Background : Oxidative stress, a key pathogenic factor in COPD, arises due to reactive oxygen species (ROS) accumulation and defective antioxidant defences in the lungs. The latter is partly due to acetylation of the antioxidant gene activator nuclear factor E2-related factor 2 (Nrf2). Bromodomain and extra-terminal (BET) proteins regulate gene transcription by binding to acetylated proteins and recruiting transcriptional regulators to gene promoters. Their role in antioxidant gene regulation is unknown. Aims & Objectives: Determine the role of BET proteins in antioxidant gene expression in human primary airway smooth muscle cells (ASMCs) and THP1 monocytic cells. Methods: BET proteins were inhibited using the selective inhibitor (+) - JQ1 [JQ1]. mRNA and protein expression was determined by real-time PCR and western blotting, respectively. Results: In ASMCs, JQ1 (50-1000nM) increased the mRNA of Nrf2-mediated antioxidants haem oxygenase (HO)-1 (∼5-fold; p Conclusions: BET proteins may augment antioxidant defences and prevent oxidative stress in addition to their known anti-inflammatory and anti-proliferative actions. They have potential as novel therapeutic targets in COPD.
No abstract is provided for this article.
DNA-binding proteins enable extracellular signals to influence cellular manufacture of substances implicated in chronic inflammation. Cross-talk between the nuclear messenger pathways subserving such regulation accounts for differences among inflammatory diseases. It also explains much of the efficacy of current therapies and may be the basis for novel, more specific approaches to treatment.
Abstract Beim mikrobiellen Abbau der Titelverbindung werden zwei Hauptprodukte, (I) und (II), sowie drei Nebenprodukte, (III), (IV) und (V), isoliert und identifiziert.
No abstract is provided for this article.
IntroductionCoronary angioplasty with stenting has revolutionized the treatment of coronary artery disease. This article describes the history of coronary angioplasty and stenting, reviews the contemporary stents and recommendations and highlights the on-going work and potential future directions.
Production of specific immunoglobulin (Ig)E is the characteristic abnormality of atopy. IgE is produced by B lymphocytes under the influence of interleukin (IL)4 and IL-13. IgE binds to high-affinity IgE receptors (Fc«RI) on mast cells to induce degranulation and mediator synthesis. IL-4 enhances the activation of Fc«RI to augment the production of cytokines and lipid mediators. These receptors may also be expressed on other cells such as basophils, monocytes and eosinophils. IgE may also activate low-affinity IgE receptors (Fc«RII or CD23) that are expressed on B lymphocytes, T lymphocytes, macrophages and airway smooth muscle cells. CD23 expression is enhanced by IL-4. Recently, a humanised murine monoclonal antibody (E25) directed against IgE has demonstrated a reduction in early and late responses to inhaled allergen and eosinophil counts in induced sputum, and reduced airway hyperresponsiveness. There is a profound reduction in circulating IgE, which may be due to switching-off IgE production from B cells. In patients with severe asthma who require oral steroids there is a significant reduction in oral steroid requirements, and several patients are able to completely withdraw oral steroids in comparison with a placebo. E25 may also reduce signalling through CD23 as IgE levels are lowered and this might explain its efficacy in chronic asthma, through an inhibitory effect on T lymphocytes, macrophages, eosinophils and airway smooth muscle.
Resveratrol has shown promising anti-inflammatory effects in airway disease models but poor pharmacokinetics and potency impede its therapeutic application. Recently, its methoxylated analogues have emerged as candidates with improved pharmacological properties. This study investigated the anti-inflammatory effects of these analogues, namely isorhapontigenin, pinostilbene and pterostilbene. A549 cells were stimulated with 1 ng/mL IL-1β and the effect on IL-6 and CXCL8 release measured using ELISA (n=4-6). Their effect on NF-κB activation was assessed using A549 cells stably transfected with NF-κB luciferase reporter gene (n=4). For IL-6 release, the IC<sub>50</sub> value of pinostilbene tended to be lower but only isorhapontigenin was significantly more potent than resveratrol. Isorhapontigenin and pterostilbene inhibited CXCL8 release with lower IC<sub>50</sub> values than resveratrol (Table 1). Resveratrol analogues, but not resveratrol, repressed NF- κB transcriptional activity (Table 1) and were more efficacious than dexamethasone which inhibited this response by ∼60% at 10 µM. This study identified analogues with superior anti-inflammatory effects than resveratrol and greater inhibition of NF-κB activity than dexamethasone. Their development as novel anti-inflammatory agents in airway inflammation is warranted.
