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

Medical Risks for Women Who Drink Alcohol

OBJECTIVE: To summarize for clinicians recent epidemiologic evidence regarding medical risks of alcohol use for women. METHODS: MEDLINE and PsychINFO, 1990 through 1996, were searched using key words “women” or “woman,” and “alcohol.” MEDLINE was also searched for other specific topics and authors from 1980 through 1996. Data were extracted and reviewed regarding levels of alcohol consumption associated with mortality, cardiovascular disease, alcohol-related liver disease, injury, osteoporosis, neurologic symptoms, psychiatric comorbidity, fetal alcohol syndrome, spontaneous abortion, infertility, menstrual symptoms, breast cancer, and gynecologic malignancies. Gender-specific data from cohort studies of general population or large clinical samples are primarily reviewed. MAIN RESULTS: Women develop many alcohol-related medical problems at lower levels of consumption than men, probably reflecting women's lower total body water, gender differences in alcohol metabolism, and effects of alcohol on postmenopausal estrogen levels. Mortality and breast cancer are increased in women who report drinking more than two drinks daily. Higher levels of alcohol consumption by women are associated with increased menstrual symptoms, hypertension, and stroke. Women who drink heavily also appear to have increased infertility and spontaneous abortion. Adverse fetal effects occur after variable amounts of alcohol consumption, making any alcohol use during pregnancy potentially harmful. CONCLUSIONS: In general, advising nonpregnant women who drink alcohol to have fewer than two drinks daily is strongly supported by the epidemiologic literature, although specific recommendations for a particular woman should depend on her medical history and risk factors

The CMS Collaboration

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