Leukotriene modifiers in the treatment of asthma in children

Asthma is one of the most common respiratory disorders in clinical practice, affecting up to 13% of people worldwide. Inflammation is the most important component of asthma and inhaled corticosteroids (ICS) are recommended as the first line controller treatment for patients of all ages. Treatment with corticosteroids is often unable to fully control asthma symptoms and progression. Recently, leukotrienes have come to the forefront of research as they have been found play a pivotal role in the airway inflammatory process, and specific drugs have been developed to target them. Cysteiny leukotriene antagonists (LTRAs) have recently emerged as important therapeutic options that show a large potential clinical utility. Three specific LTRAs are licensed for clinical use: montelukast, zafirlukast and pranlukast, although montelukast is the only drug approved in the paediatric age range. It is well tolerated (although adverse effects such as headaches, abdominal pain, rashes, angioedema, pulmonary eosinophilia and arthralgia have been reported) and shows many positive effects in asthmatic patients. Current Global Initiative for Asthma guidelines recommend LTRAs as: (1) a second choice treatment to ICS for patients with mild persistent asthma, (2) an add-on therapy to reduce the dose of ICS in patients with moderate or severe asthma, due to the different and complementary mechanisms of action of these agents. LTRAs may be particularly appropriate choices in a number of clinical situations, including the following: patients with concomitant rhinitis; patients with viral-induced wheeze; patients with exercise-induced bronchoconstriction (EIB) and, in children aged 2-5 years, to reduce the frequency of asthma exacerbations

Molecular organization of the cullin E3 ligase adaptor KCTD11

The family of human proteins containing a potassium channel tetramerization domain (KCTD) includes 21 members whose function is largely unknown. Recent reports have however suggested that these proteins are implicated in very important biological processes. KCTD11/REN, the best-characterized member of the family to date, plays a crucial role in the ubiquitination of HDAC1 by acting, in complex with Cullin3, as an E3 ubiquitin ligase. By combining bioinformatics and mutagenesis analyses, here we show that the protein is expressed in two alternative variants: a short previously characterized form (sKCTD11) composed by 232 amino acids and a longer variant (IKCTD11) which contains an N-terminal extension of 39 residues. Interestingly, we demonstrate that IKCTD11 starts with a non-canonical AUU codon. Although both sKCTD11 and IKCTD11 bear a POZ/BTB domain in their N-terminal region, this domain is complete only in the long form. Indeed, sKCTD11 presents an incomplete POZ/BTB domain. Nonetheless, sKCTD11 is still able to bind Cul3, although to much lesser extent than IKCTD11, and to perform its biological activity. The heterologous expression of sKCTD11 and IKCTD11 and their individual domains in Escherichia coil yielded soluble products as fusion proteins only for the longer form. In contrast to the closely related KCTD5 which is pentameric, the characterization of both IKCTD11 and its POZ/BTB domain by gel filtration and light scattering indicates that the protein likely forms stable tetramers. In line with this result, experiments conducted in cells show that the active protein is not monomeric. Based on these findings, homology-based models were built for IKCTD11 BIB and for its complex with Cul3. These analyses indicate that a stable IKCTD11 BTB-Cul3 three-dimensional model with a 4:4 stoichiometry can be generated. Moreover, these models provide insights into the determinants of the tetramer stability and into the regions involved in IKCTD11-Cul3 recognition. (C) 2011 Elsevier Masson SAS. All rights reserved