Antisense antiinflammatory

No abstract text is available yet for this article.

New England Journal of Medicine, Volume 372, Issue 25, Page 2461-2461, June 2015.

BACKGROUND: Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease. METHODS AND RESULTS: Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice)...

MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the "antiinflammatory" response of LPS-activated RA FLS...

OBJECTIVE: Suppressors of cytokine signaling (SOCS) proteins are intracellular regulators of receptor signal transduction, mainly Janus kinase/signal transducers and activators of transcription (JAK/STAT). We investigated the effects of SOCS modulation on the JAK/STAT-dependent responses in vascular cells, and their implication in atherosclerotic plaque development. METHODS AND RESULTS: Immunohistochemistry in human plaques revealed a high expression of SOCS1 and SOCS3 by vascular smooth muscle cells (VSMCs) and macrophages in the inflammatory region of the shoulders, when compared to the fibrous area...

Monocyte chemoattractant protein-1 (MCP-1) directs migration of blood monocytes to inflamed tissues. Despite the central role of chemotaxis in immune responses, the regulation of chemotaxis by signal transduction pathways and their in vivo significance remain to be thoroughly deciphered. In this study, we examined the intracellular location and functions of two recently identified regulators of chemotaxis, Ca(2+)-independent phospholipase (iPLA(2)beta) and cytosolic phospholipase (cPLA(2)alpha), and substantiate their in vivo importance...

Crohn's disease (CD) and ulcerative colitis (UC) are the two most common forms of chronic inflammatory bowel disease (IBD). The etiology of IBD is still unclear and should be considered as multi-factorial according to recent studies. Genetic factors seem to play a pathogenetic role as well as environmental, infectious and immulogical factors. Substantial progress, however, has been made in the understanding of the pathogenesis of IBD during the past years persuing the view, that IBD could result from disturbances of the intestinal barrier and a pathologic activation of the intestinal immune response towards luminal, bacterial antigens...

New brief reports this month include: Strategies for Duchenne Muscular Dystrophy: Various approaches are being explored to abate the dystrophic process including cellular therapies (transplanting stem cells or myogenic precursors into muscles), molecular approaches (delivering a functional or correcting the mutant dystrophin gene), such as MyoDys, Biostrophin(R) and antisense technology, and pharmacotherapeutics, which include calcium channel blockers, calpain inhibitors, phosphodiesterase inhibitors and monoclonal antibodies; Immunotherapy for Multiple Myeloma: Increasing numbers of antibodies and immunoconjugates with anticancer drugs are entering clinical development; Acute respiratory distress syndrome is among the most frequent reasons for intensive care...

Overproduction of interleukin-1 within the brain is associated with Alzheimer's disease and other neurological conditions. We report that peripheral administration of the acetylcholinesterase inhibitors tacrine, rivastigmine, neostigmine, or EN101 (an antisense oligonucleotide directed at acetylcholinesterase messenger RNA) to mice significantly attenuated the production of interleukin-1beta in the hippocampus and blood, concomitantly with the reduction in acetylcholinesterase activity. These findings demonstrate that cholinergic enhancement produces central and peripheral antiinflammatory effects and suggest a novel therapeutic mechanism for acetylcholinesterase inhibitors...

OBJECTIVE: Prostaglandin E synthases (PGESs) are being explored as antiinflammatory drug targets as alternatives to cyclooxygenase (COX)-2. Located downstream of the cyclooxygenases, PGESs catalyze PGE(2) formation, and deletion of microsomal (m)-PGES-1 abrogates inflammation. We sought to characterize the developmental expression of COX and PGES in zebrafish. METHODS AND RESULTS: We cloned zebrafish cytosolic (c) and m-PGES orthologs and mapped them to syntenic regions of chromosomes 23 and 5...

The p38 mitogen-activated protein kinase (MAPK) plays a critical role in the activation of inflammatory cells. Therefore, we investigated the antiinflammatory effects of a respirable p38alpha MAPK antisense oligonucleotide (p38alpha-ASO) in a mouse asthma model. A potent and selective p38alpha-ASO was characterized in vitro. Inhalation of aerosolized p38alpha-ASO using an aerosol chamber dosing system produced measurable lung deposition of ASO and significant reduction of ovalbumin (OVA-)-induced increases in total cells, eosinophils, and interleukin 4 (IL-4), IL-5, and IL-13 levels in bronchoalveolar lavage fluid, and dose-dependent inhibition of airway hyperresponsiveness in allergen-challenged mice...

The use of drugeluting stents (DES) has tackled the "Achilles' heel" of percutaneous coronary interventions (PCI) like no innovation before: the restenosis following initially successful PCI of de novo stenoses. Today, with DES, the pivotal clinical parameter TVF (target vessel failure) is in the upper single- digit range for "standard" lesions and 16% for long lesions. Numerous studies have assessed the effects of various antiproliferative and antiinflammatory substances, like Sirolimus, Tacrolimus, Everolimus, ABT-578, Biolimus, Paclitaxel, QP2 as well as of other drugs, like Dexamethasone, 17-beta-Estradiol, Batimastat, Actinomycin-D, Methotrexat, Angiopeptin, Tyrosinkinase inhibitors, Vincristin, Mitomycin, Cyclosporin, and also the C-myc antisense technology (Resten-NG, AVI-4126)...

The potential therapeutic applications of the antisense strategy are illustrated by numerous examples of the oligonucleotides investigated in preclinical and clinical trials especially for antiviral, antiinflammatory, anticancer and antiatherosclerotic activity. The main advantages of the antisense oligonucleotides therapeutic candidates are comparatively discussed with the classical drugs.

Bronchial asthma is a chronic inflammatory disorder of the airways. Currently available antiinflammatory treatments, represented by inhaled corticosteroids (ICS), are highly effective in controlling symptoms in the majority of patients, but their potential side effects have led to the use of adjunctive or alternative therapies and to the development of new therapies. Most of these new agents are aimed at inhibiting various components of allergic inflammation, with better safety profiles than ICS. They include inhibitors of phosphodiesterase 4, cytokine modulators, chemokine receptor antagonists and antisense oligonucleotides...

Ulcerative colitis (UC) and Crohn's disease (CD) comprise a series of inflammatory bowel disease (IBD) resulting from chronic upregulation of the mucosal immune system. Although the pathogenesis of IBD remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of antiinflammatory agents, aminosalicylates and corticosteroids. However, some patients are still refractory to these therapies...

BACKGROUND: Local anesthetics have been shown to selectively inhibit functioning of Xenopus laevis Gq proteins. It is not known whether a similar interaction exists with mammalian G proteins. The goal of this study was to determine whether mammalian Gq protein is inhibited by local anesthetics. METHODS: In Xenopus oocytes, the authors replaced endogenous Gq protein with mouse Gq (expressed in Sf9 cells using baculovirus vectors). Cells endogenously expressing lysophosphatidic acid or recombinantly expressing muscarinic m3 receptors were injected with phosphorothioate DNA antisense (or sense as control) oligonucleotides against Xenopus Gq...

The atrial natriuretic peptide (ANP) is a cardiovascular hormone possessing antiinflammatory potential due to its inhibitory action on the production of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha). The aim of this study was to determine whether ANP is able to attenuate inflammatory effects of TNF-alpha on target cells. Human umbilical vein endothelial cells (HUVECs) were treated with TNF-alpha in the presence or absence of ANP. Changes in permeability, cytoskeletal alterations, phosphorylation of p38 MAPK and HSP27, and expression of MKP-1 were determined by macromolecule permeability assay, fluorescence labeling, RT-PCR, and immunoblotting...

There is strong evidence that nonsteroidal antiinflammatory drug (NSAID) sulindac may exert a significant antineoplastic effect. The purpose of our study was to explore the effects of sulindac on human oral squamous cell carcinoma (SCCa) cells and to elucidate the underlying molecular mechanisms. The changes that sulindac treatment induced on growth, apoptosis and cell cycle distribution of human oral SCCa cell lines were assessed by cell growth and flow cytometry experiments. Utilizing quantitative RT-PCR and immunocytochemistry, we determined the effect of sulindac treatment on mRNA and protein expression of different sulindac's targets...

Alzheimer's disease is the most common cause of memory disruption in elderly people. The main pathogenic factor of the disease is beta-amyloid protein, which may cause toxic damage of neurones. Other suggested pathogenic factors include an inflammatory process around the senile plaques, apoptosis and necrotic death of neurones, and, in consequence, changes in functioning of neurotransmitter systems. In this article the authors present the main directions in pharmacotherapy of Alzheimer's disease: causal therapy, which prevents the neurodegenerative changes and slows down the pathogenetic process, and symptomatic therapy...

Interleukin-18 (IL-18) is a novel proinflammatory cytokine. Most of the immune and inflammatory genes induced by IL-18 are nuclear factor-kappaB (NF-kappaB)- and activator protein-1 (AP-1)-regulated. Interleukin-1 receptor-associated kinase-1 (IRAK-1) has recently been shown to be involved in IL-18-stimulated activation of NF-kappaB and AP-1. The purpose of this study is to investigate the effects of preventing IRAK-1 expression by antisense IRAK-1 oligodeoxynucleotide (ODN) on IL-18-stimulated activation of NF-kappaB and AP-1...