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Showing 1181–1200 of 2058 publications.
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Kitajima, Ken; Miura, Shinichiro; Yamauchi, Toshimasa; Uehara, Yoshinari; Kiya, Yoshihiro; Rye, Kerry Anne; Kadowaki, Takahashi; Saku, KeijiroA decrease in adiponectin secretion leads to the early stage of atherosclerosis. Discoidal high-density lipoproteins (HDL) accept the cholesterol that effluxes from cells expressing the ATP binding cassette transporter A1 (ABCA1) in the first step of reverse cholesterol transport (RCT). Recently, a new therapeutic strategy involving reconstituted (r)HDL has been shown to enhance RCT. Therefore, we hypothesized that adiponectin may increase the efflux associated with ABCA1 and also enhance rHDL-induced efflux in human embryonic kidney 293 (HEK293T) cells. We transfected adiponectin receptor 1 and 2 (AdipoR1 and AdipoR2) cDNA into cells. The transfected cells were labeled with [3H]cholesterol following cholesterol loading with or without adiponectin for 24h. The levels of cholesterol efflux were analyzed using a liquid scintillation counter. Treatment with adiponectin was associated with significantly higher levels of efflux in AdipoR1- and AdipoR2-transfected cells. Interestingly, rHDL-induced cholesterol efflux was enhanced in the presence of adiponectin. The down-regulation of adiponectin receptors using short-hairpin RNA decreased rHDL-induced cholesterol efflux with the down-regulation of ABCA1. In summary, adiponectin and its receptors increased cholesterol efflux and also enhanced rHDL-induced efflux at least partially through an ABCA1 pathway. These results suggest that adiponectin may enhance the RCT system and induce an anti-atherogenic effect. 2011 Elsevier Inc.
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Nicholls, Stephen J.; Borgman, Marilyn R.N.; Nissen, Steven E.; Raichlen, Joel S.; Ballantyne, Christie Mitchell; Barter, Philip J.; Chapman, Martin John; ERBEL, RAIMUND; Libby, Peter A.Background: Previous imaging studies have demonstrated that the beneficial impact of high-dose statins on the progression of coronary atherosclerosis associates with their ability to lower levels of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) and to raise high-density lipoprotein cholesterol (HDL-C). The Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus AtorvastatiN (SATURN, NCT00620542) aims to compare the effects of high-dose atorvastatin and rosuvastatin on disease progression. Methods: A total of 1385 subjects with established coronary artery disease (CAD) on angiography were randomized to receive rosuvastatin 40mg or atorvastatin 80mg for 24 months. The primary efficacy parameter will be the nominal change in percent atheroma volume (PAV), determined by analysis of intravascular ultrasound (IVUS) images of matched coronary artery segments acquired at baseline and at 24-month follow-up. The effect of statin therapy on plasma lipids and inflammatory markers, and the incidence of clinical cardiovascular events will also be assessed. The study does not have the statistical power to directly compare the treatment groups with regard to clinical events. Conclusion: Serial IVUS has emerged as a sensitive imaging modality to assess the impact of treatments on arterial structure. In this study, IVUS will be used to determine whether high-dose statins have different effects on plaque progression. 2011 Informa UK Ltd.
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Yu, Yu; Suryo Rahmanto, Yohan; Hawkins, Clare L.; Richardson, Des RaymondDi-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the iron-containing enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only N-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (p < 0.001) elevated oxidized trimeric thioredoxin levels to 213 5% (n = 3) of the control. This was most likely due to a significant (p < 0.01) decrease in thioredoxin reductase activity to 65 6% (n = 4) of the control. We were surprised to find that the non-redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 9%; n = 3) and inhibited thioredoxin reductase activity (62 5%; n = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p < 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/NADP <inf>total</inf> ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems. Copyright 2011 The American Society for Pharmacology and Experimental Therapeutics.
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Cho, Jin Gun; Witting, Paul Kenneth; Verma, Manisha; Wu, Ben Jing; Shanu, Anu; Kairaitis, Kristina; Amis, Terence C.; Wheatley, John RobertStudy Objectives: We have previously identified heavy snoring as an independent risk factor for carotid atherosclerosis. In order to explore the hypothesis that snoring-associated vibration of the carotid artery induces endothelial dysfunction (an established atherogenic precursor), we utilized an animal model to examine direct effects of peri-carotid tissue vibration on carotid artery endothelial function and structure. Design: In supine anesthetized, ventilated rabbits, the right carotid artery (RCA) was directly exposed to vibrations for 6 h (peak frequency 60 Hz, energy matched to that of induced snoring in rabbits). Similarly instrumented unvibrated rabbits served as controls. Features of OSA such as hypoxemia, large intra-pleural swings and blood pressure volatility were prevented. Carotid endothelial function was then examined: (1) biochemically by measurement of tissue cyclic guanosine monophosphate (cGMP) to acetylcholine (ACh) and sodium nitroprusside (SNP); and (2) functionally by monitoring vessel relaxation with acetylcholine in a myobath. Measurement and Results: Vessel cGMP after stimulation with ACh was reduced in vibrated RCA compared with unvibrated (control) arteries in a vibration energy dose-dependent manner. Vibrated RCA also showed decreased vasorelaxation to ACh compared with control arteries. Notably, after addition of SNP (nitric oxide donor), cGMP levels did not differ between vibrated and control arteries, thereby isolating vibration-induced dysfunction to the endothelium alone. This dysfunction occurred in the presence of a morphologically intact endothelium without increased apoptosis. Conclusions: Carotid arteries subjected to 6 h of continuous peri-carotid tissue vibration displayed endothelial dysfunction, suggesting a direct plausible mechanism linking heavy snoring to the development of carotid atherosclerosis.
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Waterhouse, Anna; Bax, Daniel V.; Wise, Steven G.; Yin, Yongbai; Dunn, Louise L.; Yeo, Giselle C.; Ng, Martin K.C.; Bilek, Marcela M.M.; Weiss, Anthony StevenPurpose: To modify blood-contacting stainless surfaces by covalently coating them with a serum-protease resistant form of tropoelastin (TE). To demonstrate that the modified TE retains an exposed, cell-adhesive C-terminus that persists in the presence of blood plasma proteases. Methods: Recombinant human TE and a point mutant variant (R515A) of TE were labeled with 125Iodine and immobilized on plasma-activated stainless steel (PAC) surfaces. Covalent attachment was confirmed using rigorous detergent washing. As kallikrein and thrombin dominate the serum degradation of tropoelastin, supraphysiological levels of these proteases were incubated with covalently bound TE and R515A, then assayed for protein levels by radioactivity detection. Persistence of the C-terminus was assessed by ELISA. Results: TE was significantly retained covalently on PAC surfaces at 88??5% and 71??5% after treatment with kallikrein and thrombin, respectively. Retention of R515A was 100??1.3% and 87??2.3% after treatment with kallikrein and thrombin, respectively, representing significant improvements over TE. The functionally important C-terminus was cleaved in wild-type TE but retained by R515A. Conclusions: Protein persists in the presence of human kallikrein and thrombin when covalently immobilized on metal substrata. R515A displays enhanced protease resistance and retains the C-terminus presenting a protein interface that is viable for blood-contacting applications. 2010 Springer Science+Business Media, LLC.
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Reimers, Gerrit J.; Jackson, Christopher Langdale; Rickards, Jasmine; Chan, Peter Y.; Cohn, Jeffrey S.; Rye, Kerry Anne; Barter, Philip J.; Rodgers, Kenneth JohnAimsPlasma concentrations of high-density lipoprotein (HDL)-cholesterol correlate inversely with the incidence of myocardial infarction in humans. We investigated the effect of treatment with human apolipoprotein A-I (apoA-I), the principal protein of HDL, on plaque disruption in an animal model.Methods and resultsSeventy apolipoprotein E knockout mice were induced to develop atherosclerotic lesions in the brachiocephalic artery by feeding a high-fat diet for 9 weeks. Mice then received twice-weekly treatment with human apoA-I (8 mg/kg) or vehicle, for 2 weeks. The incidence of acute plaque disruption was reduced by 65 in mice receiving apoA-I (P < 0.01). Plaques in treated mice had a more stable phenotype, with an increase in smooth muscle cell (SMC): macrophage ratio (P 0.05), principally the consequence of an increase in the number of SMC in plaques. In the fibrous cap, there were reductions in matrix metalloproteinase-13 (-69, P < 0.0001) and S100A4, a marker of SMC de-differentiation (-60, P < 0.0001). These results indicate that 2 weeks of treatment with small amounts of human apoA-I produces more stable plaques in a mouse model.ConclusionTreatment with apoA-I has the potential to stabilize plaques and prevent plaque rupture in humans. 2011 The Author.
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Wood, Peta; Mulay, Vishwaroop; Darabi, Masoud; Chan, Karen Cecilia; Heeren, Jrg; Pol, Albert; Lambert, Gilles; Rye, Kerry Anne; Enrich, Carlos; Grewal, ThomasThe mitogen-activated protein kinase (MAPK) Erk1/2 has been implicated to modulate the activity of nuclear receptors, including peroxisome proliferator activator receptors (PPARs) and liver X receptor, to alter the ability of cells to export cholesterol. Here, we investigated if the Ras-Raf-Mek-Erk1/2 signaling cascade could affect reverse cholesterol transport via modulation of scavenger receptor class BI (SR-BI) levels. We demonstrate that in Chinese hamster ovary (CHO) and human embryonic kidney (HEK293) cells, Mek1/2 inhibition reduces PPAR?-inducible SR-BI protein expression and activity, as judged by reduced efflux onto high density lipoprotein (HDL). Ectopic expression of constitutively active H-Ras and Mek1 increases SR-BI protein levels, which correlates with elevated PPAR? Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPAR?-depleted cells. Most strikingly, Mek1/2 inhibition promotes SR-BI degradation in SR-BI-overexpressing CHO cells and human HuH7 hepatocytes, which is associated with reduced uptake of radiolabeled and 1,1?-dioctadecyl-3,3,3?,3?-tetra-methylindocarbocyane-labeled HDL. Loss of Mek1/2 kinase activity reduces SR-BI expression in the presence of bafilomycin, an inhibitor of lysosomal degradation, indicating down-regulation of SR-BI via proteasomal pathways. In conclusion, Mek1/2 inhibition enhances the PPAR?-dependent degradation of SR-BI in hepatocytes. 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
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Cochran, Blake J.; Croucher, David R.; Lobov, Sergei A.; Saunders, Darren N.; Ranson, MarieTumor overexpression of urokinase-type plasminogen activator (uPA) and its specific inhibitor SerpinE1 (plasminogen activator inhibitor type-1) correlates with poor prognosis and increased metastatic potential. Conversely, tumor expression of uPA and another specific inhibitor, SerpinB2 (plasminogen activator inhibitor type-2), are associated with favorable outcome and relapse-free survival. It is not known how overexpression of these uPA inhibitors results in such disparate outcomes. A possible explanation may be related to the presence of a proposed low density lipoprotein receptor (LDLR)-binding motif in SerpinE1 responsible for mitogenic signaling via ERK that is absent in SerpinB2. We now show that complementation of such a LDLR-binding motif in SerpinB2 by mutagenesis of two key residues enabled high affinity binding to very LDLR (VLDLR). Furthermore, the VLDLR-binding SerpinB2 form behaved in a manner indistinguishable from SerpinE1 in terms of enhanced uPA-SerpinB2 complex endocytosis and subsequent ERK phosphorylation and cell proliferation; that is, the introduction of the LDLR-binding motif to SerpinB2 was necessary and sufficient to allow it to acquire characteristics of SerpinE1 associated with malignancy. In conclusion, this study defines the structural elements underlying the distinct interactions of SerpinE1 versus SerpinB2 with endocytic receptors and how differential VLDLR binding impacts on downstream cellular behavior. This has clear relevance to understanding the paradoxical disease outcomes associated with overexpression of these serpins in cancer. 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
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Piscitelli, Fabiana; Carta, Gianfranca; Bisogno, Tiziana; Murru, Elisabetta; Cordeddu, Lina; Berge, Kjetil; Tandy, Sally; Cohn, Jeffrey S.; Griinari, Mikko; Banni, Sebastiano; Di Marzo, VincenzoBackground: Omega-3 polyunsaturated fatty acids (-3-PUFA) are known to ameliorate several metabolic risk factors for cardiovascular disease, and an association between elevated peripheral levels of endogenous ligands of cannabinoid receptors (endocannabinoids) and the metabolic syndrome has been reported. We investigated the dose-dependent effects of dietary -3-PUFA supplementation, given as krill oil (KO), on metabolic parameters in high fat diet (HFD)-fed mice and, in parallel, on the levels, in inguinal and epididymal adipose tissue (AT), liver, gastrocnemius muscle, kidneys and heart, of: 1) the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), 2) two anandamide congeners which activate PPAR but not cannabinoid receptors, N-oleoylethanolamine and N-palmitoylethanolamine, and 3) the direct biosynthetic precursors of these compounds. Methods. Lipids were identified and quantified using liquid chromatography coupled to atmospheric pressure chemical ionization single quadrupole mass spectrometry (LC-APCI-MS) or high resolution ion trap-time of flight mass spectrometry (LC-IT-ToF-MS). Results: Eight-week HFD increased endocannabinoid levels in all tissues except the liver and epididymal AT, and KO reduced anandamide and/or 2-AG levels in all tissues but not in the liver, usually in a dose-dependent manner. Levels of endocannabinoid precursors were also generally down-regulated, indicating that KO affects levels of endocannabinoids in part by reducing the availability of their biosynthetic precursors. Usually smaller effects were found of KO on OEA and PEA levels. Conclusions: Our data suggest that KO may promote therapeutic benefit by reducing endocannabinoid precursor availability and hence endocannabinoid biosynthesis. 2011 Piscitelli et al.
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Kastrup Dalsgaard, Trine Kastrup; Nielsen, Jacob Holm; Brown, Bronwyn E.; Stadler, Nadina; Davies, Michael J.Riboflavin-mediated photo-oxidative damage to protein Tyr residues has been examined to determine whether protein structure influences competing protein oxidation pathways in single proteins and protein mixtures. EPR studies resulted in the detection of Tyr-derived o-semiquione radicals, with this species suggested to arise from oxidation of 3,4-dihydroxyphenylalanine (DOPA). The yield of this radical was lower in samples containing ?-casein than in samples containing only globular proteins. Consistent with this observation, the yield of DOPA detected on ?-casein was lower than that on two globular proteins, BSA and ?-lactoglobulin. In contrast, samples with ?-casein gave higher yields of dityrosine than samples containing BSA and ?-lactoglobulin. These results indicate that the flexible structure of ?-casein favors radical-radical termination of tyrosyl radicals to give dityrosine, whereas the less flexible structure of globular proteins decreases the propensity for tyrosyl radicals to dimerize, with this resulting in higher yields of DOPA and its secondary radical. 2011 American Chemical Society.
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Chan, Julianna Chung Ngor; Chan, Siewpheng Pheng; Deerochanawong, Chaicharn; Go, Ruby T.; Lee, Kok Onn; Ma, Ronald Ching Wan; Pan, Changyu; Sheu, Wayne Huey Herng; Barter, Philip J.Approximately 77 million persons with diabetes reside in the Western Pacific Region. This number is estimated to rise to 113 million in 2030 with increasing burden of cardio-renal disease, affecting an increasingly young population. Randomized clinical trials have confirmed the benefits of using statins to reduce low-density lipoprotein cholesterol in preventing cardiovascular disease (CVD) in Caucasians, although similar data are lacking in Asia. Experts from the Western Pacific Region met and reviewed evidence regarding risk association of diabetic dyslipidaemia with cardio-renal disease, effects of lipid lowering, recommended guidelines and clinical practices in Asian populations. There is strong evidence supporting the role of diabetic dyslipidaemia in cardio-renal disease and the benefits of lipid lowering in these populations. The high rate of diabetic kidney disease, its close links with CVD, and the benefits of lipid lowering on renal function are particularly relevant to this population. While most national guidelines use criteria similar to the West in management of diabetic dyslipidaemia, there are consistently low rates of use of lipid-lowering drugs and attaining treatment goals in the region. The group recommends conducting randomized studies, strengthening of the health care system to promote early detection, and intervention of diabetic dyslipidaemia to prevent end organ damage. 2011 Elsevier Ireland Ltd.
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Di Bartolo, Belinda Ann; Nicholls, Stephen J.; Bao, Shishan San; Rye, Kerry Anne; Heather, Alison Kay; Barter, Philip J.; Bursill, C. A.Objectives: Mimetic peptides of apolipoprotein A-I (apoA-I) present a new strategy for promoting the biological activity of high density lipoproteins (HDL). This study aimed to compare the anti-inflammatory effects of ETC-642, a new apoA-I mimetic peptide, with discoidal reconstituted HDL (rHDL). Methods: New Zealand White rabbits (n = 42) received daily infusions of saline, rHDL or discoidal complexes of an amphipathic peptide, ETC-642 (1-30. mg/kg), prior to insertion of non-occlusive carotid collars. Human coronary artery endothelial cells (HCAECs) were pre-incubated with ETC-642 or rHDL before TNF-? stimulation. Monocyte adhesion was investigated by pre-incubating HCAECs with rHDL or ETC-642, stimulating with TNF-? and incubating with THP-1 monocytes. Results: Infusion of ETC-642 resulted in dose-dependent reductions of collar-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the artery wall (p< 0.05). Pre-incubation of HCAECs with ETC-642 and rHDL reduced TNF-?-induced THP-1 monocyte adhesion (p< 0.01). Furthermore, ETC-642 and rHDL treatment reduced TNF-? induced mRNA levels of inflammatory markers VCAM-1, fractalkine, MCP-1 and the p65 subunit of NF-?B (p< 0.05). Conclusion: These studies demonstrate that ETC-642 exhibits anti-inflammatory properties that are comparable to apoA-I both in vivo and in vitro and that these effects are mediated via the NF-?B signaling pathway. 2011 Elsevier Ireland Ltd.
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Marshall, Nathaniel S.; Ayer, Julian Ganesh J.; Toelle, Brett G.; Harmer, Jason A.; Phillips, Craig L.; Grunstein, Ronald R.; Celermajer, David S.; Marks, Guy B.Aims: To study the association between childhood snoring and cardiovascular risk factors. Methods: Cross-sectional analyses of a population-based birth cohort, who had been participants in a randomised controlled trial of interventions to prevent asthma and who were assessed at age 8 years. The presence and frequency of snoring were assessed by parent-completed questionnaire. We measured a wide range of cardiovascular function markers including non-fasting serum lipoproteins, blood pressure, high-sensitivity C-reactive protein, carotid artery intima media thickness (by ultrasound), brachial pulse wave velocity and augmentation index (by applanation tonometry). Results: Of 409 children whose snoring status was assessed at age 8 years, 321 had lipid and 386 had arterial structure and function measurements. Snoring was not independently associated with blood pressure, carotid artery intima media thickness or measures of arterial stiffness (all P > 0.05). Increasing snoring frequency was independently associated with lower high-density lipoprotein cholesterol (-0.032 g/dL per step, 95% confidence interval -0.060 to -0.003), although the difference in high-density lipoprotein between snorers and non-snorers was not significant (P = 0.052). An association of snoring frequency with brachial pulse wave velocity differed according to body mass index (P = 0.03) and was the reverse of that expected. Conclusions: Parentally reported snoring was not independently associated with adverse measurements of metabolic markers, vascular structure or function in 8-year-old children. Parental reports of snoring may be below the treatment threshold without additional diagnosis via sleep studies. 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
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Barter, Philip J.; Rye, Kerry Anne; Tardif, Jean Claude; Waters, David D.; Matthijs, Boekholdt S.; Breazna, Andrei; Kastelein, Johannes Jacob PieterBackground High-density lipoproteins have antidiabetic properties in vitro. Furthermore, elevated high-density lipoprotein levels accompanying a genetic deficiency of cholesteryl ester transfer protein are associated with decreased levels of plasma glucose. We now investigate effects on glucose homeostasis of inhibiting cholesteryl ester transfer protein with torcetrapib. Methods and Results-A post hoc analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial was conducted to investigate effects of the cholesteryl ester transfer protein inhibitor torcetrapib on glycemic control in the 6661 diabetic patients in the trial. At baseline, there were no differences between the 2 treatment arms with respect to plasma glucose, insulin, hemoglobin A1c, or the homeostasis model assessment of insulin resistance. After 3 months, the diabetic subjects taking the combination of torcetrapib plus atorvastatin had plasma glucose levels 0.34 mmol/L lower (P< 0.0001) and insulin levels 11.7 ? U/mL lower (P< 0.0001) than in those receiving atorvastatin alone. Homeostasis model assessment of insulin resistance values decreased from 49.1 to 47.3 (P< 0.0001) in the torcetrapib/atorvastatin arm compared with an increase in homeostasis model assessment of insulin resistance in the atorvastatin arm. At the 6-month time point, the mean hemoglobin A1c level in the atorvastatin arm was 7.29% compared with 7.06% in the torcetrapib/atorvastatin arm (P< 0.0001). These effects of torcetrapib remained apparent for up to 12 months. Torcetrapib also lowered both glucose and insulin levels in the participants without diabetes mellitus, although the effects were not as great as in those with diabetes mellitus. Conclusions-Treatment with torcetrapib improves glycemic control in atorvastatin-treated patients with type 2 diabetes mellitus. It remains to be determined whether this effect is the consequence of raising high-density lipoprotein.at 2011 American Heart Association, Inc.
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Mai, Kelly; Smith, Nicholas C.; Feng, Zhiping; Katrib, Marilyn; Slapeta, Jan R.; lapetov Iveta; Wallach, Michael G.; Luxford, Catherine; Davies, Michael J.; Zhang, Xuecheng; Norton, Raymond S.; Belli, Sabina I.Apicomplexan parasites such as Eimeria maxima possess a resilient oocyst wall that protects them upon excretion in host faeces and in the outside world, allowing them to survive between hosts. The wall is formed from the contents of specialised organelles - wall-forming bodies - found in macrogametes of the parasites. The presence of dityrosine in the oocyst wall suggests that peroxidase-catalysed dityrosine cross-linking of tyrosine-rich proteins from wall-forming bodies forms a matrix that is a crucial component of oocyst walls. Bioinformatic analyses showed that one of these tyrosine-rich proteins, EmGAM56, is an intrinsically unstructured protein, dominated by random coil (52-70%), with some ?-helix (28-43%) but a relatively low percentage of ?-sheet (1-11%); this was confirmed by nuclear magnetic resonance and circular dichroism. Furthermore, the structural integrity of EmGAM56 under extreme temperatures and pH indicated its disordered nature. The intrinsic lack of structure in EmGAM56 could facilitate its incorporation into the oocyst wall in two ways: first, intrinsically unstructured proteins are highly susceptible to proteolysis, explaining the several differently-sized oocyst wall proteins derived from EmGAM56; and, second, its flexibility could facilitate cross-linking between these tyrosine-rich derivatives. An in vitro cross-linking assay was developed using a recombinant 42. kDa truncation of EmGAM56. Peroxides, in combination with plant or fungal peroxidases, catalysed the rapid formation of dityrosine cross-linked polymers of the truncated EmGAM56, as determined by western blotting and HPLC, confirming this protein's propensity to form dityrosine bonds. 2011 Australian Society for Parasitology Inc.
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Chen, Cheng; Cheung, Bernard Man Yung; Tso, Annette Wai Kwan; Wang, Yudong; Law, Lawrence Siu Chun; Ong, Kwok Leung; Wat, Nelson Ming Sang; Xu, Aimin; Lam, Karen Siu LingOBJECTIVE - To investigate whether circulating levels of fibroblast growth factor 21 (FGF21), which previously has been shown to be elevated in obesity, could predict the development of type 2 diabetes in a 5.4-year, population-based, prospective study. RESEARCH DESIGN AND METHODS - Baseline plasma FGF21 levels were measured using an enzyme-linked immunosorbent assay in 1,900 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). The prospective association of FGF21 with diabetes development over 5.4 years was analyzed using multiple logistic regression. RESULTS - At baseline, plasma levels of FGF21 increased progressively with worsening dysglycemia from normal glucose tolerance, through prediabetes, to diabetes (global trend, P < 0.001). Of 1,292 subjects without diabetes at baseline, a high baseline FGF21 level was a strong independent predictor for diabetes development (odds ratio 1.792; P < 0.01), together with waist circumference and fasting plasma glucose levels. CONCLUSIONS - Plasma FGF21 levels were significantly increased in subjects with prediabetes and diabetes and predicted the development of diabetes in humans. 2011 by the American Diabetes Association.
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Storkey, Corin M.; Davies, Michael J.; White, Jonathan M.L.; Schiesser, Cart H.Described is a convenient method for the syntheses of sulfur and selenium containing carbohydrate derivatives of l-gulodeoxynojirimycin and the corresponding C-5 epimer d-mannodeoxynojirimycin. The key step in the synthesis of the latter involves epimerisation of the C-5 hydroxyl group by an oxidation followed by stereo-selective reduction to obtain the desired d-sugar derivative. Both derivatives displayed a dose-dependent prevention of the oxidation of methionine residues on human plasma proteins induced by the inflammatory oxidant hypochlorous acid. The seleno-analogues were considerably more active than their thio-equivalents. The Royal Society of Chemistry 2011.
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Kennett, Eleanor C.; Chuang, Christine Y.; Degendorfer, Georg; Whitelock, John; Davies, Michael J.Considerable evidence exists for oxidative damage to extracellular materials during multiple human pathologies. Unlike cells, the extracellular compartment of most biological tissues is less well protected against oxidation than intracellular sites in terms of the presence of both antioxidants (low molecular mass and enzymatic) and repair enzymes. The extracellular compartment may therefore be subject to greater oxidative stress, marked alterations in redox balance and an accumulation of damage due to slow turnover and/or poor repair. The nature and consequences of damage to ECM (extracellular matrix) are poorly understood, despite the growing realization that changes in matrix structure not only have structural consequences, but also play a key role in the regulation of cellular adhesion, proliferation, migration and cell signalling. The ECM also plays a key role in cytokine and growth factor binding, and matrix modifications would therefore be expected to alter these parameters. In the present study, we review mechanisms of oxidative damage to ECM, resulting changes in matrix structure and how this affects cellular behaviour. The role of such damage in the development and progression of inflammatory diseases is also discussed with particular reference to cardiovascular disease. The Authors Journal compilation 2011 Biochemical Society.
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Ayer, Julian Ganesh J.; Belousova, Elena G.; Harmer, Jason A.; David, Clementine; Marks, Guy B.; Celermajer, David S.Aim s Smoking in pregnancy is common. Its effects on lipoprotein levels and arterial structure in childhood are not well characterized. We Aim ed to determine the effects of maternal smoking in pregnancy on lipoprotein levels and arterial wall thickness in healthy pre-pubertal children. Methods and resultsA community-based longitudinal study with prospective ascertainment of exposure to smoking in pregnancy and environmental tobacco smoke (ETS) since birth and then lipoprotein and arterial measurements at age 8 years. In 616 newborn infants (gestation >36 weeks and birth weight >2.5 kg) data were collected prospectively by questionnaire on smoking in pregnancy and ETS exposure in childhood. At age 8-years, 405 of the children had measurements of lipoproteins, blood pressure (BP) and carotid intima-media thickness. Children born to mothers who smoked in pregnancy had lower HDL cholesterol [1.32 vs. 1.50 mmol/L, 95 confidence interval (CI) for difference-0.28 to-0.08, P 0.0005], higher triglycerides (1.36 vs. 1.20 mmol/L, 95 CI for ratio 1.011.30, P 0.04) and higher systolic BP (102.1 vs. 99.9 mmHg, 95 CI for difference 0.63.8, P 0.006). After adjustment for maternal passive smoking, post-natal ETS exposure, gender, breast feeding duration, physical inactivity, and adiposity, smoking in pregnancy remained significantly associated with lower HDL cholesterol (difference-0.22 mmol/L, 95 CI-0.36 to-0.08, P 0.003) but not with higher systolic BP. Neither smoking in pregnancy nor post-natal ETS exposure was associated with alterations of carotid artery wall thickness.ConclusionSmoking in pregnancy is independently associated with significantly lower HDL cholesterol in healthy 8-year-old children. 2011 The Author.
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Ong, Kwok Leung; Tso, Annette Wai Kwan; Xu, Aimin; Law, Lawrence Siu Chun; Li, Mingfang; Wat, Nelson Ming Sang; Rye, Kerry Anne; Lam, Tai Hing; Cheung, Bernard Man Yung; Lam, Karen Siu LingAims/hypothesis: Hypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years. Methods: In total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not. Results: Baseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status. Conclusions/interpretation: Adiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT. 2011 The Author(s).
