Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary

<p>Abstract</p> <p>Background</p> <p>Resveratrol 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.</p> <p>Methods</p> <p>The 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.</p> <p>Results</p> <p>SIRT1 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.</p> <p>Conclusions</p> <p>These 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.</p

Genotype-Dependent Efficacy of a Dual PI3K/mTOR Inhibitor, NVP-BEZ235, and an mTOR Inhibitor, RAD001, in Endometrial Carcinomas

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235—a dual PI3K/mTOR inhibitor—and RAD001—an mTOR inhibitor—in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas

Increased tissue levels of omega-3 polyunsaturated fatty acids prevents pathological preterm birth

Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have anti-inflammatory effects. Preterm birth is an important problem in modern obstetrics and one of the main causes is an inflammation. We here showed that abundance of omega-3 fatty acids reduced the incidence of preterm birth induced by LPS with fat-1 mice, capable of converting omega-6 to omega-3 fatty acids. We also indicated that the gene expression of IL-6 and IL-1β in uteruses and the number of cervical infiltrating macrophages were reduced in fat-1 mice. The analyses of lipid metabolomics showed the high level of 18-hydroxyeicosapentaenoate in fat-1 mice, which was derived from EPA and was metabolized to anti-inflammatory product named resolvin E3 (RvE3). We finally showed that the administration of RvE3 to LPS-exposed pregnant wild type mice lowered the incidence of preterm birth. Our data suggest that RvE3 could be a potential new therapeutic for the prevention of preterm birth

Benefits of the Phytoestrogen Resveratrol for Perimenopausal Women

Endometriosis, characterized by macroscopic lesions in the ovaries, is a serious problem for women who desire conception. Damage to the ovarian cortex is inevitable when lesions are removed via surgery, which finally decreases the ovarian reserve, thereby accelerating the transition to the menopausal state. Soon after cessation of ovarian function, in addition to climacteric symptoms, dyslipidemia and osteopenia are known to occur in women aged &gt;50 years. Epidemiologically, there are sex-related differences in the frequencies of dyslipidemia, hypertension, and osteoporosis. Females are more susceptible to these diseases, prevention of which is important for healthy life expectancy. Dyslipidemia and hypertension are associated with the progression of arteriosclerosis, and arteriosclerotic changes in the large and middle blood vessels are one of the main causes of myocardial and cerebral infarctions. Osteoporosis is associated with aberrant fractures in the spine and hip, which may confine the patients to the bed for long durations. Bone resorption is accelerated by activated osteoclasts, and rapid bone remodeling reduces bone mineral density. Resveratrol, a plant-derived molecule that promotes the function and expression of the sirtuin, SIRT1, has been attracting attention, and many reports have shown that resveratrol might exert cardiovascular protective effects. Preclinical reports also indicate that it can prevent bone loss and endometriosis. In this review, I have described the possible protective effects of resveratrol against arteriosclerosis, osteoporosis, and endometriosis because of its wide-ranging functions, including anti-inflammatory and antioxidative stress functions. As ovarian function inevitably declines after 40 years, intake of resveratrol can be beneficial for women with endometriosis aged &lt;40 years

Special Issue “Impact of Endometriosis on Women’s Health”

Endometriosis is one of the most common diseases in women of reproductive age, and although there are many theories to explain this enigmatic disease, such as reflux theory, metastasis theory, and metaplasia theory, there is still no single theory that can wholly explain the pathogenesis of the disease, and it is considered a mysterious disease until now [...

Utility of a minimal skin incision laparotomy technique for removing uterine leiomyomas at a regional core hospital: a retrospective study

Abstract Background We present a minimal skin wound abdominal myomectomy performed in our hospital and attempt to identify the optimal range of this technique by considering the characteristics of target leiomyomas. In this procedure, we attempted to make the skin wound as small as possible, with a maximum length of approximately 5 cm. Methods In addition to introducing the minimal skin wound abdominal myomectomy, we retrospectively collected and analyzed the medical records of 76 patients treated with minimal skin wound abdominal myomectomy exclusively by the same physician at Maruyama Memorial General Hospital between January 2007 and December 2016. We statistically investigated relationships between ten factors, including body mass index; patient’s age; patient’s parity; administration of gonadotropin-releasing hormone analogue; presence of anemia; the uterine leiomyomas’ number, size, weight, and location; operation time; and blood loss. Results First, we introduce a case in which we performed minimal skin wound abdominal myomectomy for a 36-year-old Japanese patient with a large leiomyoma (10 cm in diameter). Then, we assessed the impacts of patient characteristics and leiomyoma characteristics on operation time and blood loss for this surgical method. In a multivariate analysis, only the number of resected leiomyomas significantly affected massive bleeding. Other factors showed no difference on operation time and the amount of blood loss. Conclusions Minimal skin wound abdominal myomectomy is safe and effective for use in many patients, because only the number of leiomyomas affects the amount of blood loss. No other factor affected operation time. We suggest the possibility that the expanded use of minimal skin wound abdominal myomectomy may reduce the number of patients waiting for long periods to undergo laparoscopic surgery and may optimize the use of medical resources in rural areas

Prediction of the operative time for hysteroscopic myomectomy for leiomyomas penetrating the intramural cavity using leiomyoma weight and clinical characteristics of patients

Abstract Purpose To preoperatively predict the operative time (OT) for hysteroscopic myomectomy for G1 or G2 leiomyoma based on leiomyoma weight. Methods The data from 544 patients who underwent one‐step hysteroscopic myomectomy were analyzed retrospectively. A total of 340 patients with leiomyoma penetrating the intramural cavity were identified as suitable candidates for calculation of the OT based on leiomyoma weight; we considered leiomyoma weight to be the most objective parameter for evaluating leiomyoma tissues. Additionally, 460 patients with a single leiomyoma were analyzed to estimate the weight of the resected leiomyoma based on its diameter. Results Considering total leiomyoma weight (TLW) and two additional coefficients (1.5: G2 leiomyoma, 0.75: vaginal parity of the patient), we demonstrated that our formula correlated well with OT (R2 = 0.72). TLW also correlated well with the cube of the average diameter (AD) of leiomyomas (R2 = 0.89). Predicting TLW significantly improved the application of specific coefficients depending on its value (1.0: AD 0.1‐2.0 cm, 0.8: AD 2.1‐3.0 cm, 0.7: AD 3.1‐5.7 cm). Conclusion The OT for hysteroscopic myomectomy of intracavital leiomyoma can be predicted prior to surgery using simple clinical information of the target leiomyoma and the patient

Assisted reproductive technology pregnancy complications are significantly associated with endometriosis severity before conception: a retrospective cohort study

Abstract Background Endometriosis has been shown to be associated with second- to third-trimester pregnancy complications such as preterm birth and placenta previa, but the evidence is inconsistent. We hypothesized that endometriosis severity might affect these inconsistent results. Therefore we aimed to conduct a retrospective cohort study to elucidate whether endometriosis severity is associated with the incidence rates of adverse pregnancy outcomes. Methods The patients who achieved singleton pregnancy by assisted reproductive technology (ART) in our facility between March 2000 and December 2014 (N = 631) were included in this analysis. Among them, 92 women demonstrated surgically proven endometriosis, and 512 women were shown to not have endometriosis as a complication. Among the 92 cases of endometriosis, 10 were classified as revised American Society for Reproductive Medicine (rASRM) stage I and II, 31 cases were rASRM stage III, and 43 cases were rASRM stage IV; in 8 cases, the rASRM stage was unavailable. Logistic regression analysis was performed to calculate odds ratios (OR) and 95 % confidence interval (CI) for the rates of preterm birth, placenta previa, and small for gestational age. OR were adjusted by age, parity and the number of transferred embryos. Results First we confirmed the frequency of preterm birth and placenta previa were significantly increased in women with endometriosis (preterm birth OR, 2.08; 95 % CI, 1.07–3.89, placenta previa OR, 15.1; 95 % CI, 4.40–61.7), while the frequency of small for gestational age was not. Moreover, we found the frequencies of preterm birth and placenta previa were significantly increased in women with rASRM stage IV endometriosis compared to other two groups: women with rASRM stage I-III endometriosis (preterm birth OR, 7.40; 95 % CI, 1.83–50.3; placenta previa OR, 11.0; 95 % CI, 1.75–216.5) and women without endometriosis (preterm birth adjusted OR, 4.11; 95 % CI, 1.88–8.55; placenta previa adjusted OR, 39.8; 95 % CI, 10.1–189.1). There were no significant difference between women with rASRM I-III endometriosis and women without endometriosis. Conclusions We found that the frequencies of preterm birth and placenta previa were significantly increased in women with endometriosis, and the severity of endometriosis might have an adverse impact on ART pregnancy