BackgroundResveratrol is a natural polyphenolic compound known for its beneficial effects on energy homeostasis, and it also has multiple properties, including anti-oxidant, anti-inflammatory, and anti-tumor activities. Recently, silent information regulator genes (Sirtuins) have been identified as targets of resveratrol. Sirtuin 1 (SIRT1), originally found as an NAD+-dependent histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. To date, the presence and physiological role of SIRT1 in the ovary are not known. Here we found that SIRT1 was localized in granulosa cells of the human ovary.MethodsThe physiological roles of resveratrol and SIRT1 in the ovary were analyzed. Immunohistochemistry was performed to localize the SIRT1 expression. SIRT1 protein expression of cultured cells and luteinized human granulosa cells was investigated by Western blot. Rat granulosa cells were obtained from diethylstilbestrol treated rats. The cells were treated with increasing doses of resveratrol, and subsequently harvested to determine mRNA levels and protein levels. Cell viability was tested by MTS assay. Cellular apoptosis was analyzed by caspase 3/7 activity test and Hoechst 33342 staining.ResultsSIRT1 protein was expressed in the human ovarian tissues and human luteinized granulosa cells. We demonstrated that resveratrol exhibited a potent concentration-dependent inhibition of rat granulosa cells viability. However, resveratrol-induced inhibition of rat granulosa cells viability is independent of apoptosis signal. Resveratrol increased mRNA levels of SIRT1, LH receptor, StAR, and P450 aromatase, while mRNA levels of FSH receptor remained unchanged. Western blot analysis was consistent with the results of quantitative real-time RT-PCR assay. In addition, progesterone secretion was induced by the treatment of resveratrol.ConclusionsThese results suggest a novel mechanism that resveratrol could enhance progesterone secretion and expression of luteinization-related genes in the ovary, and thus provide important implications to understand the mechanism of luteal phase deficiency.

Abstract-Although an association between high blood pressure and cognitive decline has been reported, no studies have investigated the association between home blood pressure and cognitive decline. Home blood pressure measurements can also provide day-to-day blood pressure variability calculated as the within-participant SD. The objectives of this prospective study were to clarify whether home blood pressure has a stronger predictive power for cognitive decline than conventional blood pressure and to compare the predictive power of the averaged home blood pressure with day-to-day home blood pressure variability for cognitive decline. Of 485 participants (mean age, 63 years) who did not have cognitive decline (defined as Mini-Mental State Examination score, <24) initially, 46 developed cognitive decline after a median follow-up of 7.8 years. Each 1-SD increase in the home systolic blood pressure value showed a significant association with cognitive decline (odds ratio, 1.48; P=0.03). However, conventional systolic blood pressure was not significantly associated with cognitive decline (odds ratio, 1.24; P=0.2). The day-to-day variability in systolic blood pressure was significantly associated with cognitive decline after including home systolic blood pressure in the same model (odds ratio, 1.51; P=0.02), whereas the odds ratio of home systolic blood pressure remained positive, but it was not significant. Home blood pressure measurements can be useful for predicting future cognitive decline because they can provide information not only on blood pressure values but also on day-to-day blood pressure variability. provided. 7 Thus, it can be hypothesized that home BP can better predict future cognitive decline than conventional BP.One of the clinically significant aspects of home BP measurements is produced by the multiple BP measurements. 6 These multiple home BP measurements can also produce day-to-day BP variability that is calculated from the SD of home BP. Our previous studies demonstrated that high day-to-day BP variability was associated with an increased risk of cardiovascular mortality, independent of home BP values, and other risk factors. 8,9 However, no studies have investigated the associations of day-to-day BP variability with cognitive impairment.The objectives of this prospective study were to examine and to confirm the stronger predictive power of home BP values for cognitive decline than conventional BP and to compare the predictive power of the averaged home BP and the day-to-day home BP variability for cognitive decline. Methods DesignThis report was part of the Ohasama study, a community-based BP measurement project ongoing since 1987. Socioeconomic and demographic characteristics of this region and details of the study have been described previously. 5,6 Study PopulationOf the remaining 2400 eligible individuals, 1436 participated in the baseline examination, and 1396 gave informed consent for follow-up analyses. Of these, the total number of participants included in the present analyses was 48...

SIRT3 is a member of the sirtuin family and has recently emerged as a vital molecule in controlling the generation of reactive oxygen species (ROS) in oocytes. Appropriate levels of ROS play pivotal roles in human reproductive medicine. The aim of the present study was to investigate SIRT3 expression and analyze the SIRT3-mediated oxidative response in human luteinized granulosa cells (GCs). Human ovarian tissues were subjected to immunohistochemical analysis to localize SIRT3 expression. Hydrogen peroxide and human chorionic gonadotropin were used to analyze the relationship between ROS and SIRT3 by quantitative RT-PCR and Western blotting. Intracellular levels of ROS were investigated by fluorescence after small interfering RNA-mediated knockdown of SIRT3 in human GCs. To uncover the role of SIRT3 in folliculogenesis and luteinization, mRNA levels of related genes and the progesterone concentration were analyzed by quantitative RT-PCR and immunoassays, respectively. We detected the expression of SIRT3 in the GCs of the human ovary. The mRNA levels of SIRT3, catalase, and superoxide dismutase 1 were up-regulated by hydrogen peroxide in both COV434 cells and human GCs and down-regulated by human chorionic gonadotropin. Knockdown of SIRT3 markedly elevated ROS generation in human GCs. In addition, SIRT3 depletion resulted in decreased mRNA expression of aromatase, 17β-hydroxysteroid dehydrogenase 1, steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, and 3β-hydroxysteroid dehydrogenase in GCs and thus resulted in decreased progesterone secretion. These results have the important clinical implication that SIRT3 might play a positive role in the folliculogenesis and luteinization processes in GCs, possibly by sensing and regulating the generation of ROS. Activation of SIRT3 function might help to sustain human reproduction by maintaining GCs as well as oocytes.

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