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

Domestication and ontogeny effects on the stress response inyoung chickens (Gallus gallus)

Domestication is thought to increase stress tolerance. The connection between stressor exposure,glucocorticoids and behavioural responses has been studied in adults, where domestication effectsare evident. Early stress exposure may induce detrimental effects both in short-and long term.Previous research has reported a lack of glucocorticoid response in newly hatched chickens (Gallusgallus), whereas others have found opposite results. Hence it remains unclear whether the HPA-axis isfunctional from hatch, and if domestication has affected the early post-hatch ontogeny of the stressresponse. Our aims were to investigate the early ontogeny of the HPA-axis and characterize behaviouraland hormonal stress responses in ancestral Red Junglefowl and in two domestic layer strains. Plasmacorticosteone and behavioural responses before and after physical restraint was measured on dayone, nine, 16 and 23 post hatch. The results showed significant increases of corticosterone after stressin all three breeds at all the different ages. The HPA-response decreased with age and was lower inRed Junglefowl. Behavioural responses also decreased with age, and tended to be stronger in RedJunglefowl. In summary, the HPA-axis is reactive from day one, and domestication may have affectedits development and reactivity, alongside with related behaviour responses.Funding agencies: Swedish Research Council (VR); Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS); European Research Council (ERC) [Genewell 322206]</p