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Showing 1481–1500 of 2058 publications.
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Barter, Philip J.; Rye, Kerry Anne[No abstract available]
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Hime, Neil J.; Drew, Kate J.; Wee, Kevin; Barter, Philip J.; Rye, Kerry AnneHuman plasma HDLs are classified on the basis of apolipoprotein composition into those that contain apolipoprotein A-I (apoA-I) without apoA-II [(A-I)HDL] and those containing apoA-I and apoA-II [(A-I/A-II)HDL]. ApoA-I enters the plasma as a component of discoidal particles, which are remodeled into spherical (A-I)HDL by LCAT. ApoA-II is secreted into the plasma either in the lipidfree form or as a component of discoidal high density lipoproteins containing apoA-II without apoA-I [(A-II)HDL]. As discoidal (A-II)HDL are poor substrates for LCAT, they are not converted into spherical (A-II)HDL. This study investigates the fate of apoA-II when it enters the plasma. Lipidfree apoA-II and apoA-II-containing discoidal reconstituted HDL [(A-II)rHDL] were injected intravenously into New Zealand White rabbits, a species that is deficient in apoA-II. In both cases, the apoA-II was rapidly and quantitatively incorporated into spherical (A-I)HDL to form spherical (A-I/A-II)HDL. These particles were comparable in size and composition to the (A-I/A-II)HDL in human plasma. Injection of lipid-free apoA-II and discoidal (A-II)rHDL was also accompanied by triglyceride enrichment of the endogenous (A-I)HDL and VLDL as well as the newly formed (A-I/A-II)HDL. We conclude that, irrespective of the form in which apoA-II enters the plasma, it is rapidly incorporated into spherical HDLs that also contain apoA-I to form(A-I/AII) HDL. Copyright 2006 by the American Society for Biochemistry and Molecular Biology, Inc.
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Curtiss, Linda K.; Valenta, David T.; Hime, Neil J.; Rye, Kerry AnneAn initial step in reverse cholesterol transport is the movement of unesterified cholesterol from peripheral cells to high-density lipoproteins (HDLs). This transfer usually occurs in extracellular spaces, such as the subendothelial space of a vessel wall, and is promoted by the interaction of lipid-free or lipid-poor apolipoprotein (apo)AI with ATP binding cassette A1 cellular transporters on macrophages (M?). Because HDL does not interact with M? ATP binding cassette A1 and apoAI is not synthesized by macrophages, this apoAI must be generated from spherical HDL. In this brief review, we propose that spherical apoAI is derived from HDL by remodeling events that are accomplished by proteins secreted by cholesteryl ester-loaded foam cells, including the lipid transfer proteins, phospholipid transfer protein, and cholesteryl ester transfer protein, and the triglyceride hydrolases hepatic lipase and lipoprotein lipase. 2005 American Heart Association, Inc.
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Pattison, David I.; Davies, Michael J.Solar radiation is the primary source of human exposure to ultraviolet (UV) radiation. Overexposure without suitable protection (i.e., sunscreen and clothing) has been implicated in mutagenesis and the onset of skin cancer. These effects are believed to be initiated by UV-mediated cellular damage, with proteins and DNA as primary targets due to a combination of their UV absorption characteristics and their abundance in cells. UV radiation can mediate damage via two different mechanisms: (a) direct absorption of the incident light by the cellular components, resulting in excited state formation and subsequent chemical reaction, and (b) photosensitization mechanisms, where the light is absorbed by endogenous (or exogenous) sensitizers that are excited to their triplet states. The excited photosensitizers can induce cellular damage by two mechanisms: (a) electron transfer and hydrogen abstraction processes to yield free radicals (Type I); or (b) energy transfer with O2 to yield the reactive excited state, singlet oxygen (Type II). Direct UV absorption by DNA leads to dimers of nucleic acid bases including cyclobutane pyrimidine species and pyrimidine (6-4) pyrimidone compounds, together with their Dewar isomers. These three classes of dimers are implicated in the mutagenicity of UV radiation, which is typified by a high level of CC-->TT and C-->T transversions. Single base modifications can also occur via sensitized reactions including Type 1 and Type II processes. The main DNA product generated by (1)O2 is 8-oxo-Gua; this is a common lesion in DNA and is formed by a range of other oxidants in addition to UV. The majority of UV-induced protein damage appears to be mediated by (1)O2, which reacts preferentially with Trp, His, Tyr, Met, Cys and cystine side chains. Direct photo-oxidation reactions (particularly with short-wavelength UV) and radicals can also be formed via triplet excited states of some of these side chains. The initial products of (1)O2-mediated reactions are endoperoxides with the aromatic residues, and zwitterions with the sulfur-containing residues. These intermediates undergo a variety of further reactions, which can result in radical formation and ring-opening reactions; these result in significant yields of protein cross-links and aggregates, but little protein fragmentation. This review discusses the formation of these UV-induced modifications and their downstream consequences with particular reference to mutagenesis and alterations in protein structure and function.
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Barter, Philip J.; Kastelein, Johannes Jacob Pieter[No abstract available]
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Barter, Philip J.; Ballantyne, Christie Mitchell; Carmena, Rafael; Castro-Cabezas, Manuel C.; Chapman, Martin John; Couture, Patrick; de Graaf, Jacqueline J.; Durrington, Paul N.; Faergeman, Ole F.; Frlich, Ji?i J.; Furberg, Curt D.; Gagn Claude; Haffner, Steven M.; Humphries, Steve Eric; Jungner, Ingmar; Krauss, Ronald M.; Kwiterovich, Peter Oscar; Marcovina, Santica Marija; Packard, Christopher J.D.; Pearson, Thomas A.; Reddy, K. Srinath; Rosenson, Robert Sidney; Sarrafzadegan, Nizal S.; Sniderman, Allan David; Stalenhf, Anton F.H.; Stein, Evan A.; Talmud, Philippa J.; Tonkin, Andrew Maxwell; Walldius, Gan; Williams, Ken M.S.There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL-1 in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL-1 be considered. The evidence also indicates that the apo B/apo A-I ratio is superior q3to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease. 2006 Blackwell Publishing Ltd.
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Xu, Bei; Makris, Angela; Thornton, Charlene Eliza; Ogle, Robert F.; Horvath, John Stephen; Hennessy, AnnemarieBackground: Antihypertensive drugs such as clonidine, diazoxide, hydralazine and furosemide are used in the hypertensive disorders of pregnancy to control blood pressure, but it is not clear if they modulate the production of placental or circulating cytokines. Objective: To examine the effect of pharmaceutical doses of well known antihypertensive drugs used for blood pressure control on the production of the cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-? in placental tissue and peripheral blood mononuclear cells (PBMCs) in normal pregnancy. Design: Placental biopsies were taken from the decidual surface of placentas after delivery of normal pregnancies (n = 6) and PBMCs were separated from the whole blood of normal term pregnant women (n = 7). Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs. The dose effect of drugs on the production of placental and circulating cytokines (IL-6, IL-10 and TNF-?) were examined by enzyme-linked immunosorbent assay. Results: Placental production of IL-10 was not affected by clonidine, but decreased significantly after incubation of the tissue with diazoxide, hydralazine or furosemide. Production of IL-10 by PBMCs increased significantly: by from 3.4 2.7% [16.3 pg/ml (range 6.1-21.5 pg/ml)] to 24.5 3.3% [30.4 pg/ml (range 16.9-34.8 pg/ml)] with increasing concentrations of clonidine (0.08-1.3 ?g/ml), and by 8.8 3.5% [4.1 pg/ml (range 3.0-17.8 pg/ml)] and 17.2 1.9% [22.6 pg/ml (range 13.2-23.2 pg/ml)] with lower doses of hydralazine (6.3 and 12.5 ?g/ml) (all P values < 0.05). There was a stepwise reduction in production of TNF-? and IL-6 with increasing doses of diazoxide, hydralazine and furosemide by placentas and PBMCs from these women with normal pregnancies. Conclusion: Our data suggest that the antihypertensive drugs clonidine and hydralazine can stimulate production of the circulating anti-inflammatory cytokine IL-10, whereas furosemide and diazoxide inhibit the production of this cytokine and the proinflammatory cytokines TNF-? and IL-6 by placentas and PBMCs. 2006 Lippincott Williams & Wilkins.
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Barter, Philip J.Patient profile Peter is a 42-year-old man who had had three myocardial infarctions at ages 29, 32, and 33 years. His myocardial function was so compromised after the last episode that he was considered for a heart transplant, which was performed at age 34 years. He had a lipid abnormality for which he had been receiving treatment with a statin. After the transplant, statin therapy was stopped because of a concern that the cyclosporin he was taking to prevent organ rejection may interact adversely with the statin. He was referred to the Lipid Clinic in December 1997, 4 months after the transplant. His plasma lipids at this time were: LDL-cholesterol 9.6 mmol/l, HDL-cholesterol 0.6 mmol/l, and triglyceride 5.7 mmol/l. 2007 Informa UK Ltd.
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Aristoteli, Lina Panayiota; Mler, Holger Jon; Bailey, Brian P.; Moestrup, Sen Kragh; Kritharides, LeonardBackground: CD163 is a monocyte-macrophage lineage specific scavenger receptor that mediates the uptake and clearance of haptoglobin-haemoglobin complexes, and soluble CD163 (sCD163) is also present in plasma. As atherosclerosis involves infiltration by monocyte-derived macrophages, we investigated whether sCD163 may act as a marker of coronary atherosclerosis (CAD). Methods and results: Clinical features were identified and plasma was collected from 147 consecutive patients presenting for coronary angiography. Patients were classified as having CAD+, or being free of CAD- haemodynamically significant (>50% luminal diameter) coronary stenoses in one or more major coronary arteries (1, 2 or 3 vessel disease), and sCD163 concentration was measured by ELISA. Plasma sCD163 was non-parametrically distributed, being significantly higher in CAD+ patients (median 2.47 mg/L, 25th-75th percentile, 1.79-3.5 mg/L) than in CAD- patients (2.09, 1.31-2.72 mg/L) (p = 0.021, Mann-Whitney U-test). Log sCD163 increased significantly with increasing CAD extent (p = 0.0036) and was significantly greater in patients with 3 vessel disease than in CAD- patients (p < 0.001). Whereas log sCD163 correlated with CAD extent (Spearman r = 0.22, p = 0.008), log CRP did not, and sCD163 was only weakly correlated with CRP (r = 0.19, p = 0.039). Importantly, multivariate linear regression identified that sCD163 (p = 0.0021) was a significant predictor of CAD extent and was independent of conventional risk factors age (p < 0.0001), hypercholesterolemia (p = 0.0023), hypertension (p = 0.068), and current smoking (p = 0.066). Conclusions: The monocyte-specific marker sCD163 is a novel potential plasma marker of coronary atherosclerotic burden. 2005 Elsevier Ireland Ltd. All rights reserved.
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Barter, Philip J.; Kastelein, Johannes Jacob PieterEpidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors - torcetrapib and JTT-705 - are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events. 2006 by the American College of Cardiology Foundation.
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Agon, Vanessa V.; Bubb, William A.; Wright, Adam; Hawkins, Clare L.; Davies, Michael J.Exposure of proteins to visible light in the presence of a sensitizer results in the oxidation of Met, Trp, Tyr, Cys, and His side chains. These reactions are only partially understood, particularly with His. In this study, the oxidation of free His, His derivatives, and His-containing peptides has been examined using visible light and a range of sensitizers. It is shown that photooxidation gives rise to unstable peroxides, in a light-, illumination time-, and sensitizer-dependent manner. The yield of these materials is increased when reactions are carried out in solutions prepared with D <inf>2</inf>O, which prolongs the lifetime of 1O<inf>2</inf>, and decreased in the presence of the potent 1O<inf>2</inf> scavenger azide, consistent with the involvement of this excited state. These peroxides have half-lives of hours, though the rate of decomposition is enhanced by elevated temperatures, reductants, and metal ions. Reducing metal ions catalyze the formation of radicals, which have been detected by EPR spin trapping. Structural analysis of His photo-products using NMR spectroscopy has provided evidence for the formation of oxygenated and cyclized compounds (e.g., 6a-hydroxy-2-oxo-octahydro-pyrollo[2,3-d]imidazole-5-carboxylic acid) and cross-linked materials. The latter materials may be partly responsible for the high yield of aggregated materials detected on photooxidation of His-containing proteins. 2005 Elsevier Inc. All rights reserved.
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Ji, Juying; Watts, Gerald F.; Johnson, Anthony G.; Chan, Dick C.F.; Ooi, Esther M.; Rye, Kerry Anne; Serone, Adrian Pierce; Barrett, Hugh Hugh R.Context: Reduced high density lipoprotein (HDL) concentration in the metabolic syndrome (MetS) is associated with increased risk of diabetes and cardiovascular disease and is related to defects in the kinetics of HDL apolipoprotein (apo) A-I and A-II. Objective: The objective of the study was to investigate HDL apoA-I and apoA-II kinetics in nondiabetic men with MetS and lean controls by developing a model that describes the kinetics of lipoprotein (Lp)A-I and LpA-I:A-II particles. Design: Twenty-three MetS men and 10 age-matched lean controls were investigated. ApoA-I and apoA-II tracer/tracee ratios were studied after iv d<inf>3</inf>-leucine administration using gas chromatography mass spectrometry. Results: Compared with lean subjects, MetS subjects had accelerated catabolism of LpA-I (P < 0.001), LpA-I:A-II (P = 0.005), and apoA-II (P = 0.005); the production rate of LpA-I was also significantly elevated in MetS, so that the dominant changes in plasma concentrations were reduction in LpA-I:A-II (P < 0.001) and apoA-II (P < 0.05). Increased catabolism of LpA-I and LpA-I:A-II was directly related to increased waist circumference, hypertriglyceridemia, low HDL-cholesterol, small HDL particle size, hyperinsulinemia, and low phospholipid transfer protein (PLTP) activity; overproduction of LpA-I was significantly associated with increased waist circumference, insulin resistance, and low PLTP activity. Conclusions: MetS men exhibit hypercatabolism of the two major HDL lipoprotein particles, LpA-I and LpA-I:A-II, but selective over-production of LpA-I maintains a normal plasma concentration of LpA-I. These kinetic perturbations are probably related to central obesity, insulin resistance, hypertriglyceridemia, and low plasma PLTP activity. Copyright 2006 by The Endocrine Society.
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Amoroso, Steve; Agon, Vanessa V.; Starke-Peterkovic, Thomas; McLeod, Malcolm D.; Apell, Hans Jgen; Sebban, Pierre; Clarke, Ronald JamesRH421 is a widely used voltage-sensitive fluorescent membrane probe. Its exposure to continuous illumination with 577 nm light from an Hg lamp leads, however, to an increase in its steady-state fluorescence level when bound to lipid membranes. The increase occurs on the second time scale at typical light intensities and was found to be due to a single-photon excited-state isomerization. Modifications to the dye structure are, therefore, necessary to increase photochemical stability and allow wider application of such dyes in kinetic studies of iontransporting membrane proteins. The related probe ANNINE 5, which has a rigid polycyclic structure, shows no observable photochemical reaction when bound to DMPC vesicles on irradiation with 436 nm light. The voltage sensitivity of ANNINE 5 was tested with the use of Na+,K+-ATPase membrane fragments. As long as ANNINE 5 is excited on the far red edge of its visible absorption band, it shows a similar sensitivity to RH421 in detecting charge-translocating reactions triggered by ATP phosphorylation. Unfortunately the wavelengths necessary for ANNINE 5 excitation are in a region where the Hg lamps routinely used in stopped-flow apparatus have no significant lines available for excitation. 2006 American Society for Photobiology.
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Heather, Alison Kay; McGrath, Kristine C.Y.; Handelsman, David J.Anti-convulsant treatment is associated with a high prevalence of reproductive dysfunction compared with age-matched non-epileptics. We examined the widely used anti-convulsants valproate (VPA) and carbamazepine (CBZ) for steroidal bioactivity using a yeast-based steroid receptor-?-galactosidase reporter assay for the androgen receptor (AR), progesterone receptor (PR) or estrogen receptor (ER). Bioassays were performed (a) to detect agonist activity by exposing yeast to 100 ?M CBZ or VPA or (b) to detect antagonist activity by exposing yeast stimulated with testosterone (5 10-9 M, AR), progesterone (1.6 10-9 M, PR) or estradiol (2.6 10-11 M, ER) together with either VPA or CBZ for 4 (PR) or 16 (AR, ER) hours. VPA showed dose-dependent (1-800 ?M) inhibition of progesterone-induced PR- and testosterone-induced AR activity but had no ER antagonist bioactivity and no significant PR, AR or ER agonist bioactivity. VPA also showed a dose-dependent (1-200 ?M) blockade of DHT's suppression of AR-mediated NF-?B activation in human mammalian cells. By contrast, CBZ had no significant PR, AR or ER agonist or AR and ER antagonist bioactivity but at the highest concentration tested (800 ?M) it did antagonize PR activity. We conclude that VPA is a non-steroidal antagonist for human AR and PR but not ER. VPA's androgen and progesterone antagonism at concentrations within therapeutic blood levels (350-700 ?M) seems likely to contribute to the frequency of reproductive endocrine disturbances among patients treated with VPA. 2005 Elsevier Inc. All rights reserved.
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Jahangiri, Anisa; Rader, Daniel J.; Marchadier, Dawn H.L.; Curtiss, Linda K.; Bonnet, David J.; Rye, Kerry AnneEndothelial lipase (EL) is a triglyceride lipase gene family member that has high phospholipase and low triglyceride lipase activity. The aim of this study was to determine whether the phospholipase activity of EL is sufficient to remodel HDLs into small particles and mediate the dissociation of apolipoprotein A-I (apoA-I). Spherical, reconstituted HDLs (rHDLs) containing apoA-I only [(A-I)rHDLs], apoA-II only [(A-II)rHDLs], or both apoA-I and apoA-II [(A-I/A-II) rHDLs] were prepared. The rHDLs, which contained only cholesteryl esters in their core and POPC on the surface, were incubated with EL. As the rHDLs did not contain triacylglycerol, only the POPC was hydrolyzed. Hydrolysis was greater in the (A-I/A-II)rHDLs than in the (A-I)rHDLs. The (A-II)rHDL phospholipids were not hydrolyzed by EL. EL remodeled the (A-I)rHDLs and (A-I/A-II)rHDLs, but not the (A-II)rHDLs, into smaller particles. The reduction in particle size was related to the amount of phospholipid hydrolysis, with the diameter of the (A-I/A-II)rHDLs decreasing more than that of the (A-I)rHDLs. These changes did not affect the conformation of apoA-I, and neither apoA-I nor apoA-II dissociated from the rHDLs. Comparable results were obtained when human plasma HDLs were incubated with EL. These results establish that the phospholipase activity of EL remodels plasma HDLs and rHDLs into smaller particles without mediating the dissociation of apolipoproteins. Copyright 2005 by the American Society for Biochemistry and Molecular Biology, Inc.
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Orr, Yishay; Taylor, Jude Matthew; Bannon, Paul Gerard; Geczy, Carolyn L.; Kritharides, LeonardCirculating neutrophil phenotype and function are altered during neutrophilia associated with acute inflammatory states, however, the contribution of bone marrow neutrophil release to these changes has been difficult to quantify in humans. Accelerated release of neutrophils, with potentially distinct attributes, from the bone marrow and their dilution within the circulating pool may produce these apparent changes. Unfortunately selective analysis of these newly emergent neutrophils is difficult given their morphologic similarity to those already in the circulation and the coincident effect of soluble inflammatory mediators on circulating neutrophil phenotype and function. Using whole blood flow cytometry and cardiac surgery as an inflammatory stimulus, we demonstrate the emergence of a unique subpopulation of circulating neutrophils characterised as CD10-/CD16low, indicative of active bone marrow neutrophil release peri-operatively. CD10 -/CD16low neutrophils emerge at the same operative stages as band forms and a left shift, yet represent over 40% of circulating neutrophils postoperatively, and generate a greater stimulus-induced [Ca 2+]<inf>i</inf> flux than their CD10+ counterparts. We conclude that CD10-/CD16low neutrophils represent a significant proportion of the circulating pool after cardiac surgery and that bone marrow release, a major contributor to neutrophilia, influences the phenotype and functional activity of circulating neutrophils following this acute inflammatory stimulus. 2005 Blackwell Publishing Ltd.
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Hawkins, Clare L.; Davies, Michael J.Hypobromous acid (HOBr) generated by activated eosinophils has been implicated in tissue injury observed in asthma, allergic reactions, and some infections. Proteins are major targets for this oxidant, but the mechanisms by which HOBr induces loss of function are not well-established. In this study, we have examined the effect of HOBr on protein structure (as assessed by amino acid loss, side chain oxidation, fragmentation, aggregation, and unfolding) and activity of a model protease inhibitor, soybean trypsin inhibitor (STI), and the protective enzyme lysozyme. Exposure of both proteins to low oxidant concentrations (?5-fold molar excess) results in loss of function. In each case, loss of activity is associated with the selective oxidation of His, Trp, and Tyr residues, which results in protein unfolding (with lysozyme) and protein aggregation (with STI). Reaction with these residues accounts for 25 and 50% of the HOBr with STI (25-fold excess) and lysozyme (4-fold excess), respectively. These processes are believed to lead to changes in the structure of the proteins, which disrupts substrate binding. With both proteins, the oxidation of other residues, including Met, does not appear to play a major role. Bromamines, formed by reaction with amine groups, are major products, which account for 45 and 35% of the HOBr with STI (25-fold excess) and lysozyme (4-fold excess), respectively. Decomposition of these species correlates with secondary oxidation reactions, and with lysozyme, a time-dependent loss in activity. Overall, 70% of the HOBr can be accounted for with STI and 95% with lysozyme. 2005 American Chemical Society.
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Nicholls, Stephen J.; Di Bartolo, Belinda Ann; Worthley, Stephen Grant; Kee, Patrick H.; Rye, Kerry Anne; Bao, Shishan San; Barter, Philip J.Objective - This study investigates effects of short-term administration of high-density lipoproteins (HDL) and a statin on atherosclerosis in cholesterol-fed rabbits. Effects of HDL apolipoprotein and phospholipid composition have also been investigated. Methods and Results - Aortic atherosclerosis was established over 17 weeks in 46 rabbits by balloon denudation and cholesterol feeding. During the past 5 days of the cholesterol-feeding period, animals received: (1) no treatment; (2) oral atorvastatin 5 mg/kg on each of the 5 days; or (3) infusions of HDL (8 mg/kg apolipoprotein A-I) on days 1 and 3 of the treatment phase. After euthanization, lesion size and composition were assessed by histological and immunohistochemical analysis. HDL (but not atorvastatin) reduced lesion size by 36% (P<0.05). The ratio of smooth muscle cells to macrophages in the lesions increased 2.6-fold in animals infused with HDL (P<0.05) and 4-fold in those receiving atorvastatin (P<0.01). HDL and atorvastatin reduced matrix metalloproteinase (MMP)-9 expression by 42% (P<0.05) and 45% (P<0.03), respectively. HDL increased thrombomodulin expression 2-fold (P<0.03). The beneficial effects on lesion area and plaque cellular composition were influenced by HDL phospholipid and apolipoprotein composition. Conclusion - Infusing small amounts of HDL rapidly reduces lesion size and is comparable to atorvastatin in promoting a stable plaque phenotype. 2005 American Heart Association, Inc.
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Makris, Angela; Thornton, Charlene Eliza; Xu, Bei; Hennessy, AnnemariePreeclampsia is a multisystem disorder manifest by hypertension after 20 weeks' gestation associated with end organ damage, usually proteinuria. The placenta is thought to be pivotal in the pathogenesis of the disease. Both the placenta and the maternal systemic response are characterised by heightened inflammation. Garlic has been shown to have anti-inflammatory and pro-apoptotic properties amongst others. It was hypothesised that treating placental explants with garlic may inhibit the production of inflammatory cytokines (interleukin-6 (IL-6) and tumour necrosis factor (TNF?)) and stimulate the production of anti-inflammatory cytokines (interleukin-10 (IL-10)) by the placental explants. Garlic, we hypothesised, would also stimulate apoptosis in the explants as measured by soluble TNF-related apoptosis-inducing ligand/Apo-2L (sTRAIL) production. Normal placental explants (n = 5) and explants from women who had preeclampsia (n = 4) were cultured in the presence of various garlic concentrations (10-1000 ?g/mL). The lowest garlic concentration (10 ?g/mL) increased the normal explant production of IL-10 by 29.2% (12.2, 57.5%; p < 0.01) while inhibiting the production of IL-6 by 23.5% (8.9, 32.5%; p < 0.01) (normal explants) and TNF? by 19.4% (4.5, 35.3%; p < 0.05) (preeclamptic explants). Garlic resulted in an increase in IL-10 production at lower doses (normal explants only) and inhibition of the production of IL-10 at higher doses (normal and preeclamptic explants). Garlic also resulted in a dose-dependent reduction of IL-6 and TNF?. Initially there was no change in sTRAIL production; however, at the highest garlic concentrations there was a significant increase in production. We thus conclude that garlic may have an immunomodulatory effect on normal and preeclamptic placentas. 2004 Elsevier Ltd. All rights reserved.
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Sieveking, Daniel P.; Woo, Kamsang; Fung, Kwok Pui; Lundman, Pia; Nakhla, Shirley; Celermajer, David S.Danshen (Salvia miltiorrhiza) and Gegen (Radix puerariae) are two herbs used in traditional Chinese medicine, most commonly for their putative cardioprotective and anti-atherosclerotic effects. In this study, we investigated the effect of a preparation of these herbs on two key processes in the early stages of atherosclerosis; macrophage lipid loading and monocyte adhesion to endothelial cells. Human monocyte derived macrophages (HMDMs) were treated with 0.1-1.0 mg/ml of the herbal mixture in aqueous buffers and loaded with acetylated LDL (AcLDL) (50 ?g/ml) for 72 h, and analyzed for cholesterol (C) and cholesteryl esters (CE), via HPLC. Human endothelial cell monolayers were also treated with 0.1-1.0 mg/ml of the herbal mixture and monocyte adhesion measured. Cell adhesion molecules E-selectin, ICAM-1 and VCAM-1 were assessed via ELISA. Compared to control conditions, the herbal mixture induced a significant dose-related decrease in the total cholesterol (free and esterified) in the HMDMs (p<0.001 by ANOVA). By contrast, the herbs also induced an increase in ICAM-1 expression (p<0.001) and monocyte adhesion at higher concentrations (p<0.05). In conclusion, treatment of cells with this preparation of Danshen and Gegen, a commonly used Chinese health supplement, results in a dose-related suppression of AcLDL uptake by human macrophages, and an increase in the level of ICAM-1 expression and adhesion of monocytes to endothelial cells. These herbs therefore show the ability to modulate key early events in atherosclerosis. 2005 Elsevier Ireland Ltd. All rights reserved.
