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

Addressing Anxiety and Stress for Healthier Eating in Teens (ASSET): A Pilot Randomized Controlled Trial Protocol for Reducing Anxiety, Disinhibited Eating, Excess Weight Gain, and Cardiometabolic Risk in Adolescent Girls

(1) Background: Standard-of-care lifestyle interventions show insufficient effectiveness for the prevention and treatment of excess weight and its associated cardiometabolic health concerns in adolescents, necessitating more targeted preventative approaches. Anxiety symptoms are common among adolescents, especially girls at risk for excess weight gain, and have been implicated in the onset and maintenance of disinhibited eating. Thus, decreasing elevated anxiety in this subset of adolescent girls may offer a targeted approach to mitigating disinhibited eating and excess weight gain to prevent future cardiometabolic health problems. (2) Methods: The current paper describes the protocol for a multisite pilot and feasibility randomized controlled trial of group cognitive behavioral therapy (CBT) and group interpersonal psychotherapy (IPT) in N = 40 adolescent girls (age 12–17 years) with elevated anxiety symptoms and body mass index (BMI; kg/m2) ≥ 75th percentile for age/sex. (3) Results: Primary outcomes are multisite feasibility of recruitment, protocol procedures, and data collection, intervention fidelity, retention at follow-ups, and acceptability of interventions and study participation. (4) Conclusions: Findings will inform the protocol for a future fully-powered multisite randomized controlled trial to compare CBT and IPT efficacy for reducing excess weight gain and preventing adverse cardiometabolic trajectories, as well as to evaluate theoretically-informed treatment moderators and mediators