Asthma is an inflammatory airway disease that is estimated to affect 339 million people globally. The symptoms of about 5-10% of patients with asthma are not adequately controlled with current therapy, and little success has been achieved in developing drugs that target the underlying mechanisms of asthma rather than suppressing symptoms. Over the past 3 years, well powered genetic studies of asthma have increased the number of independent asthmaassociated genetic loci to 128. In this Series paper, we describe the immense progress in asthma genetics over the past 13 years and link asthma genetic variants to possible drug targets. Further studies are needed to establish the functional significance of gene variants associated with asthma in subgroups of patients and to describe the biological networks within which they function. The genomics-guided discovery of plausible drug targets for asthma could pave the way for the repurposing of existing drugs for asthma and the development of new treatments.

IntroductionBoiling ethanol extraction is a frequently used method for metabolomics studies of biological samples. However, the stability of several central carbon metabolites, including nucleotide triphosphates, and the influence of the cellular matrix on their degradation have not been addressed.ObjectivesTo study how a complex cellular matrix extracted from yeast (Saccharomyces cerevisiae) may affect the degradation profiles of nucleotide triphosphates extracted under boiling ethanol conditions.MethodsWe present a double-labelling LC–MS approach with a 13C-labeled yeast cellular extract as complex surrogate matrix, and 13C15N-labeled nucleotides as internal standards, to study the effect of the yeast matrix on the degradation of nucleotide triphosphates.ResultsWhile nucleotide triphosphates were degraded to the corresponding diphosphates in pure solutions, degradation was prevented in the presence of the yeast matrix under typical boiling ethanol extraction conditions.ConclusionsExtraction of biological samples under boiling ethanol extraction conditions that rapidly inactivate enzyme activity are suitable for labile central energy metabolites such as nucleotide triphosphates due to the stabilizing effect of the yeast matrix. The basis of this phenomenon requires further study.Graphical abstract Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-016-1140-4) contains supplementary material, which is available to authorized users.

Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-κB could attenuate inflammatory responses in COPD via modulation of the NF-κB signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro- and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-κB activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD.

No abstract