Lee; Kroon, Paul A.; Rimm, Eric B.; Cohn, Jeffrey S.; Harvey, Ian M.; Le Cornu, Kathryn A.; Ryder, Jonathan J.; Hall, Wendy Louise; Cassidy, AedBackground: The beneficial effects of flavonoid consumption on cardiovascular risk are supported by mechanistic and epidemiologic evidence. Objective: We aimed to systematically review the effectiveness of different flavonoid subclasses and flavonoid-rich food sources on cardiovascular disease (CVD) and risk factors - ie, lipoproteins, blood pressure, and flow-mediated dilatation (FMD). Design: Methods included a structured search strategy on MEDLINE, EMBASE, and Cochrane databases; formal inclusion or exclusion, data extraction, and validity assessment; and meta-analysis. Results: One hundred thirty-three trials were included. No randomized controlled trial studied effects on CVD morbidity or mortality. Significant heterogeneity confirmed differential effects between flavonoid subclasses and foods. Chocolate increased FMD after acute (3.99%; 95% CI: 2.86, 5.12; 6 studies) and chronic (1.45%; 0.62, 2.28; 2 studies) intake and reduced systolic (-5.88 mm Hg; -9.55, -2.21; 5 studies) and diastolic (-3.30 mm Hg; -5.77, -0.83; 4 studies) blood pressure. Soy protein isolate (but not other soy products or components) significantly reduced diastolic blood pressure (-1.99 mm Hg; -2.86, -1.12; 9 studies) and LDL cholesterol (-0.19 mmol/L; -0.24, -0.14; 39 studies). Acute black tea consumption increased systolic (5.69 mm Hg; 1.52, 9.86; 4 studies) and diastolic (2.56 mm Hg; 1.03, 4.10; 4 studies) blood pressure. Green tea reduced LDL (-0.23 mmol/L; -0.34, -0.12; 4 studies). For many of the other flavonoids, there was insufficient evidence to draw conclusions about efficacy. Conclusions: To date, the effects of flavonoids from soy and cocoa have been the main focus of attention. Future studies should focus on other commonly consumed subclasses (eg, anthocyanins and flavanones), examine dose-response effects, and be of long enough duration to allow assessment of clinically relevant endpoints. 2008 American Society for Nutrition.
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Ahn, Sung-hoon; Shah, Yatrik Madhukar; Inoue, Junko; Morimura, Keiichirou; Kim, Insook; Yim, Sun-hee; Lambert, Gilles; Kurotani, Reiko; Nagashima, Kunio; Gonzalez, Frank J.; Inoue, YusukeBackground: Hepatocyte nuclear factor 4? (HNF4?; NR2A1) is an orphan member of the nuclear receptor superfamily expressed in liver and intestine. While HNF4? expression is critical for liver function, its role in the gut and in the pathogenesis of inflammatory bowel disease (IBD) is unknown. Methods: Human intestinal biopsies from control and IBD patients were examined for expression of mRNAs encoding HNF4? and other nuclear receptors. An intestine-specific HNF4? null mouse line (Hnf4??IEpC) was generated using an Hnf4?-floxed allele and villin-Cre transgene. These mice and their control floxed counterparts (Hnf4?F/F), were subjected to a dextran sulfate sodium (DSS)-induced IBD colitis protocol and their clinical symptoms and gene expression patterns determined. Results: In human intestinal biopsies, HNF4? was significantly decreased in intestinal tissues from Crohn's disease and ulcerative colitis patients. HNF4? expression was also suppressed in the intestine of DSS-treated mice. In Hnf4? ?IEpC mice, disruption of HNF4? expression was observed in the epithelial cells throughout the intestine. In the DSS-induced colitis model Hnf4??IEpC mice showed markedly more severe changes in clinical symptoms and pathologies associated with IBD including loss of body weight, colon length, and histological morphology as compared with Hnf4?F/F mice. Furthermore, the Hnf4? ?IEpC mice demonstrate a significant alteration of mucin-associated genes and increased intestinal permeability, which may play an important role in the increased susceptibility to acute colitis following an inflammatory insult. Conclusions: While HNF4? does not have a major role in normal function of the intestine, it protects the gut against DSS-induced colitis. Copyright 2008 Crohn's & Colitis Foundation of America, Inc.
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Szuchman-Sapir, Andrea J.; Pattison, David I.; Ellis, Natasha A.; Hawkins, Clare L.; Davies, Michael J.; Witting, Paul KennethAfter acute myocardial infarction (AMI), infiltrating proinflammatory cells generate two-electron oxidants such as hypochlorous acid (HOCl). Myoglobin (Mb) is present at ? 0.3mM in cardiomyocytes and, therefore, represents a significant target for oxidation. Exposure of horse Mb (50?M) to reagent HOCl (0-500?M) or activated human neutrophils (4-40 106 cells/ml) yielded oxidized Mb (Mb<inf>ox</inf>) as judged by amino acid analysis and peptide mass mapping. HOCl/Mb ratios of 1-5mol/mol gave Mb<inf>ox</inf> with up to four additional oxygen atoms. Hydrolysis of Mb<inf>ox</inf> followed by amino acid analysis indicated that methionine (Met) and tryptophan (Trp) residues were modified by HOCl. Peptide mass mapping revealed that Met55 was oxidized at a lower HOCl/Mb ratio than Met131 and this preceded Trp7/14 modification (susceptibility Met55 > Met131 > Trp7 > Trp14). Incubation of Mb with activated neutrophils and physiological chloride anion yielded Mb<inf>ox</inf> with a composition similar to that determined with HOCl/Mb ratios < 2mol/mol, with oxidation of Met, but not Trp, detected. These data indicate that Mb undergoes site-specific oxidation depending on the HOCl/protein ratio. As Mb is released from necrotic cardiomyocytes into the vasculature after AMI, HOCl-modified Mb may be a useful surrogate marker to gauge the extent of myocardial inflammation. 2008 Elsevier Inc. All rights reserved.
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Davies, Michael J.[No abstract available]
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Lind, Joanne Maree; Chiu, Christine L.; Ingles, Jodie; Yeates, Laura; Humphries, Stephen Eric; Heather, Alison Kay; Semsarian, ChristopherHypertrophic cardiomyopathy (HCM) is a clinically heterogeneous disease, which suggests that a number of factors exist which modify disease outcome. Gender may be one such factor as more males present with the disease compared with females. The aim of the present study was to determine if an association exists between genetic variation in sex hormone receptors and the development of left ventricular hypertrophy in HCM. The study population included 200 unrelated individuals from an Australian HCM cohort. Clinical evaluation was performed. Genetic analysis of the androgen receptor (AR), estrogen receptor 1 (ESR1), estrogen receptor 2 (ESR2), and aromatase (CYP19A1) genes, was carried out in all patients. Fewer (CAG)n repeats within the AR gene were significantly associated with higher maximal left ventricular wall thickness (LVWT) in males (P = 0.008), adjusting for age. Male carriers of the A allele at SNP rs6915267, located in the promoter region of ESR1, had an 11% decrease in mean LVWT compared to male GG homozygotes (P = 0.047). We report for the first time that variation at the AR gene is associated with left ventricular hypertrophy in males with HCM. Understanding the impact of sex hormones on phenotype will be helpful in the risk stratification and clinical management of HCM patients. 2008 Elsevier Inc. All rights reserved.
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Skaff, Ojia; Pattison, David I.; Davies, Michael J.Plasmalogens, which contain a vinyl ether bond, are major phospholipids of the plasma membranes of endothelial and vascular smooth muscle cells and cardiac myocytes. These lipids, in contrast to other phospholipids, have been reported to be targets of HOCl/HOBr generated by myeloperoxidase, with elevated levels of the products of these reactions (?-chloro/?-bromo aldehydes and unsaturated lysophospholipids) having been detected in human atherosclerotic lesions. The reason(s) for the targeting of this lipid class, over other phospholipids, is poorly understood, and is examined here. It is shown that HOCl and HOBr react with a model vinyl ether (ethylene glycol vinyl ether) 200-300-fold faster (k = 1.6 103 and 3.5 10 6 M-1 s-1, respectively) than with aliphatic alkenes (models of phospholipids). True plasmalogens react ca. 20-fold slower than the models. Chloramines and bromamines (from reaction of HOCl/HOBr with primary amines and ?-amino groups) also react with vinyl ethers, unlike aliphatic alkenes, with k = 10-3-102 M-1 s -1 for chloramines (with the His side chain chloramine being the most reactive, k = 172 M-1 s-1) and k = 103-10 4 M-1 s-1 for bromamines. The bromamine rate constants are typically 105-106 larger than those of the chloramines. Intermolecular vinyl ether oxidation by phospholipid headgroup bromamines can also occur. These kinetic data indicate that plasmalogens are significantly more susceptible to oxidation than the aliphatic alkenes of phospholipids, thereby rationalizing the detection of products from the former, but not the latter, in human atherosclerotic lesions. 2008 American Chemical Society.
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Silva, R. A.Gangani D.; Huang, Rong; Morris, Jamie; Fang, Jianwen; Gracheva, Elena O.; Ren, Gang; Kontush, Anatol S.; Jerome, W. Gray Jay; Rye, Kerry Anne; Davidson, William SeanSpherical high density lipoproteins (HDL) predominate in human plasma. However, little information exists on the structure of the most common HDL protein, apolipoprotein (apo) A-I, in spheres vs. better studied discoidal forms. We produced spherical HDL by incubating reconstituted discoidal HDL with physiological plasma-remodeling enzymes and compared apoA-I structure in discs and spheres of comparable diameter (79-80 and 93-96 . Using cross-linking chemistry and mass spectrometry, we determined that the general structural organization of apoA-I was overall similar between discs and spheres, regardless of diameter. This was the case despite the fact that the 93 spheres contained three molecules of apoA-I per particle compared with only two in the discs. Thus, apoA-I adopts a consistent general structural framework in HDL particles - irrespective of shape, size and the number of apoA-Is present. Furthermore, a similar cross-linking pattern was demonstrated in HDL particles isolated from human serum. We propose the first experiment-based molecular model of apoA-I in spherical HDL particles. This model provides a new foundation for understanding how apoA-I structure modulates HDL function and metabolism. 2008 by The National Academy of Sciences of the USA.
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Kennett, Eleanor C.; Davies, Michael J.The extracellular matrix (ECM) provides strength and elasticity to tissues and plays a key role in regulating cell behavior; damage to this material is believed to be a major factor in many inflammatory diseases. Peroxynitrite/peroxynitrous acid, which is generated at elevated levels at sites of inflammation, is believed to play a role in ECM damage; however, the mechanisms involved are poorly understood. Here we examined the reactions of bolus peroxynitrite, and that generated in a time-dependent manner by SIN-1 decomposition, with ECM isolated from a vascular smooth muscle cell line and porcine thoracic aorta. Bolus peroxynitrite caused the release of ECM glycosaminoglycans and proteins, the formation of 3-nitroTyr, and the detection of ECM-derived radicals (by immuno-spin trapping) in a concentration-dependent manner. Release and nitration of ECM components were modulated by the local pH and bicarbonate. SIN-1 caused the release of glycosaminoglycan, but not protein, from vascular smooth muscle cell-derived ECM in a concentration-, time-, and pH-dependent manner. The data presented here suggest that peroxynitrite-mediated damage to ECM occurs via a radical-mediated pathway. These reactions may contribute to ECM damage at sites of inflammation and play a role in disease progression, including rupture of atherosclerotic lesions. 2008 Elsevier Inc. All rights reserved.
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Cohn, Jeffrey S.Intestinal chylomicrons and their remnants are believed to contribute both directly and indirectly to the onset and development of atherosclerosis. Measurement of postprandial triglyceridemia or the plasma concentration of apoB-48 (the principle structural protein of chylomicrons) is not however standard clinical practice. The reason is that a standardized fat tolerance test has not been established, and age- and gender-specific normal ranges have not been determined. Appropriate cost-benefit analysis is also lacking, although such analysis depends upon reliable prospective data demonstrating that plasma parameters measured after a defined oral fat load can predict the presence of cardiovascular disease (CVD) better than existing lipid and non-lipid risk factors. In addition to being of prognostic value, positive prospective data linking plasma chylomicron levels and CVD would be of therapeutic importance and would reemphasize advice to restrict the size, frequency and fat content of individual meals. 2008 Elsevier Ireland Ltd. All rights reserved.
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Lloyd, Mitchell M.; Van Reyk, David M.; Davies, Michael J.; Hawkins, Clare L.Hypohalous acids are generated by activated leucocytes, via the formation of H<inf>2</inf>O<inf>2</inf> and the release of peroxidase enzymes (myeloperoxidase and eosinophil peroxidase). These species are important bactericidal agents, but HOCI (hypoeblorous acid) and HOBr (hypobromous acid) have also been implicated in tissue damage in a number of inflammatory diseases. HOSCN (hypothiocyanous acid; cyanosulfenic acid) is a milder, more thiol-specific, oxidant than HOCI or HOBr and as such may be a more potent inducer of cellular dysfunction due to selective targeting of critical thiol residues on proteins. In the present study, HOCI and HOBr are shown to react rapidly with macrophage (J774A.1) cells, resulting in a greater extent of cell lysis compared with HOSCN. However, HOSCN induces apoptosis and necrosis with greater efficacy, and at lower concentrations, than HOCI or HOBr. Apoptosis occurs in conjunction with an increased release of cytochrome c into the cytosol, but no associated increase in caspase activity. Similarly, apoptosis is observed on treating the cells in the presence of a caspase inhibitor, suggesting that it is mediated by a caspase-independent pathway. HOSCN oxidized protein thiols more efficiently than either HOCI or HOBr. The greater efficacy of HOSCN in inducing apoptosis is attributed to selective damage to critical mitochondrial membrane protein thiol groups, resulting in increased permeability and subsequent leakage of cytochrome c into the cytosol. This induction of damage by HOSCN may be of critical importance in people with elevated levels of SCN- (thiocyanate ions) arising from cigarette smoking, and plays a role in the pathologies associated with this biological insult. 2008 Biochemical Society.
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Summers, Fiona A.; Morgan, Philip E.; Davies, Michael J.; Hawkins, Clare L.Hypochlorous acid (HOCl), the major strong oxidant produced by myeloperoxidase, reacts readily with free amino groups to form N-chloramines. Although HOCl and N-chloramines play an important role in the human immune system by killing bacteria and invading pathogens, they have also been shown to cause damage to tissues, which is believed to contribute to a number of diseases. It has been shown previously that N-chloramines react more readily with protein thiols than with other targets in plasma, but the nature of the plasma thiol-containing proteins oxidized is unknown. In this study, the ability of N-chloramines to selectively oxidize thiol-containing plasma proteins was determined using the thiol-specific probe, 5-iodoacetamidofluorescein, combined with two-dimensional sodium dodecyl sulfate-Polyacrylamide gel electrophoresis. Experiments were performed with N-chloramines formed on N?-acetyl-lysine, N?-acetyl-histidine (HisCA), glycine, taurine, and ammonia. With the exception of HisCA, the N-chloramines were more efficient than HOCl at oxidizing plasma thiols. The thiol-containing plasma proteins ?<inf>1</inf>- antitrypsin and transthyretin were found to be oxidized in addition to albumin, with this treatment resulting in the inactivation of ?<inf>1</inf> -antitrypsin. A similar selectivity of reaction and extent of thiol oxidation were also observed with myeloperoxidase in the presence of hydrogen peroxide and chloride ions. 2008 American Chemical Society.
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Powell, Brenda L.; Wiltshire, Steven; Arscott, Gillian M.; McCaskie, Pamela A.; Hung, Joseph C.; McQuillan, Brendan M.; Thompson, Peter Lindsay; Carter, Kim Warwick; Palmer, Lyle J.; Beilby, John P.PARL (presenilin-associated rhomboid-like) is a mitochondrial protein involved in mitochondrial membrane remodelling, and maps to a quantitative trait locus (3q27) associated with metabolic traits. Recently the rs3732581 (Leu262Val) variant was found to be associated with increased levels of plasma insulin, a finding not replicated in a larger cohort. The aim of the current study was to investigate the associations between rs3732581 and levels of plasma insulin, metabolic syndrome (MetS) and its components, and cardiovascular disease. The CUPID population consisted of 556 subjects with angiographically proven CAD and the CUDAS cohort consisted of 1,109 randomly selected individuals from Perth, Western Australia. Samples were genotyped using mutation-specific PCR. No significant associations were observed between rs3732581 and levels of plasma insulin, glucose, BMI or MetS in either population. However, carriers of the minor allele had significantly lower mean intima-media thickness (IMT) [0.69 mm, 95% CI (0.69, 0.70 mm); P = 0.004], compared with major allele homozygotes [mean IMT = 0.71 mm, 95% CI (0.70, 0.72 mm)] in the CUDAS population. Further analysis using a recessive model showed homozygous carriers of the minor allele were predisposed to CAD [OR 1.55, 95% CI (1.11, 2.16); P = 0.01]. Despite the functional evidence for a role of PARL in regulating insulin levels, no association with rs3732581 was found in the current study. Additionally, there were no associations with glucose levels, BMI or MetS. There were significant effects of the variant on mean IMT and risk of CAD. A role for PARL in metabolic conditions cannot be excluded and more comprehensive genetic studies are warranted. Springer-Verlag 2008.
