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

Contribution of genetic resources to grain storage protein composition and wheat quality

The technological quality of wheat flour is defined by a range of dough characteristics relevant to the breadmaking processes and practices of individual countries and for particular products. The influence of storage protein diversity on wheat quality has been widely documented in the last three decades. The present chapter focuses on several aspects of wheat quality that merit more attention. The huge genetic diversity of wheat storage proteins means that all the possible allelic combinations and their interactions are too numerous to be tested in terms of their influence on the major quality parameters. However it is still relevant to describe the variation in rheological and viscoelastic properties of gluten in relation to its component proteins, glutenin and gliadin. Although gluten plays a major role in determining the properties of dough, the abundance of the two major storage protein fractions does not solely explain the observed variation in those properties. We therefore examine the influence of some genetic factors, including those affecting the protein composition, on the variation in the glutenin polymer sizes. Some examples will be given to illustrate how end-use quality can be improved by taking advantage of the available genetic resources in parallel with molecular genome analyses with the dual aim of widening the scope of characteristics that can be harnessed in breeding and ensuring consistent wheat quality in changing agro-climatic situations. The known alleles of the major genes are highlighted in the context of the challenges that the research community is facing regarding wheat allele nomenclature, exchange of gene bank material and the numerous quality attributes of interest. Finally, important research objectives are proposed for breeding future wheats with grain protein quality and technological properties tailored for different food products