Etsuko Nobumoto

The Effects of High-Fat Diet Exposure In Utero on the Obesogenic and Diabetogenic Traits Through Epigenetic Changes in Adiponectin and Leptin Gene Expression for Multiple Generations in Female Mice

Recent studies demonstrate that epigenetic changes under malnutrition in utero might play important roles in transgenerational links with metabolic diseases. We have previously shown that exposure to a high-fat diet (HFD) in utero may cause a metabolic syndrome-like phenomenon through epigenetic modifications of Adiponectin and Leptin genes. Because an association of obesity between mother and offspring endured in multiple generations, we examined whether HFD exposure in utero might affect the metabolic status of female offspring through multigenerational epigenetic changes of Adiponectin and Leptin genes and whether a normal diet in utero for multiple generations might abolish such epigenetic changes after exposure to a HFD in utero using ICR mice. We observed that the effect of maternal HFD on offspring over multiple generations in metabolic syndrome-like phenomenon such as weight and fat mass gain, glucose intolerance, hypertriglyceridemia, abnormal adiponectin and leptin levels, and hypertension, were accumulated with expression and epigenetic changes in Adiponectin and Leptin genes. A normal diet in utero in the subsequent generations after HFD exposure in utero diminished, and a normal diet in utero for 3 generations completely abolished, the effect of HFD in utero on weight and fat mass gain, insulin resistance, serum triglyceride, adiponectin, and leptin levels, with epigenetic changes of Adiponectin and Leptin genes. Exposure to a HFD in utero might affect glucose and lipid metabolism of female offspring through epigenetic modifications to Adiponectin and Leptin genes for multiple generations. Obesogenic and diabetogenic traits were abolished after a maternal normal diet for 3 generations.

Superimposed Preeclampsia in Women with Chronic Kidney Disease

Aim: To evaluate whether pregnant women with chronic kidney disease (CKD) adapt poorly to increases in renal blood flow. This can exacerbate renal function and impair perinatal outcome, as there is a major interplay between CKD and preeclampsia (PE). Methods: We analyzed the outcomes of 90 pregnant women with preexisting CKD. The estimated glomerular filtration rate (eGFR) was measured along with the levels of angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor, which might act in the pathophysiology of PE. Results: In pregnancies with CKD, PE and preterm delivery were increased and the increased blood pressure worsened the perinatal outcomes much more than the increased proteinuria. All pregnancies with severe renal insufficiency were delivered preterm because of impaired renal function. The eGFR was correlated significantly with 24-hour creatinine clearance (r = 0.830). Significant differences in sFlt-1 and placental growth factor levels were found between severe PE without any complications and severe superimposed PE (p < 0.05), and between women with and without declining renal function in superimposed PE (p < 0.01). Conclusion: Pregnancies with CKD have a high risk of obstetrical complications. The eGFR might serve for evaluating renal function during pregnancy. Angiogenic factors might be potential markers for a differential diagnosis between PE and worsening renal function.

The inhibition of constitutive androstane receptor-mediated pathway enhances the effects of anticancer agents in ovarian cancer cells.

BACKGROUNDnOvarian cancer is commonly treated with anticancer agents; however, many tumors become resistant. Resistance is regulated, in part, by P-glycoprotein, which is encoded by the gene multiple drug resistance 1 (MDR1) and functions as a transmembrane efflux pump for the elimination of anticancer agents. Constitutive androstane receptor (CAR) is a nuclear receptor that regulates drug metabolism through control of MDR1 and other genes.nnnPURPOSEnWe examined whether the inhibition of CAR-mediated pathway could influence the cytotoxicity of three anticancer drugs, cisplatin, paclitaxel, and arsenic trioxide, in ovarian cancer cells.nnnRESULTSnWe observed that the cell proliferation of several ovarian cell lines expressing CAR significantly increased when CITCO was combined with anticancer agents compared with any anticancer agent alone. The up-regulation of MDR1 and UGT1A1 by anticancer agents was further enhanced in the presence of CITCO. We confirmed that combining CITCO with anticancer agents induced significantly lower levels of apoptosis than those achieved with any single anticancer drug. CAR down-regulation by RNA interference caused a significant increase in cell growth inhibition and enhancement of apoptosis in the presence of anticancer agents. Combination of CITCO with any anticancer agents significantly enhanced CAR-mediated transcription compared with any anticancer agents alone and CAR down-regulation completely inhibited the transcription in the presence of CITCO and/or anticancer agents.nnnCONCLUSIONnInhibition of CAR pathway could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance, in the treatment of ovarian cancer.

Potential interaction of brain natriuretic peptide with hyperadiponectinemia in preeclampsia

Adiponectin was reported recently to have roles in the pathophysiology of preeclampsia. Moreover, elevation of adiponectin and brain natriuretic peptide (BNP) has been observed in preeclampsia. We examined the possible links between adiponectin and BNP in the pathophysiology of preeclampsia. We performed a cross-sectional study in 56 preeclampsia patients and 56 controls matched for gestational age and body mass index. The BNP, leptin, and adiponectin levels were measured by ELISA, and their mRNA expressions were evaluated in omental adipose tissue by real-time PCR. The effects of BNP on adiponectin and leptin mRNA expression and secretion were investigated in primary cultures of adipocytes from obese and normal-weight women. The BNP, adiponectin, and leptin levels were significantly higher in preeclampsia patients compared with controls. The adiponectin level was increased significantly in normal-weight preeclampsia patients compared with overweight preeclampsia patients. Adiponectin mRNA expression was increased significantly in adipose tissues of preeclampsia patients compared with controls and was also increased significantly in normal-weight preeclampsia patients compared with overweight preeclampsia patients, whereas leptin was not. BNP and adiponectin showed significant positive correlations in both normal-weight and overweight preeclampsia patients. BNP had a significantly weaker effect on adiponectin in overweight compared with normal-weight preeclampsia patients. Moreover, BNP had a weaker effect on adiponectin production in adipocytes from overweight women compared with adipocytes from normal-weight women using primary culture of human adipocytes. These data suggested that BNP may play a role in hyperadiponectinemia of preeclampsia patients. The weaker effect of BNP on adiponectin production may participate in the pathophysiology of overweight preeclampsia patients.

Inhibition of pregnane X receptor pathway contributes to the cell growth inhibition and apoptosis of anticancer agents in ovarian cancer cells

Epithelial ovarian cancer remains the most devastating gynecologic cancer with drug resistance and rapid recurrence. Pregnane X receptor (PXR) is a nuclear receptor that affects drug metabolism/efflux and drug-drug interaction through control of multiple drug resistance 1 (MDR1), which implies a major role in multidrug resistance, and other genes. We examined whether the inhibition of PXR-mediated pathway using siRNA interference and an antagonist for PXR could influence the paclitaxel and cisplatin cytotoxicity in ovarian cancer cells. PXR agonists, phthalate and pregnenolone had significant positive effects on cytochromexa0P450 (CYP) 3A4 expression and PXR-mediated transcription through the CYP3A4 promoter, whereas MDR1 expression and PXR-mediated transcription though the MDR1 promoter were significantly increased in the presence of paclitaxel or cisplatin. Downregulation of PXR suppressed the augmented MDR1 expression and PXR-mediated transcription by PXR ligands, and significantly enhanced cell growth inhibition and apoptosis in the presence of paclitaxel or cisplatin. Additionally, ketoconazole, a PXR antagonist, suppressed the augmented MDR1 expression and PXR-mediated transactivation by paclitaxel and cisplatin, and enhanced cell growth inhibition and apoptosis in their presence. In conclusion, inhibition of PXR-mediated pathways could be a novel means of augmenting sensitivity, or overcoming resistance to anticancer agents for ovarian cancer.

Differences in uterine artery blood flow and fetal growth between the early and late onset of pregnancy-induced hypertension

PurposeWe continuously measured bilateral uterine artery (UA) blood flow and compared differences in UA blood flow to investigate the differences in pathophysiology between early- and late-onset pregnancy-induced hypertension (PIH) and the usefulness of continuous monitoring of UA blood flow for the prediction of early-onset PIH.MethodsThe subjects were 76 PIH patients. The mean pulsatility index of bilateral UA (UAPI), an early diastolic notch in the velocity waveform, and regression curves were retrospectively examined and compared between early- and late-onset groups and the groups with and without fetal growth restriction (FGR).ResultsRegression curves of the UAPI in the early-onset group persisted at +2.0 standard deviations or more from the second to third trimester, while the UAPI in the late-onset group stayed within the normal range. A significantly higher mean UAPI with a high frequency of an early diastolic notch was observed in the early-onset group compared with the late-onset group in all pregnancy trimesters. There was a significant difference in UA resistance between the mild and severe groups and between the FGR and non-FGR groups, but to a small extent compared with the onset period.ConclusionThere was a difference in pathophysiology between early- and late-onset PIH. Continuous monitoring of UA blood flow might be useful for the prediction of early-onset PIH if high UA resistance has been observed.

Creation of a cerebellar diameter reference standard and its clinical application to the detection of cerebellar hypoplasia unique to trisomy 18.

We created a new reference standard focusing on the hemispheric anteroposterior cerebellar diameter (APCD) in addition to the transverse cerebellar diameter (TCD) and discussed whether or not the cerebellar measurement was useful for the detection of trisomy 18 (T18).

Effect of the new diagnostic criteria for gestational diabetes mellitus among Japanese women

BackgroundThe new diagnostic criteria for gestational diabetes mellitus (GDM), proposed by the International Association of Diabetes and Pregnancy Study Groups in 2010, were recently accepted in Japan. Therefore, the frequency of GDM is four times higher than previously recorded. This means that GDM has become a more clinically important disease. This study aimed to assess how the number of patients with GDM as well as its complications have changed after adoption of the new criteria.MethodsA total of 3,610 pregnant women in the Japan Assessment of GDM Screening Trial and Okayama University Hospital were included. We analyzed the prevalence of GDM and its complications using the old and new criteria.ResultsThe prevalence of perinatal outcomes was increased by adopting the new criteria. There were many important perinatal complications in the additional new GDM criteria; therefore, patients with mild GDM, such as one-point disorder patients, should have careful interventions. Admission to the neonatal intensive care unit was significantly increased (pxa0=xa00.01) according to the new GDM criteria because the old criteria were stricter than the new ones. GDM patients with obesity (BMIxa0≥xa025xa0kg/m2) had a high frequency of perinatal complications that could require active intervention and strict follow-up.ConclusionsBecause the new GDM criteria greatly affect perinatal complications, intervention for GDM starting at an early stage and strict follow-up (especially GDM with obesity) are important for reducing complications as well as the incidence of diabetes and metabolic syndrome in the mother and child.

Acknowledgment to the Reviewers

The editors greatly appreciate the support of all reviewers whose comments and scientific evaluation of submitted manuscripts are invaluable for ensuring the scientific quality of this journal. In addition to the listed permanent members of the Editorial Board, the following distinguished clinicians and scientists listed below acted as reviewers for Gynecologic and Obstetric Investigation from the beginning of November 2011 to the end of October 2012. The Editors hereby express their sincere gratitude for and their appreciation of the work done as well as the support given to this journal.