563 research outputs found

    The NR4A subgroup: immediate early response genes with pleiotropic physiological roles

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    The nuclear hormone receptor (NR) superfamily includes the orphan NR4A subgroup, comprised of Nur77 (NR4A1), Nurr1 (NR4A2) and NOR-1 (NR4A3). These NRs are classified as early response genes, are induced by a diverse range of signals, including fatty acids, stress, growth factors, cytokines, peptide hormones, phorbol esters, neurotransmitters, and physical stimuli (for example magnetic fields, shear stress). The ability to sense and rapidly respond to changes in the cellular environment thus appears to be a hallmark of this subfamily. The members of the NR4A subgroup are well conserved in the DNA binding domain (~91-95%) and the C-terminal ligand-binding domain (~60%), but are divergent in the N-terminal AB region. These receptors bind as monomers, homodimers and heterodimers with RXRs (to mediate retinoid signaling) to different permutations of the canonical NR binding motif. The NR4A subgroup activates gene expression in a constitutive ligand-independent manner. NR4A-mediated trans-activation (LBD) involves unusually active N-terminal AF-1 domains that mediate coactivator recruitment. Moreover, the NR4A receptors encode atypical LBDs and AF-2 domains. For example, the LBDs contain no cavity due to bulky hydrophobic residue side chains, and lack the classical coactivator-binding cleft constituted by helices 3, 4 and 12. However, a hydrophobic patch exists between helices 11 and 12, that encodes a novel cofactor interface that modulates transcriptional activity. In line with the pleiotropic physiological stimuli that induce the NR4A subgroup, these orphan NRs have been implicated in cell cycle regulation (and apoptosis), neurological disease, steroidogenesis, inflammation, carcinogenesis and atherogenesis

    The association between secondhand smoke and the risk of developing acute coronary syndromes, among non-smokers, under the presence of several cardiovascular risk factors: The CARDIO2000 case-control study

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    BACKGROUND: The purpose of this study was to investigate the association between secondhand smoke and the risk of developing a first event of acute coronary syndromes (ACS), i.e. acute myocardial infarction or unstable angina, among non-smokers, in relation to the presence of several other cardiovascular risk factors. METHODS: Eight hundred and forty-eight patients with first event of ACS and 1078 cardiovascular disease-free matched controls completed a detailed questionnaire regarding their exposure to secondhand smoke, among other investigated parameters. RESULTS: Two hundred and ninety–seven (35%) of the patients and 259 (24%) of the controls were defined as secondhand smokers. After controlling for several potential confounders, the results showed that non-smokers occasionally (< 3 time per week) exposed to cigarette smoke were associated with 26% higher risk of ACS (OR = 1.26, P-value < 0.01) compared to non-smokers not exposed to smoke, while regular exposure is associated with 99% higher risk of developing ACS (OR = 1.99, P-value < 0.001). Moreover, the previous risk increases progressively from 15% to 256% if one or more of the classical cardiovascular risk factors (i.e. hypertension, hypercholesterolemia, diabetes mellitus, sedentary life and family history of premature coronary heart disease) are present. CONCLUSIONS: Consequently, this study supports the hypothesis that even occasional secondhand smoke increases the risk of developing acute coronary syndromes, especially when other risk factors are present. Given the high prevalence of cigarette smoking, the public health consequences of passive smoking with regard to coronary heart disease are important

    Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle

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    Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Ror alpha (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet-induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) alpha action in skeletal muscle was involved in the regulation of glucose metabolism
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