132 research outputs found

    Oxygen in metabolic dysfunction and its therapeutic relevance

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    Significance: In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease and cancer. Recent Advances: Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the worldwide increasing rates of metabolic disorders. In this regard, intermittent hypoxia training and hyperoxia could be potential treatments through oxygen-related adaptations. Moreover, living at high altitude may have a protective effect against the development of abnormal metabolic conditions. In addition, oxygen delivery systems may be of therapeutic value for supplying the tissue-specific oxygen requirements. Critical Issues: Precise in vivo methods to measure oxygenation are vital to disentangle some of the controversies related to this research area. Furthermore, it is evident that there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction in order to find appropriate therapeutic targets. Future directions: Based on the existing evidence, it is suggested that oxygen availability has a key role in obesity and related comorbidities. Oxygen should be considered in relation to potential therapeutic strategies in the treatment and prevention of metabolic disorders

    Dietary polyphenols as antidiabetic agents: Advances and opportunities

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    Plasmonic quantum size effects in silver nanoparticles are dominated by interfaces and local environments

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    International audienceThe physical properties of metals change when their dimensions are reduced to the nano-scale and new phenomena like the Localized Surface-Plasmon Resonance (LSPR) appear. This collective electronic excitation can be tuned over a large spectral range by adapting the material, size and shape. The existing literature is as rich as controversial as e.g. size-dependent spectral shifts of the LSPR in small metal nanoparticles, induced by quantum effects, are reported to the red, to the blue or entirely absent. Here we report how complementary experiments on mass-selected small silver nanoparticles embedded in silica can yield inconsistent results on the same system: while optical absorption shows no size-effect in the range between only a few atoms and ~10 nm, a clear spectral shift is observed in single-particle electron spectroscopy. Our quantitative interpretation, based on a mixed classical/quantum model, resolves the apparent contradictions, not only within our experimental data, but also in the literature. Our comprehensive model describes how the local environment is the crucial parameter controlling the manifestation or absence of size effects

    Impact of sleep restriction on metabolic outcomes induced by overfeeding: a randomized controlled trial in healthy individuals.

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    Overconsumption of energy-dense foods and sleep restriction are both associated with the development of metabolic and cardiovascular diseases, but their combined effects remain poorly evaluated. The aim of this study was to assess whether sleep restriction potentiates the effects of a short-term overfeeding on intrahepatocellular lipid (IHCL) concentrations and on glucose homeostasis. Ten healthy subjects were exposed to a 6-d overfeeding period (130% daily energy needs, with 15% extra energy as sucrose and 15% as fat), with normal sleep (8 h sleep opportunity time) or sleep restriction (4 h sleep opportunity time), according to a randomized, crossover design. At baseline and after intervention, IHCL concentrations were measured by proton magnetic resonance spectroscopy, and a dual intravenous [6,6-2H2]-, oral 13C-labeled glucose tolerance test and a polysomnographic recording were performed. Overfeeding significantly increased IHCL concentrations (Poverfeeding < 0.001; overfeeding + normal sleep: +53% ± 16%). During the oral glucose tolerance test, overfeeding significantly increased endogenous glucose production (Poverfeeding = 0.034) and the oxidation of 13C-labeled glucose load (Poverfeeding = 0.038). Sleep restriction significantly decreased total sleep time, and the duration of stages 1 and 2 and rapid eye movement sleep (all P < 0.001), whereas slow-wave sleep duration was preserved (Poverfeeding × sleep = 0.809). Compared with overfeeding, overfeeding + sleep restriction did not change IHCL concentrations (Poverfeeding × sleep = 0.541; +83% ± 33%), endogenous glucose production (Poverfeeding × sleep = 0.567), or exogenous glucose oxidation (Poverfeeding × sleep = 0.118). Sleep restriction did not significantly alter blood pressure, heart rate, or plasma cortisol concentrations (all Poverfeeding × sleep = NS). Six days of a high-sucrose, high-fat overfeeding diet significantly increased IHCL concentrations and increased endogenous glucose production, suggesting hepatic insulin resistance. These effects of overfeeding were not altered by sleep restriction. This trial was registered at clinicaltrials.gov as NCT02075723. Other study ID numbers: SleepDep 02/14

    Ligand Effects on Optical Properties of Small Gold Clusters: A TDDFT Study

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    A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) protein, a key member of the STAT family of signaling proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, Stat5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∌150) against STAT5, as well as against STAT3 and STAT1 proteins for SH2 domain selectivity. We herein report the identification of several potent (K i \u3c 5 ÎŒM) and STAT5 selective (\u3e3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC 50\u27s ∌ 20 ÎŒM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date. © 2011 American Chemical Society

    Glomerular and tubular function following orthotopic liver transplantation in children

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    Since its advent, cyclosporine nephrotoxicity has been a major concern to pediatricians attending to liver transplant recipients. The aims of this study were to examine glomerular and tubular function after orthotopic liver transplantation (OLT) in children, their correlation to CsA, and how they differed according to the underlying disease. Patients and methods: Glomerular and tubular function was examined in 28 patients aged 7 months to 14 yr at the time of transplantation (mean 4.0 +/- 3.6), retrospectively examining creatinine clearance, tubular phosphate reabsorption (TRP), calcium/creatinine ratio, sodium excretion fraction, and protein/creatinine ratio. The group with metabolic disease and an underlying tubulopathy was compared with the group with liver disease only. The effect of CsA trough levels and cumulated dose on these indices was examined, as was the effect of antihypertensives on creatinine clearance. Both glomerular and tubular functions improved significantly following liver transplantation. In patients on CsA (n = 21), CrCl decreased significantly at 1 month post-OLT (42.6 +/- 26.6 mL/min/1.73 m(2)) when compared with pretransplantation, and 3, 12 and 60 months post-OLT (p < 0.05). It improved between 12 and 60 months post-OLT (p < 0.05). It was correlated with cyclosporine trough levels (p < 0.03), and with total dose of CsA at 12 months. This was not true for patients on tacrolimus (n = 7). Overall pretransplant TRP was below normal (73.7% +/- 19.6), which was significantly lower than the values at years 2, 3, and 5 post-OLT (p < 0.05), owing mainly to the metabolic group which recovered normal proximal tubular function by the end of the second week post-OLT. Calcium/creatinine ratio was significantly worse in the group with liver disease only (p < 0.01). Protein/creatinine ratio normalized rapidly in both groups. Urinary sodium excretion fraction (FENa) was very abnormal in the early postoperative phase, normalizing thereafter in both groups. Kidney function improved after liver transplantation in patients with and without pre-existing kidney dysfunction. Overall, creatinine clearance was correlated to CsA trough levels suggesting CsA did not have an irreversible 'sclerosing' effect in the medium term. Combined antihypertensive therapy using nifedipine and enalapril may be the optimal choice for patients requiring medical management of their hypertension, although the observed effect on creatinine clearance did not reach statistical significance in this study. Tubular dysfunction is frequent in both groups of patients, pre- and post-transplant, and may contribute to bone mineral density as well as to metabolic disturbances in this population

    Study of hadronic events and measurements of alpha(s) between 30 and 91 GeV RID C-4549-2008 RID C-5719-2008

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    We have studied the structure of hadronic events with a hard, isolated photon in the final state (e(+)e(-) --> Z --> hadrons + gamma) in the 3.6 million hadronic events collected with the L3 detector at centre-of-mass energies around 91 GeV. The centre-of-mass energy of the hadronic system is in the range 30 GeV to 86 GeV. Event shape variables have been measured at these reduced centre-of-mass energies and have been compared with the predictions of different QCD Monte Carlo programs. The event shape variables and the energy dependence of their mean values are well reproduced by QCD models. We fit distributions of several global event shape variables to resummed O/alpha(s)(2)/calculations to determine the strong coupling constant a, over a wide range of energies. We find that the strong coupling constant alpha(s) decreases with increasing energy, as expected from QCD. (C) 1997 Elsevier Science B.V