Although estrogen is known to activate endothelial nitric oxide synthase (eNOS) in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells ( The inhibitory effect of estrogen on the development of atherosclerosis has been suggested by abundant human epidemiological and animal experimental data (1-9). The incidence of atherosclerotic diseases is lower in premenopausal women than in men, steeply rises in postmenopausal women, and is reduced to premenopausal levels in postmenopausal women who receive estrogen therapy (10 -12). Until recently, the atheroprotective effects of estrogen were attributed principally to the effects on serum lipid concentrations. However, estrogeninduced alterations in serum lipids account for only approximately one-third of the observed clinical benefits of estrogen (12)(13)(14). Recent evidence suggests that the direct actions of estrogen on blood vessels contribute to the cardioprotective effects of estrogen (13, 15). There are many kinds of direct effects of estrogen on blood vessels, such as estrogen-induced increases of vasodilatation and inhibition of the response of blood vessels to injury and the development of atherosclerosis. However, the molecular mechanism underlying the estrogeninduced vasodilatation has not yet been determined. Several studies suggest that a key mediator of this vasodilator response could be the endothelium-derived relaxing factor nitric oxide (NO), and that brief treatment with estrogen increases basal NO release in endothelial cells without elevation of eNOS mRNA or protein (16). Estrogen activates endothelial nitric oxide synthase (eNOS) without altering expression of the eNOS gene in vascular endothelium (17)(18)(19)(20). However, the details of the mechanism of the estrogen-induced eNOS activation are not yet well understood.The serine/threonine kinase termed Akt or protein kinase B (PKB) 1 is an important regulator of various cellular processes, including glucose metabolism and cell survival (21, 22). Activation of receptor tyrosine kinases and G-protein-coupled receptors, and stimulation of cells by mechanical force, can lead to the phosphorylation and activation of . Akt was identified as a downstream component of survival signaling through phosphatidylinositol 3-kinase (PI3K) (26 -30). Akt may be regulated by both phosphorylation and the direct binding of PI3K lipid products to the Akt pleckstrin homology domain. Akt can then phosphorylate substrates such as glycogen synthase kinase-3, 6-phosphofructo-2-kinase, and BAD. More recently, it was found that eNOS is also an Akt substrate and is activated by Akt-dependent phosphorylation to release NO in endothelial cells (31-34).The actions of estrogen can be mediated by the classical nuclear receptors, ER␣ and ER␤ (35,36) or through other putative membrane receptors. By definition, rapid effects of estrogen that involve nongenomic mechanisms are independent of transcriptional activation by the nuclea...

We investigated whether inhibition of nuclear factor-B (NF B) increases the efficacy of paclitaxel in in vitro

To investigate the prevalence and impact of premenstrual symptoms in Japanese women, we developed the PSQ "The Premenstrual Symptoms Questionnaire" for the screening of premenstrual symptoms. The PSQ translates DSM-IV criteria into a rating scale with degrees of severity. One thousand one hundred and eighty-seven Japanese women between the ages of 20 and 49 yrs, who were seen at a clinic for uterine cancer screening, were assessed regarding their premenstrual symptoms using the PSQ. As many as 95% of these women were found to suffer from premenstrual symptoms. The rates of prevalence of moderate to severe PMS and PMDD in Japanese women were 5.3 and 1.2%, respectively, which are lower than those in Western women. Only 5.3% of women with moderate to severe PMS and PMDD were treated. The results of this study suggest that race and ethnicity influence the expression of premenstrual symptoms and that the current state of medical care for Japanese women with moderate to severe PMS and PMDD is not satisfactory.

Glucose transporter 1 (GLUT1) plays an important role in the transport of glucose in the placenta. During early pregnancy, placentation occurs in a relatively hypoxic environment that is essential for appropriate embryonic development, and GLUT1 expression is enhanced in response to oxygen deficiency in the placenta. Hypoxia-inducible factor-1 (HIF-1)alpha is involved in the induction of GLUT1 expression in other cells. The present study was designed to test whether HIF-1alpha is involved in hypoxia-induced activation of GLUT1 expression using trophoblast-derived human BeWo and rat Rcho-1 cells as models. GLUT1 mRNA and protein expression were elevated under 5% O2 or in the presence of cobalt chloride, which has been shown to mimic hypoxia. Using rat GLUT1 (rGLUT1) promoter-luciferase constructs, we showed that this up-regulation was mediated at the transcriptional level. Deletion mutant analysis of the rGLUT1 promoter indicated that a 184 bp hypoxia-responsive element (HRE) of the promoter was essential to increase GLUT1 reporter gene expression in response to low-oxygen conditions. BeWo and Rcho-1 cells cultured under 5% O2 or with CoCl2 showed increased expression of HIF-1alpha protein compared with those cultured under 20% O2. To test whether this factor is directly involved in hypoxia-induced GLUT1 promoter activation, BeWo and Rcho-1 cells were transiently transfected with an HIF-1alpha expression vector. Exogeneous HIF-1alpha markedly increased the GLUT1 promoter activity from constructs containing the HRE site, while the GLUT1 promoter constructs lacking the HRE site were not activated by exogenous HIF-1alpha These data demonstrate that GLUT1 is up-regulated under 5% O2 or in the presence of CoCl2 in the placental cell lines through HIF-1alpha interaction with a consensus HRE site of the GLUT1 promoter.

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