Rabbit Anti-Human RELA (Phospho-Thr254) polyclonal antibody

Cyclic guanosine monophosphate (cGMP) signaling is an important regulator of newborn lung function and development. Although cGMP signaling is decreased in many models of newborn lung injury, the mechanisms are poorly understood. We determined how IL-1 beta regulates the expression of the alpha 1-subunit of soluble guanylate cyclase (sGC alpha 1), a prime effector of pulmonary cGMP signaling. Physiologic levels of IL-1 beta were discovered to rapidly decrease sGC alpha 1 mRNA expression in a human fetal lung fibroblast cell line (IMR-90 cells) and protein levels in primary mouse pup lung fibroblasts. This sGC alpha 1 expression inhibition appeared to be at a transcriptional level; IL-1 beta treatment did not alter sGC alpha 1 mRNA stability, although it reduced sGC alpha 1 promoter activity. Transforming growth factor-beta (TGF beta)-activated kinase-1 (TAK1) was determined to be required for IL-1 beta's regulation of sGC alpha 1 expression; TAK1 knockdown protected sGC alpha 1mRNA expression in IL-1 beta-treated IMR-90 cells. Moreover. heterologously expressed TAK1 was sufficient to decrease sGC alpha 1 mRNA levels in those cells. Nuclear factor-kappa B (NF-kappa B) signaling played a critical role in the IL-1 beta-TAK1-sGC alpha 1 regulatory pathway; chromatin immunoprecipitation studies demonstrated enhanced activated NF-kappa B subunit (RelA) binding to the sGC alpha 1 promoter after IL-1 beta treatment unless treated with an I kappa B kinase-2 inhibitor. Also, this NF-kappa B signaling inhibition protected sGC alpha 1 expression in IL-1 beta-treated fibroblasts. Lastly, using transgenic mice in which active IL-1 beta was conditionally expressed in lung epithelial cells, we established that IL-1 beta expression is sufficient to stimulate TAK1 and decrease sGC alpha 1 protein expression in the newborn lung. Together these results detail the role and mechanisms by which IL-1 beta inhibits cGMP signaling in the newborn lung.

Problems with sustained attention are a key clinical feature of Attention Deficit/Hyperactivity Disorder (ADHD) which also manifests in poor performance and abnormal fronto-striato-parietal activation during sustained attention. Methylphenidate and atomoxetine improve attention functions and upregulate abnormal fronto-cortical activation during executive function tasks in ADHD patients. Despite this, no functional Magnetic Resonance Imaging (fMRI) study has compared the effects of methylphenidate and atomoxetine on the neurofunctional substrates of sustained attention in ADHD. This randomised, double-blind, placebo-controlled, cross-over study investigated the comparative normalisation effects of methylphenidate and atomoxetine on fMRI correlates and performance in 14 ADHD adolescents relative to 27 age-matched healthy controls during a parametric sustained attention/vigilance task with progressively increasing load of sustained attention. ADHD patients were scanned three times under a single clinical dose of either methylphenidate, atomoxetine, or placebo in pseudo-randomised order. Healthy controls were scanned once and compared to patients under each drug condition to test for potential drug-normalisation effects. Relative to controls, ADHD boys under placebo were impaired in performance and had underactivation in predominantly right-hemispheric fronto-parietal, and striato-thalamic regions. Both drugs normalised all underactivations, while only methylphenidate improved performance deficits. Within patients, methylphenidate had a drug-specific effect of upregulating left ventrolateral prefrontal/superior temporal activation rela-tive to placebo and atomoxetine, while both drugs increased activation of right middle/superior temporal cortex, posterior cingulate, and precuneus relative to placebo. The study shows shared normalisation effects of methylphenidate and atomoxetine on fronto-striato-thalamo-parietal dysfunction in ADHD during sustained attention but a drug-specific upregulation effects of methylphenidate on ventral fronto-temporal regions. (C) 2019 Elsevier B.V. and ECNP. All rights reserved.