Pigment epithelium-derived factor expression and role in follicular development.

RESEARCH QUESTION: What is the involvement of pigment epithelium-derived factor (PEDF), expressed in granulosa cells, in folliculogenesis? DESIGN: mRNA expression of PEDF and other key factors [Cyp19, anti-Müllerian hormone receptor (AMHR) and vascular endothelial growth factor (VEGF)] in mice follicles was examined in order to typify the expression of PEDF in growing follicles and in human primary granulosa cells (hpGC), and to follow the interplay between PEDF and the other main players in folliculogenesis: FSH and AMH. RESULTS: mRNA expression of PEDF increased through folliculogenesis, although the pattern differed from that of the other examined genes, affecting the follicular angiogenic and oxidative balance. In hpGC, prolonged exposure to FSH stimulated the up-regulation of PEDF mRNA. Furthermore, a negative correlation between AMH and PEDF was observed: AMH stimulation reduced the expression of PEDF mRNA and PEDF stimulation reduced the expression of AMHR mRNA. CONCLUSIONS: Folliculogenesis, an intricate process that requires close dialogue between the oocyte and its supporting granulosa cells, is mediated by various endocrine and paracrine factors. The current findings suggest that PEDF, expressed in granulosa cells, is a pro-folliculogenesis player that interacts with FSH and AMH in the process of follicular growth. However, the mechanism of this process is yet to be determined.

The Role of PEDF in Reproductive Aging of the Ovary.

Reproductive aging is characterized by a decline in ovarian function and in oocytes' quantity and quality. Pigment epithelium-derived factor (PEDF), a pivotal player in ovarian angiogenic and oxidative balance, was evaluated for its involvement in reproductive aging. Our work examines the initial stage of reproductive aging in women and mice, and the involvement of PEDF in the process. Granulosa cells from reproductively-aged (RA) women and mice (36-44 years old and 9-10 months old, respectively) indicated an increase in the level of PEDF mRNA (qPCR), with yet unchanged levels of AMH and FSHR mRNAs. However, the PEDF protein level in individual women showed an intra-cellular decrease (ELISA), along with a decrease in the corresponding follicular fluid, which reflects the secreted fraction of the protein. The in vitro maturation (IVM) rate in the oocytes of RA mice was lower compared with the oocytes of young mice, demonstrated by a reduced polar body extrusion (PBE) rate. The supplementation of PEDF improved the hampered PBE rate, manifested by a higher number of energetically-competent oocytes (ATP concentration and mtDNA copy number of individual oocytes). Our findings propose PEDF as an early marker of reproductive aging, and a possible therapeutic in vitro agent that could enhance the number of good-quality oocytes in older IVF patients.

Lowering fasting blood glucose with non-dialyzable material of cranberry extract is dependent on host genetic background, sex and diet.

BACKGROUND: Type 2 diabetes (T2D) is a polygenic metabolic disease, characterized by high fasting blood glucose (FBG). The ability of cranberry (CRN) fruit to regulate glycemia in T2D patients is well known. Here, a cohort of 13 lines of the genetically diverse Collaborative Cross (CC) mouse model was assessed for the effect of non-dialyzable material (NDM) of cranberry extract in lowering fasting blood glucose. METHODS: Eight-week-old mice were maintained on either a standard chow diet (control group) or a high-fat diet (HFD) for 12 weeks, followed by injections of intraperitoneal (IP) NDM (50 mg/kg) per mouse, three times a week for the next 6 weeks. Absolute FBG (mg/dl) was measured bi-weekly and percentage changes in FBG (%FBG) between weeks 0 and 12 were calculated. RESULTS: Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD. However, a non-significant increase in FBG values was observed in male and female mice maintained on HFD during the same period. Following administration of NDM during the following 6 weeks, the results show a variation in significant levels of FBG lowering between lines, male and female mice and under the different diets. CONCLUSION: The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background (pharmacogenetics), sex of the mouse (pharmacosex), and diet (pharmacodiet). All these results support the need for follow-up research to better understand and implement a personalized medicine approach/utilization of NDM for reducing FBG.