Search results for "PD"

Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease

2013

Background Glucocorticoid functions are markedly impaired in patients with chronic obstructive pulmonary disease (COPD). The phosphodiesterase 4 inhibitor roflumilast N-oxide (RNO) is the active metabolite of roflumilast approved as a treatment to reduce the risk of exacerbations in patients with severe COPD. Objective We sought to characterize the differential effects of RNO versus corticosteroids and their potential additive/synergistic effect in neutrophils from patients with COPD, thus providing scientific rationale for the combination of roflumilast with corticosteroids in the clinic. Methods Peripheral blood neutrophils were isolated from patients with COPD (n = 32), smokers (n = 7), …

Roflumilast improves corticosteroid resistance COPD bronchial epithelial cells stimulated with toll like receptor 3 agonist

2015

Chronic obstructive pulmonary disease (COPD) is characterised by chronic pulmonary inflammation punctuated by periods of viral exacerbations. Recent evidence suggests that the combination of roflumilast with corticosteroids may improve the compromised anti-inflammatory properties of corticosteroids in COPD. We analyzed differential and combination anti-inflammatory effects of dexamethasone and roflumilast N-oxide in human bronchial epithelial cells (HBECs) stimulated with viral toll like receptor (TLR) agonists. Lung tissue and HBECs were isolated from healthy (n = 15), smokers (n = 12) and smokers with COPD (15). TLR3 expression was measured in lung tissue and in HBECs. IL-8 secretion was …

Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

2015

Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (…

The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease

2009

After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A-D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500…

γδ T cell-based anticancer immunotherapy: Progress and possibilities

2015

High Reynolds number Navier-Stokes solutions and boundary layer separation induced by a rectilinear vortex

2013

Abstract We compute the solutions of Prandtl’s and Navier–Stokes equations for the two dimensional flow induced by a rectilinear vortex interacting with a boundary in the half plane. For this initial datum Prandtl’s equation develops, in a finite time, a separation singularity. We investigate the different stages of unsteady separation for Navier–Stokes solution at different Reynolds numbers Re = 103–105, and we show the presence of a large-scale interaction between the viscous boundary layer and the inviscid outer flow. We also see a subsequent stage, characterized by the presence of a small-scale interaction, which is visible only for moderate-high Re numbers Re = 104–105. We also investi…

Kaitējuma atlīdzināšanas problemātika sauszemes transportlīdzekļu īpašnieku civiltiesiskās atbildības obligātajā apdrošināšanā

2015

Pētījuma mērķis ir parādīt šī brīža aktuālākās problēmas kaitējumu atlīdzināšanā sauszemes transportlīdzekļu tiesīgo lietotāju obligātajā civiltiesiskajā apdrošināšanā. Darbā tiek konstatētas problēmas spēkā esošo tiesību normu pielietojumā reālās situācijās, konstatējot transportlīdzekļu tiesīgo lietotāju atbildības pakāpi un atlīdzinot radīto kaitējumu trešajām personām. Tāpat tiek analizētas Latvijas tiesību normu savstarpējās pretrunas, kā arī to atbilstība Eiropas Savienības tiesību normām un Eiropas Savienības Tiesu nolēmumiem. Ņemot vērā Eiropas Savienības tiesību avotu ietekmi uz Latvijas tiesību normām, mēģināts sniegt iespējamos risinājumus, kas izpaužas gan interpretācijā, gan iz…

Single molecule localization microscopy of the distribution of chromatin using Hoechst and DAPI fluorescent probes.

2014

Several approaches have been described to fluorescently label and image DNA and chromatin in situ on the single-molecule level. These superresolution microscopy techniques are based on detecting optically isolated, fluorescently tagged anti-histone antibodies, fluorescently labeled DNA precursor analogs, or fluorescent dyes bound to DNA. Presently they suffer from various drawbacks such as low labeling efficiency or interference with DNA structure. In this report, we demonstrate that DNA minor groove binding dyes, such as Hoechst 33258, Hoechst 33342, and DAPI, can be effectively employed in single molecule localization microscopy (SMLM) with high optical and structural resolution. Upon ill…

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Ent…

Bronchial microbiome, PA biofilm-forming capacity and exacerbation in severe COPD patients colonized by P. aeruginosa

2017

Aim: The bronchial microbiome of severe chronic obstructive pulmonary disease patients colonized by Pseudomonas aeruginosa was analyzed using 16S rRNA gene sequencing to identify differences related to biofilm-forming capacity. Patients & methods: Patient sputum samples from 21 patients were studied. Results: Statistically significant differences related to biofilm-forming capacity were only found for genera with relative abundances <1%, and Fusobacterium was over-represented when biofilm-forming capacity was high. Genera with relative abundances >50% which increased from baseline were observed in 10/14 exacerbations, but corresponded to Pseudomonas only in three episodes, while …