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

Carbocatalysis by graphene-based materials

[EN] Carbon materials derived from biomass are considered paradigmatic examples of sustainability.6,7 Other factors besides sustainability that may also favor carbon-based versus inorganic materials as catalysts are economic considerations, since the price of some precious metals is considerably higher than the feedstock carbon materials. For these reasons, there is much interest in developing metal-free catalysts; carbocatalysis is one of the most important examples of this tendency to reduce the dependency on metalsFinancial support by the Spanish Ministry of Economy and Competitiveness (MINECO, Severo Ochoa program, CTQ 2012-32315 and CTQ2010-18671) and Generalitat Valenciana (GV/2013/040) is gratefully acknowledged. A.D.M. thanks University Grants Commission, New Delhi for the award of Assistant Professorship under its Faculty Recharge Programme.Navalón Oltra, S.; Dhakshinamoorthy, A.; Alvaro Rodríguez, MM.; García Gómez, H. (2014). Carbocatalysis by graphene-based materials. Chemical Reviews. 114(12):6179-6212. https://doi.org/10.1021/cr4007347S617962121141