Development of a novel database to review and assess the clinical effects of EPA and DHA omega-3 fatty acids.

Due to their multiple mechanisms of biological action, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been the focus of ongoing active research for decades. In spite of the resulting body of knowledge, there remain significant gaps in our understanding of EPA/DHA health effects. Further, the volume of existing research makes it challenging to conduct systematic investigations to identify or resolve those gaps. The purpose of this article is to introduce the GOED Clinical Study Database (CSD), a comprehensive, manually-curated relational database that catalogs this research.

Differential effects of the 1,25D3-MARRS receptor (ERp57/PDIA3) on murine mammary gland development depend on the vitamin D3 dose.

1,25 dihydroxyvitamin D3 (1,25D3) is the most potent biologically active form of vitamin D3. Its actions on the mammary gland include cell growth inhibition and anti-cancer effects. This study's purpose was to explore the role of the 1,25D3-membrane associated rapid response steroid (MARRS) receptor in the mammary gland using a tissue-specific knockout mouse model and a vitamin D3 dietary intervention. Three genotype groups were created using the Cre/loxp system to knock-down (+/-) and knockout (-/-) the MARRS receptor in epithelial cells of mammary glands (MG). Abdominal MGs were collected from 6-week old female mice (n = 94) on diets of 10,000 IU/kg (excess), 1,000 IU/kg (sufficient) or 0 IU/kg (deficient) of D3. There was a significant interaction between genotype and diet regarding number of terminal end buds (TEBs) (p = 0.001) and ductal coverage of the fat pad (p = 0.03). MARRS -/- mice on the sufficient diet had significantly fewer TEBs (p = 0.001) compared to MARRS +/+ on the same diet, but the opposite effect was seen in mice on the excess diet. There were no effects of genotype on TEBs when animals were vitamin D3 deficient. These results suggest that there is an effect of MARRS on mammary gland development that is dependent on 25(OH)D status, specifically, altering the number of highly proliferative TEBs. Increased numbers of TEBs have been correlated with increased breast cancer risk later in life. Therefore the results of this study warrant further examination of 25(OH)D status and recommendations in adolescent humans to reduce dietary effects on future breast cancer risk.

Role of the ERp57 protein (1,25D3-MARRS receptor) in murine mammary gland growth and development.

The protein disulfide isomerase ERp57 (GRp58/PDIA3/1,25D3-MARRS) has been implicated in a multitude of signaling pathways throughout the entire body. Most thoroughly studied for its protein-folding role, ERp57 has also been found to have multiple binding partners, and have significant effects on cellular growth. ERp57 has been studied n the context of several neurodegenerative disorders, metabolic conditions, and can be used as a prognosis marker in certain cancers. One role, as an alternate vitamin D binding receptor, has prompted research in tissues with known vitamin D activity, such as the intestine and bone. Vitamin D has been studied in relation to mammary gland growth and development, but it is not yet known if ERp57 plays an independent role in this tissue. In this study, ERp57 was knocked out in murine mammary gland epithelial cells of 30 4-week old mice. Several markers of mammary gland growth were measured, including number of terminal end buds (TEB), ductal coverage of the fat pad, and ductal extension. It was found the knockout animals had decreased numbers of TEBs (p = 0.019), and decreased ductal extension (p = 0.018) compared to wildtype animals, with no differences in gross body weight. Immunohistochemistry analysis of mammary glands showed ERp57 localized to the apical side of alveolar branches, and on leading edges of TEBs. These results provide further evidence for ERp57 functioning separately to the VDR, and further insights into the roles of ERp57.