Hideki Nakatsukasa

Down-regulation of pregnane X receptor contributes to cell growth inhibition and apoptosis by anticancer agents in endometrial cancer cells.

Recent studies have revealed that pregnane X receptor (PXR) can function as a master regulator to control the expression of drug-metabolizing enzymes, cytochrome P450 3A (CYP3A) family, and members of the drug transporter family, including multiple drug resistance 1 (MDR1). We demonstrated previously that steroid/xenobiotic metabolism by tumor tissue through the PXR-CYP3A pathway might play an important role in endometrial cancer and that PXR ligands enhance PXR-mediated transcription in a ligand- and promoter-dependent fashion, leading to differential regulation of individual PXR targets, especially CYP3A4 and MDR1. In this study, we investigated the potential contribution of PXR down-regulation by RNA interference toward the augmentation of drug sensitivity and the overcoming of drug resistance. We observed the protein levels of both CYP3A4 and MDR1 in PXR small interfering RNA (siRNA)-transfected cells were not increased in the presence of PXR ligands, paclitaxel, cisplatin, estradiol, or medroxyprogesterone acetate (MPA) compared with control siRNA-transfected cells. There was no PXR-mediated transactivation or augmentation of transcription by coactivators in the presence of these ligands. We then found that PXR down-regulation caused a significant increase in cell growth inhibition and enhancement of apoptosis in the presence of the anticancer agents, paclitaxel, cisplatin, and MPA. Finally, we demonstrated that PXR overexpression caused a significant decrease in cell growth inhibition and inhibited apoptosis in the presence of paclitaxel or cisplatin. These data suggest that PXR down-regulation could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance to them, in the treatment of endometrial cancer.

Elevated level of serum retinol‐binding protein 4 in pregnancy‐induced hypertension

Aim:  Recent progress in adiposcience has revealed several important adipose‐tissue‐originated factors, so‐called adipokines. Retinol‐binding protein 4 (RBP4), a protein expressed and secreted by adipocytes, has been identified as a novel regulator of insulin resistance. Physiological insulin resistance occurs during the pregnancy of mammals to accommodate fetal growth, and it has been suggested that insulin resistance and hyperinsulinemia might also be associated with pregnancy‐induced hypertension (PIH). In order to shed light on the role of RBP4 during pregnancy, we attempted to assess RBP4 levels during pregnancy. Fetal growth could be affected by aberrant regulation of RBP4 levels in fetal circulation per se, so we examined the RBP4 levels in cord blood samples of growth restricted cases.

Relation between neonatal jaundice and oncostatin M, hepatocyte growth factor and soluble gp130 levels in umbilical cord.

Objectives. Oncostatin M (OSM), hepatocyte growth factor (HGF) and soluble glycoprotein 130 (sgp130) have been demonstrated to be involved in fetal liver development. In this study, we examined the relation between neonatal jaundice and OSM, gp130 or HGF levels in umbilical cord blood. Design. A cross‐sectional study of 160 neonates born at Okayama University Hospital. Setting. Tertiary referral center serving a population of three million. Methods. The serum concentrations of OSM, HGF and sgp130 in umbilical venous cord blood were measured and compared with the clinical records of these neonates. Results. The HGF level was correlated to both gestational week (p = 0.007) and birthweight (p = 0.015), as well as to total bilirubin on Day 1 (p = 0.032). In preterm neonates, the HGF levels were lower in neonates who received phototherapy (photo group) than in those who did not receive phototherapy (non‐photo group) (p = 0.002). In contrast, in term neonates, OSM levels were lower in the photo group than in the non‐photo group (p = 0.0003). Conclusions. These findings suggest that the phototherapy requirement for neonatal jaundice may be associated with lower umbilical HGF concentration in preterm neonates and with lower umbilical OSM concentration in term neonates.