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Showing 1061–1080 of 2058 publications.
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Kadi?ska, Maria B.; Basu, Samar; Brot, Nathan; Cooper, Christopher C.; Csallany, A. Saari; Davies, Michael J.; George, Magdalena M.; Murray, Dennis M.; Roberts, Lyman Jackson; Shigenaga, Mark K.; Sohal, Rajindar S.; Stocker, Roland; Van Thiel, David H.; Wiswedel, Ingrid; Hatch, Gary E.; Mason, Ronald PaulOzone exposure effect on free radical-catalyzed oxidation products of lipids, proteins, and DNA in the plasma and urine of rats was studied as a continuation of the international Biomarker of Oxidative Stress Study (BOSS) sponsored by NIEHS/NIH. The goal was to identify a biomarker for ozone-induced oxidative stress and to assess whether inconsistent results often reported in the literature might be due to the limitations of the available methods for measuring the various types of oxidative products. The time- and dose-dependent effects of ozone exposure on rat plasma lipid hydroperoxides, malondialdehyde, F<inf>2</inf>-isoprostanes, protein carbonyls, methionine oxidation, and tyrosine- and phenylalanine oxidation products, as well as urinary malondialdehyde and F<inf>2</inf>-isoprostanes were investigated with various techniques. The criterion used to recognize a marker in the model of ozone exposure was that a significant effect could be identified and measured in a biological fluid seen at both doses at more than one time point. No statistically significant differences between the experimental and the control groups at either ozone dose and time point studied could be identified in this study. Tissue samples were not included. Despite all the work accomplished in the BOSS study of ozone, no available product of oxidation in biological fluid has yet met the required criteria of being a biomarker. The current negative findings as a consequence of ozone exposure are of great importance, because they document that in complex systems, as the present in vivo experiment, the assays used may not provide meaningful data of ozone oxidation, especially in human studies. Published by Elsevier Inc .
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Arsenault, Beno J.; Barter, Philip J.; DeMicco, David A.; Bao, Weihang; Preston, Gregory M.; LaRosa, John C.; Grundy, Scott M.; Deedwania, Prakash ?.; Greten, Heiner; Wenger, Nanette Kass; Shepherd, James; Waters, David D.; Kastelein, Johannes Jacob Pieter[No abstract available]
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Mulay, Vishwaroop; Wood, Peta; Manetsch, Melanie; Darabi, Masoud; Cairns, Rose F.J.; Hoque, Monira; Chan, Karen Cecilia; Reverter, Meritxell; varez-Guaita, Anna; Rye, Kerry Anne; Rentero, Carles; Heeren, Jrg; Enrich, Carlos; Grewal, ThomasSignal transduction modulates expression and activity of cholesterol transporters. We recently demonstrated that the Ras/mitogen-activated protein kinase (MAPK) signaling cascade regulates protein stability of Scavenger Receptor BI (SR-BI) through Proliferator Activator Receptor (PPAR?) -dependent degradation pathways. In addition, MAPK (Mek/Erk 1/2) inhibition has been shown to influence liver X receptor (LXR) -inducible ATP Binding Cassette (ABC) transporter ABCA1 expression in macrophages. Here we investigated if Ras/MAPK signaling could alter expression and activity of ABCA1 and ABCG1 in steroidogenic and hepatic cell lines. We demonstrate that in Chinese Hamster Ovary (CHO) cells and human hepatic HuH7 cells, extracellular signal-regulated kinase 1/2 (Erk1/2) inhibition reduces PPAR?-inducible ABCA1 protein levels, while ectopic expression of constitutively active H-Ras, K-Ras and MAPK/Erk kinase 1 (Mek1) increases ABCA1 protein expression, respectively. Furthermore, Mek1/2 inhibitors reduce ABCG1 protein levels in ABCG1 overexpressing CHO cells (CHO-ABCG1) and human embryonic kidney 293 (HEK293) cells treated with LXR agonist. This correlates with Mek1/2 inhibition reducing ABCG1 cell surface expression and decreasing cholesterol efflux onto High Density Lipoproteins (HDL). Real Time reverse transcriptase polymerase chain reaction (RT-PCR) and protein turnover studies reveal that Mek1/2 inhibitors do not target transcriptional regulation of ABCA1 and ABCG1, but promote ABCA1 and ABCG1 protein degradation in HuH7 and CHO cells, respectively. In line with published data from mouse macrophages, blocking Mek1/2 activity upregulates ABCA1 and ABCG1 protein levels in human THP1 macrophages, indicating opposite roles for the Ras/MAPK pathway in the regulation of ABC transporter activity in macrophages compared to steroidogenic and hepatic cell types. In summary, this study suggests that Ras/MAPK signaling modulates PPAR?- and LXR-dependent protein degradation pathways in a cell-specific manner to regulate the expression levels of ABCA1 and ABCG1 transporters. 2013 Mulay et al.
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Karlson, Bjn Wilgot; Nicholls, Stephen J.; Lundman, Pia; Palmer, Mike K.; Barter, Philip J.Objective: Guidelines published in 2011 by the European Atherosclerosis Society and the European Society of Cardiology recommend a goal of either low-density lipoprotein cholesterol (LDL-C) <70 mg/dl (?1.8 mmol/l) or ?50% reduction in LDL-C for patients at very high cardiovascular risk. The aim of this study was to determine the percentage of high-risk patients from the VOYAGER individual patient data meta-analysis treated with rosuvastatin 10-40 mg, atorvastatin 10-80 mg or simvastatin 10-80 mg who achieved this goal. Methods: We analysed 25,075 patient exposures from high-risk patients. Paired comparisons were made between each rosuvastatin dose and an equal or higher dose of either atorvastatin or simvastatin, with a series of meta-analyses that included only randomised studies that directly compared rosuvastatin and its comparator treatments. Results: As statin dose increased, higher percentages of patients achieved LDL-C <70 mg/dl or ?50% LDL-C reduction. A greater percentage achieved this goal with rosuvastatin 10-40 mg (43.8-79.0%) than with equal or double milligram doses of atorvastatin (16.1-65.2%) or simvastatin (0-39.7%).Paired comparisons showed statistically significant differences for: rosuvastatin 10 mg vs. atorvastatin 10-20 mg and simvastatin 10-20 mg; rosuvastatin 20 mg vs. atorvastatin 20-40 mg and simvastatin 20-80 mg; and rosuvastatin 40 mg vs. atorvastatin 40-80 mg and simvastatin 40-80 mg (all p < 0.001). Conclusion: These data from VOYAGER highlight the importance of an effective statin at an appropriate dose to achieve treatment goals for LDL-C in patients with very high cardiovascular risk. 2013 Elsevier Ireland Ltd.
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Lau, Edmund M.T.; Morgan, Philip E.; Belousova, Elena G.; Toelle, Brett G.; Ayer, Julian Ganesh J.; Celermajer, David S.; Marks, Guy B.[No abstract available]
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Thompson, Peter LindsayWhile the Australian National Health and Medical Research Council guideline document of 2009 on reducing health risks from drinking alcohol provided sensible advice for public policy on alcohol, it appeared to dismiss the cardiovascular benefits of low to moderate consumption. Undue prominence was given to a hypothesis from a single research group that the well documented J-curve relationship of lower risk of ischaemic heart disease events with low to moderate intake alcohol consumption may have been due to a misclassification of drinking patterns. The misclassification hypothesis suggested that the higher risks among abstainers may have been due to the inclusion of high-risk subjects who had become abstainers later in life. Recent studies have separated recent abstainers from lifetime abstainers and the misclassification hypothesis has not been confirmed as an explanation for the J-shaped curve. The J-shaped relationship between alcohol consumption and cardiovascular risk has been studied and confirmed in multiple studies; while it complicates the formulation of public policy on alcohol consumption, it cannot be dismissed.
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Dunn, Louise L.; Prosser, Hamish C.G.; Tan, Joanne Tsui Ming; Vanags, Laura Z.; Ng, Martin K.C.; Bursill, C. A.Wound healing and repair are the most complex biological processes that occur in human life. After injury, multiple biological pathways become activated. Impaired wound healing, which occurs in diabetic patients for example, can lead to severe unfavorable outcomes such as amputation. There is, therefore, an increasing impetus to develop novel agents that promote wound repair. The testing of these has been limited to large animal models such as swine, which are often impractical. Mice represent the ideal preclinical model, as they are economical and amenable to genetic manipulation, which allows for mechanistic investigation. However, wound healing in a mouse is fundamentally different to that of humans as it primarily occurs via contraction. Our murine model overcomes this by incorporating a splint around the wound. By splinting the wound, the repair process is then dependent on epithelialization, cellular proliferation and angiogenesis, which closely mirror the biological processes of human wound healing. Whilst requiring consistency and care, this murine model does not involve complicated surgical techniques and allows for the robust testing of promising agents that may, for example, promote angiogenesis or inhibit inflammation. Furthermore, each mouse acts as its own control as two wounds are prepared, enabling the application of both the test compound and the vehicle control on the same animal. In conclusion, we demonstrate a practical, easy-to-learn, and robust model of wound healing, which is comparable to that of humans. 2013 Journal of Visualized Experiments.
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Lim, Hwee Ying; Thiam, Chung Hwee; Yeo, Kim Pin; Bisoendial, Radjesh J.; Hii, Chung Shii; McGrath, Kristine C.Y.; Tan, Karwai; Heather, Alison Kay; Alexander, Jonathan Steven; Angi, VoniqueRemoval of cholesterol from peripheral tissues to the bloodstream via reverse cholesterol transport (RCT) is a process of major biological importance. Here we demonstrate that lymphatic drainage is required for RCT. We have previously shown that hypercholesterolemia in mice is associated with impaired lymphatic drainage and increased lipid accumulation in peripheral tissues. We now show that restoration of lymphatic drainage in these mice significantly improves cholesterol clearance. Conversely, obstruction of lymphatic vessels in wild-type mice significantly impairs RCT. Finally, we demonstrate using silencing RNA interference, neutralizing antibody, and transgenic mice that removal of cholesterol by lymphatic vessels is dependent on the uptake and transcytosis of HDL by scavenger receptor class B type I expressed on lymphatic endothelium. Collectively, this study challenges the current view that lymphatic endothelium is a passive exchange barrier for cholesterol transport and provides further evidence for its interplay with lipid biology in health and disease. 2013 Elsevier Inc.
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Morgan, Philip E.; Sheahan, Pamela J.; Pattison, David I.; Davies, Michael J.Inadequate control of plasma and cellular glucose and ketone levels in diabetes is associated with increased generation of reactive aldehydes, including methylglyoxal (MGO). These aldehydes react with protein side chains to form advanced glycation end-products (AGEs). Arg residues are particularly susceptible to MGO glycation and are essential for binding NADP+ in several enzymes that generate NADPH, a coenzyme for many critical metabolic and antioxidant enzymes. In most animal cells, NADPH is produced predominantly by glucose-6-phosphate dehydrogenase (G6PD) in the oxidative phase of the pentose phosphate pathway and, to a lesser extent, by isocitrate dehydrogenase (IDH) and malic enzyme (ME). In this study, the activities of isolated G6PD, IDH, and ME were inhibited by MGO (0-2.5 mM, 2-3 h, 37 C), in a dose- and time-dependent manner, with G6PD and IDH more sensitive to modification than ME. Significant inhibition of these two enzymes occurred with MGO levels ?500 ?M. Incubation with radiolabeled MGO (0-500 ?M, 0-3 h, 37 C) demonstrated dose- and time-dependent adduction to G6PD and IDH. HPLC analysis provided evidence for AGE formation and particularly the hydroimidazolones MG-H1 and MG-H2 from Arg residues, with corresponding loss of parent Arg residues. Peptide mass mapping studies confirmed hydroimidazolone formation on multiple peptides in G6PD and IDH, including those critical for NADP+ binding, and substrate binding, in the case of IDH. These results suggest that modification of NADPH-producing enzymes by reactive aldehydes may result in alterations to the cellular redox environment, potentially predisposing cells to further damage by oxidants and reactive aldehydes. 2013 Elsevier Inc.
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Hirsh, Stacey L.; Bilek, Marcela M.M.; Bax, Daniel V.; Kondyurin, Alexey V.; Kosobrodova, Elena A.; Tsoutas, Kostadinos; Tran, Clara T.H.; Waterhouse, Anna; Yin, Yongbai; Nosworthy, Neil J.; McKenzie, David R.; Dos Remedios, Cris G.D.; Ng, Martin K.C.; Weiss, Anthony StevenProtein immobilization through the use of direct radical induced covalent coupling is described. Ions implanted in a polymer surface generate a highly cross-linked surface layer that is rich in radicals. These radicals can diffuse to the surface and covalently immobilize physically adsorbed proteins, as illustrated in a kinetic model for the covalent attachment process. Radical induced covalent coupling provides rapid covalent attachment, while also retaining native protein conformation and enabling control over the composition of the adsorbed protein layer when adsorbed from a protein mixture. Advantages of using this method for improving the biocompatibility of implanted biomedical devices and for immobilizing antibodies in protein microarrays for disease diagnosis and early detection are highlighted. 2013 AIP Publishing LLC.
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Thompson, Peter Lindsay[No abstract available]
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Brown, Bronwyn E.; Nobourt, Estelle; Zeng, Jingmin; Jenkins, Alicia J.; Rye, Kerry Anne; Davies, Michael J.Increased protein glycation in people with diabetes may promote atherosclerosis. This study examined the effects of non-enzymatic glycation on the association of lipid-free apolipoproteinA-I (apoA-I) with phospholipid, and cholesterol efflux from lipid-loaded macrophages to lipid-free and lipid-associated apoA-I. Glycation of lipid-free apoA-I by methylglyoxal and glycolaldehyde resulted in Arg, Lys and Trp loss, advanced glycation end-product formation and protein cross-linking. The association of apoA-I glycated by glucose, methylglyoxal or glycolaldehyde with phospholipid multilamellar vesicles was impaired in a glycating agent dose-dependent manner, with exposure of apoA-I to both 30 mM glucose (42% decrease in k<inf>slow</inf>) and 3 mM glycolaldehyde (50% decrease in k<inf>fast</inf>, 60% decrease in k<inf>slow</inf>) resulting is significantly reduced affinity. Cholesterol efflux to control or glycated lipid-free apoA-I, or discoidal reconstituted HDL containing glycated apoA-I (drHDL), was examined using cholesterol-loaded murine (J774A.1) macrophages treated to increase expression of ATP binding cassette transporters A1 (ABCA1) or G1 (ABCG1). Cholesterol efflux from J774A.1 macrophages to glycated lipid-free apoA-I via ABCA1 or glycated drHDL via an ABCG1-dependent mechanism was unaltered, as was efflux to minimally modified apoA-I from people with Type 1 diabetes, or controls. Changes to protein structure and function were prevented by the reactive carbonyl scavenger aminoguanidine. Overall these studies demonstrate that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages. 2013 Brown et al.
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Graham, Garry G.; Davies, Michael J.; Day, Richard Osborne; Mohamudally, Anthoulla; Scott, Kieran F.Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA. 2013 Springer Basel.
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Ong, Kwok Leung; Allison, Matthew A.; Cheung, Bernard Man Yung; Wu, Ben Jing; Barter, Philip J.; Rye, Kerry AnneC-reactive protein (CRP) is a well-known biomarker of systemic inflammation and cardiovascular disease. We investigated the trends in prevalence of elevated CRP levels (>3.0 mg/L) in a general population of US adults. Data from 27,214 subjects aged ?20 years in the 1999-2010 National Health and Nutrition Examination Survey were analyzed. After adjustment for age, sex, race/ethnicity, body mass index (weight (kg)/height (m)2), and medications for lowering blood pressure, glucose, and lipids, the prevalence of elevated CRP decreased significantly from 36.7% in 1999-2002 to 32.0% in 2007-2010, corresponding to a decrease in mean CRP level from 1.92 to 1.66 mg/L (both P < 0.001). The trend remained significant after additional adjustment for several traditional cardiovascular risk factors and use of different medications, including statins. However, the decreasing trends were attenuated after additional adjustment for total bilirubin (P = 0.08 and 0.02), which increased from 0.62 to 0.73 mg/dL over 12 years (P < 0.001). The decreasing trend of CRP levels is encouraging and may be related to the increase in total bilirubin levels. Such trends may be explained in part by the increasing use of medications such as statins, which can increase bilirubin levels and decrease CRP levels. 2013 The Author.
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Puri, Rishi; Nissen, Steven E.; Ballantyne, Christie Mitchell; Barter, Philip J.; Chapman, Martin John; ERBEL, RAIMUND; Libby, Peter A.; Raichlen, Joel S.; St John, Julie; Wolski, Kathy E.; Uno, Kiyoko; Kataoka, Yu; Nicholls, Stephen J.AimsStatins can inhibit the progression of coronary atherosclerosis. We aimed to characterize clinical factors that associate with differing measures of coronary atheroma volume following potent statin therapy.Methods and resultsSATURN employed serial intravascular ultrasound (IVUS) to monitor changes in measures of coronary atheroma burden [total atheroma volume (TAV) and per cent atheroma volume (PAV)] in 1039 patients with coronary artery disease, treated with rosuvastatin (40 mg) or atorvastatin (80 mg) daily for 24 months. Rosuvastatin-treated patients demonstrated greater reductions in low-density lipoprotein cholesterol (LDL-C, 47 vs. 40%, P < 0.001) and greater increases in high-density lipoprotein cholesterol (HDL-C, 13 vs. 10%, P = 0.02). These alterations in the lipid profile associated with greater TAV (-6.4 vs.-4.4 mm3, P = 0.01), but not PAV (-1.22 vs.-0.99%, P = 0.17) regression. Greater TAV reductions with rosuvastatin vs. atorvastatin occurred in patients with diabetes (P = 0.01, treatment by diabetic status interaction P-value 0.05). Greater PAV reductions with rosuvastatin were evident in females (P = 0.01, treatment by sex interaction P-value 0.03) and in those with greater than or equal to median baseline LDL-C (P = 0.02, treatment by LDL-C group interaction P-value 0.03) or HDL-C levels (P = 0.02, treatment by HDL-C group interaction P-value 0.04). On multivariable analysis assessing change in TAV and PAV, both higher baseline TAV and PAV independently associated with TAV and PAV regression, respectively (standardized estimates: TAV-0.25, P < 0.001; PAV-0.23, P < 0.001).ConclusionHigher-risk patients, particularly those with greater baseline coronary atheroma volume, are more likely to experience less disease progression with potent statin therapy. 2013 Author(s).
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Santner-Nanan, Brigitte; Straubinger, Kathrin; Hsu, Peter S.; Parnell, Grant Peter; Tang, Benjamin M.P.; Xu, Bei; Makris, Angela; Hennessy, Annemarie; Peek, Michael J.; Busch, Dirk H.; Prazeres Da Costa, Clarissa U.; Nanan, Ralph Kay HeinrichTransplacental immune regulation refers to the concept that during pregnancy, significant cross-talk occurs between the maternal and fetal immune system with potential long-term effects for both the mother and child. In this study, we made the surprising observation that there is a strong correlation of peripheral blood regulatory T (Treg) cells between the mother and the fetus. In contrast, there is no significant Treg cell correlation between paternal fetal dyads (pairs), suggesting that the specific context of pregnancy, rather than the genetic parental similarity to the fetus, is responsible for this correlation. Gene microarray analysis of Treg cells identified a typical IL-10-dependent signature in maternal and fetal Treg cells. In addition, a direct correlation of serum IL-10 protein levels between maternal fetal dyads was observed. Furthermore, we show that maternal serum IL-10 levels correlate with serum estradiol and estriol, implicating hormonal involvement in this alignment. Interestingly, we show that Treg cells possess higher expression of IL-10 receptor ? and that Treg cell IL-10 receptor a expression directly correlates with their Bcl-2 expression. Indeed, in vitro data in both humans and mice demonstrate that IL-10 upregulates Bcl-2 specifically in Treg cells but not non-Treg cells. Our results provide evidence for transplacental regulation of cellular immunity and suggest that IL-10 may influence Treg cell homeostasis through its effect on Treg cell Bcl-2 expression. These novel findings have important implications on immune tolerance in pregnancy and beyond in areas of autoimmunity, allergy, and transplantation. Copyright 2013 by The American Association of Immunologists, Inc.
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Thompson, Peter LindsayPURPOSE OF REVIEW: This review will assess whether the 25-year-old evidence base to support routine prescribing of ?-blockers after myocardial infarction (MI) is relevant to modern management. RECENT FINDINGS: The evidence base to support the recommendation for the widespread use of ?-blockers after MI was near-finalized in the mid-1980s. Whereas the use of intravenous ?-blockers is waning, the routine use of oral ?-blockers after MI is still regarded as evidence based. In the past 25 years, the introduction of coronary reperfusion and of effective nonreperfusion therapies has changed the natural history of MI and there have been substantial changes in the definition of MI. The relevance of old clinical trial data collected in patients who bear little resemblance to today's MI patients is questioned. Recent analyses have shown that there is no convincing evidence for the use of ?-blockers as first-line therapy in hypertension or in patients with stable coronary heart disease. In contrast, the evidence base for the use of ?-blockers in heart failure is strong and contemporary. SUMMARY: A rational recommendation for the modern treatment of MI would be to limit the use of ?-blockers in the post-MI patient to higher-risk patients with evidence of ongoing ischemia, heart failure, or left ventricular dysfunction. There is no evidence to support the routine use of oral ?-blockers in low-risk MI patients. 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.
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Yu, Young; Gray, Belinda R.; Lowe, Harry Claude; Halmagyi, Michael G.; Ng, Martin K.C.[No abstract available]
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Naser, Nadim; Januszewski, Andrzej S.; Brown, Bronwyn E.; Jenkins, Alicia J.; Hill, Michael A.; Murphy, Timothy V.Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs) are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca2++] and Ca2++ signaling, the aim of this study was to examine the acute effects of AGEs on Ca2++ signaling in bovine aortic endothelial cells (BAEC). Ca2++ signaling was studied using the fluorescent indicator dye Fura-2-AM. AGEs were generated by incubating bovine serum albumin with 0-250 mM glucose or glucose-6-phosphate for 0-120 days at 37C. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML) as assayed using both gas-liquid chromatograph-mass spectroscopy and high-performance liquid chromatography. In Ca2++-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2++] and attenuated the increase in intracellular [Ca2++] caused by ATP (100 ?M). In the absence of extracellular Ca2++, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2++] and attenuated subsequent intracellular Ca2++ release caused by ATP, thapsigargin (0.1 ?M), and ionomycin (3 ?M), but AGEs did not affect extracellular Ca2++ entry induced by the re-addition of Ca2++ to the bathing solution in the presence of any of these agents. The anti-oxidant a-lipoic acid (2 ?M) and NAD(P)H oxidase inhibitors apocynin (500 ?M) and diphenyleneiodonium (1 ?M) abolished these effects of AGEs on BAECs, as did the IP<inf>3</inf> receptor antagonist xestospongin C (1 ?M). In summary, AGEs caused an acute depletion of Ca2++ from the intracellular store in BAECs, such that the Ca2++ signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of reactive oxygen species from NAD(P)H oxidase and possible activation of the IP<inf>3</inf> receptor. 2013 Naser, Januszewski, Brown, Jenkins, Hill andMurphy.
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Li, Xiaohong; McGrath, Kristine C.Y.; Tran, Van Hoan; Li, Yiming; Duke, Colin Charles; Roufogalis, Basil D.; Heather, Alison KayIntroduction. Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S-[6]-Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor B (NFB) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S-[6]-gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1? to establish an in vitro hepatic inflammatory model. Results. S-[6]-Gingerol attenuated IL1?-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S-[6]-gingerol reduced IL1?-induced COX2 upregulation as well as NFB activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NFB inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1?-induced overexpression of COX2. Of particular note, the protective effect of S-[6]-gingerol against the IL1?-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1?-induced inflammatory insults through inhibition of the ROS/NFB/COX2 pathway. 2013 Xiao-Hong Li et al.
