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

Decreased plasma orexin-A levels in obese individuals

Orexin-A and -B stimulate appetite and food intake in rats. Orexins and orexin receptors are present in the hypothalamus as well as the enteric nervous system, the pancreas and the gut. The presence of orexins in peripheral blood, however, has not yet been reported. To determine whether orexin-A is present in human plasma and is related to body weight, we measured plasma orexin-A and leptin levels in a population with a body mass index (BMI) range from 19.8 to 59 kg/m(2). Plasma orexin-A levels correlated negatively and plasma leptin levels correlated positively with BMI. In obese and morbidly obese individuals, orexin-A levels were significantly lower and leptin levels were significantly higher when compared to normal. Our results support previous data suggesting that orexin-A acts also in a peripheral manner. The fact that lower levels of plasma orexin-A are present in obese individuals suggests that it is involved in the regulation of human energy metabolis

Author Correction: A guiding map for inflammation

Correction to: Nature Immunology https://doi.org/10.1038/ni.3790, published online 19 July 2017