A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

The genetic architecture of sexually selected traits in two natural populations of Drosophila montana

The work was supported by the National Environment Research Council (grant NE/E015255/1 to MGR and RKB) and the Academy of Finland (project 132619 to AH).We investigated the genetic architecture of courtship song and cuticular hydrocarbon traits in two phygenetically distinct populations of Drosophila montana. To study natural variation in these two important traits, we analysed within-population crosses among individuals sampled from the wild. Hence, the genetic variation analysed should represent that available for natural and sexual selection to act upon. In contrast to previous between-population crosses in this species, no major quantitative trait loci (QTLs) were detected, perhaps because the between-population QTLs were due to fixed differences between the populations. Partitioning the trait variation to chromosomes suggested a broadly polygenic genetic architecture of within-population variation, although some chromosomes explained more variation in one population compared with the other. Studies of natural variation provide an important contrast to crosses between species or divergent lines, but our analysis highlights recent concerns that segregating variation within populations for important quantitative ecological traits may largely consist of small effect alleles, difficult to detect with studies of moderate power.PostprintPeer reviewe

Sexual and postmating reproductive isolation between allopatric Drosophila montana populations suggest speciation potential

This work was funded by a European Commission Research Training Grant RTN2-2001-00049, the Centre of Excellence for Evolutionary Research at the University of Jyväskylä and a Marie Curie Initial Training Network, ‘Understanding the evolutionary origin of biological diversity’ (ITN-2008-213780 SPECIATION)Background: Widely distributed species with populations adapted to different environmental conditions can provide valuable opportunities for tracing the onset of reproductive incompatibilities and their role in the speciation process. Drosophila montana, a D. virilis group species found in high latitude boreal forests in Nearctic and Palearctic regions around the globe, could be an excellent model system for studying the early stages of speciation, as a wealth of information concerning this species' ecology, mating system, life history, genetics and phylogeography is available. However, reproductive barriers between populations have hereto not been investigated. Results: We report both pre- and postmating barriers to reproduction between flies from European (Finnish) and North American (Canadian) populations of Drosophila montana. Using a series of mate-choice designs, we show that flies from these two populations mate assortatively (i.e., exhibit significant sexual isolation) while emphasizing the importance of experimental design in these kinds of studies. We also assessed potential postmating isolation by quantifying egg and progeny production in intra-and interpopulation crosses and show a significant one-way reduction in progeny production, affecting both male and female offspring equally. Conclusion: We provide evidence that allopatric D. montana populations exhibit reproductive isolation and we discuss the potential mechanisms involved. Our data emphasize the importance of experimental design in studies on premating isolation between recently diverged taxa and suggest that postmating barriers may be due to postcopulatory-prezygotic mechanisms. D. montana populations seem to be evolving multiple barriers to gene flow in allopatry and our study lays the groundwork for future investigations of the genetic and phenotypic mechanisms underlying these barriers.Publisher PDFPeer reviewe