14 research outputs found
Innovative Approaches to the Imidazo[4,5-b]pyridine Ring System. Development of an Efficient Process for Industrial-Scale Production of a Key Intermediate for Potent Angiotensin II Receptor Antagonists
Two syntheses of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine, an important intermediate for the synthesis of several potent angiotensin II antagonists, have been investigated. The first route involves conversion of 1,1-bis(methylthio)-2-nitroethene (17) to 2-amino-4,6-dimethyl-3-nitropyridine (6); catalytic hydrogenation of 2-amino-4,6-dimethyl-3-nitropyridine in propionic acid gave 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in high yield. In the second synthesis, propionitrile is converted to imidate hydrochloride 15, which is neutralised and reacted with aminoacetonitrile in the presence of acetylacetone to give 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in 55% overall yield. The propionitrile route was scaled up to produce 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine 3 in the pilot plant
Selection, Purification, Characterisation, and Cloning of a Novel Heat-Stable Stereo-Specific Amidase from Klebsiella
Asthmatic farm children show increased CD3(+) CD8(low) T-cells compared to non-asthmatic farm children
Several studies report an important role of CD8(+) cytotoxic T-cells in atopy. Farm children show protection against atopy development, partly explained by CD4(+) T-cell subtypes. Additional effects of CD8(+) T-cells are unknown being investigated in this study within the PASTURE/EFRAIM birth cohort in PBMCs from farming and non-farming 6-year-old (N = 76) German children. CD3(+) CD8(+) CD25(+) T-cells were analyzed by flow cytometry. Genotyping of 17q21 locus-SNPs associated with childhood asthma was performed. No differences in CD8(+) T-cell subsets were seen between farmers and non-farmers regardless of asthma. Among farm children, asthmatics displayed increased CD3(+) CD8(low)(CD25(+)) T-cells compared to non-asthmatics. Asthmatic farm children exhibited a lower PI-induced stimulatory capacity of CD3(+) CD8(low)(CD25(+)) cells and a lower IFN-gamma secretion than non-asthmatic farm children. Among farm children with GSDMB and ORMDL3 risk alleles, asthmatics displayed higher CD3(+) CD8(low) cells than non-asthmatics. Our data indicates a specific role of CD8(low) T-cells in asthmatic farm children. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe
IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort
Asthmatic farm children show increased CD3(+) CD8(low) T-cells compared to non-asthmatic farm children
TNF-alpha-induced protein 3 is a key player in childhood asthma development and environment-mediated protection
Nature and distribution of diagenetic phases and petrophysical properties of carbonates: The Mississippian Madison Formation (Bighorn Basin, Wyoming, USA)
TNF-α–induced protein 3 is a key player in childhood asthma development and environment-mediated protection
Background: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-alpha-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling, mediates environmentally induced asthma protection. Objective: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. Methods: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective'' farms or LPS. NF-kappa B signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. Results: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P <.05), reflecting their increased inflammatory status. Ex vivo farm dust or LPS stimulation restored TNFAIP3 expression to healthy levels in asthmatic patients and shifted NF-kappa B signaling-associated gene expression toward an anti-inflammatory state (P <.001). Farm/rural children had lower expression, indicating tolerance induction by continuous environmental exposure. Newborns with asthma at school age had reduced TNFAIP3 expression at birth, suggesting TNFAIP3 as a possible biomarker predicting subsequent asthma. Conclusion: Our data indicate TNFAIP3 as a key regulator during childhood asthma development and its environmentally mediated protection. Because environmental dust exposure conferred the anti-inflammatory effects, it might represent a promising future agent for asthma prevention and treatment.Peer reviewe