Publications

OBJECTIVE

Experimental and observational data suggest that a higher dietary intake of long-chain omega-3 polyunsaturated acids may lead to a decreased risk of depressive disorders. We assessed multivariable-adjusted associations of fish consumption and dietary intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with depressive symptoms in a population-based sample of 3317 African-American and Caucasian men and women from the Coronary Artery Risk Development in Young Adults study.

METHODS

Diet was assessed in year 7 (1992-1993) and depressive symptoms were measured in years 10 (1995-1996), 15 (2000-2001), and 20 (2005-2006) by the 20-item Center for Epidemiological Studies Depression Scale. Depressive symptoms were defined as a Center for Epidemiological Studies Depression Scale score > or =16 or self-reported use of antidepressant medication.

RESULTS

In the entire cohort, the highest quintiles of intakes of EPA (> or =0.03% energy), DHA (> or =0.05% energy), and EPA + DHA (> or =0.08% energy) were associated with a lower risk of depressive symptoms at year 10 (P for trends = 0.16, 0.10, and 0.03, respectively). The observed inverse associations were more pronounced in women. For the total number of occasions with depressive symptoms, the multivariable adjusted odds ratios (95% confidence interval) in women were 0.75 (0.55-1.01) for fish intake, 0.66 (0.50-0.89) for EPA, 0.66 (0.49-0.89) for DHA, and 0.71 (0.52-0.95) for EPA + DHA when comparing the highest with the lowest quintiles. Analyses of continuous Center for Epidemiological Studies Depression Scale scores revealed inverse associations with fourth-root-transformed omega-3 variables in women.

CONCLUSION

Our findings suggest that dietary intakes of fish and long-chain omega-3 fatty acids may be inversely associated with chronic depressive symptoms in women.

Guanine nucleotide exchange factors (GEFs) stimulate guanine nucleotide exchange and the subsequent activation of Rho-family proteins in response to extracellular stimuli acting upon cytokine, tyrosine kinase, adhesion, integrin, and G-protein-coupled receptors (GPCRs). Upon Rho activation, several downstream events occur, such as morphological and cytoskeletal changes, motility, growth, survival, and gene transcription. The leukemia-associated RhoGEF (LARG) is a member of the regulators of G-protein signaling homology domain (RH) family of GEFs originally identified as a result of chromosomal translocation in acute myeloid leukemia. Using a novel fluorescence polarization guanine nucleotide-binding assay using BODIPY-Texas Red-GTPgammaS (BODIPY-TR-GTPgammaS), the authors performed a 10,000-compound high-throughput screen for inhibitors of LARG-stimulated RhoA nucleotide binding. Five compounds identified from the high-throughput screen were confirmed in a nonfluorescent radioactive guanine nucleotide-binding assay measuring LARG-stimulated [( 35)S] GTPgammaS binding to RhoA, thus ruling out nonspecific fluorescent effects. All 5 compounds selectively inhibited LARG-stimulated RhoA [( 35)S] GTPgammaS binding but had little to no effect on RhoA or Galpha( o) [(35)S] GTPgammaS binding. Therefore, these 5 compounds should serve as promising starting points for the development of small-molecule inhibitors of LARG-mediated nucleotide exchange as both pharmacological tools and therapeutics. In addition, the fluorescence polarization guanine nucleotide-binding assay described here should serve as a useful approach for both high-throughput screening and general biological applications.