Nobuhiro Sugiyama

A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is usually described as a pathological proliferation of prostatic fibroblasts/myofibroblasts and epithelial cells. In the present study of BPH samples, we have made a morphological and immunohistochemical study of BPH prostatic sections using markers of proliferation, apoptosis, hormone receptors, and TGF-β signaling. We found no evidence of proliferation in the stroma but in the epithelium of some ducts; 0.7% of the basal and 0.4% of luminal cells were positive for Ki67 and PCNA. Androgen receptor and estrogen receptor beta (ERβ)1 and ERβcx were abundant in both stromal and epithelial compartments but cells expressing ERα were very rare. What was very common in all BPH samples was the following: (i) regions of the ductal epithelium where the epithelial cells did not express E-cadherin, had lost their polarization, and become spindle shaped (the nuclei of these cells were strongly positive for pSmad 3 and Snail); and (ii) regions where the walls of the blood vessels were extremely thick and there was loss of endothelial layer. Loss of E-cadherin, increased pSmad 3, and high expression of Snail are all characteristic of epithelial-mesenchymal transition (EMT). We conclude that BPH is not a disease of prostatic stromal proliferation but rather of accumulation of mesenchymal-like cells derived from the prostatic epithelium and the endothelium. TGF-β is thought to play a key role in EMT. Our data suggests that TGF-β/Smad should be considered as targets for treatment of BPH.

Involvement of estrogen receptor β in maintenance of serotonergic neurons of the dorsal raphe

The serotonergic neurons of the dorsal raphe (DR) nucleus in the CNS are involved in fear, anxiety and depression. Depression and anxiety occur quite frequently in postmenopausal women, but estrogen replacement to correct these CNS disorders is at present not favored because estrogen carries with it an increased risk for breast cancer. Serotonin synthesis, release and reuptake in the DR are targets of pharmaceuticals in the treatment of depression. In the present study we have examined by immunohistochemistry, the expression of two nuclear receptors, that is, the estrogen receptors ERα and ERβ. We found that ERβ but not ERα is strongly expressed in the DR and there is no sex difference and no change with ageing in the number of tryptophan hydroxylase (TPH)-positive neurons in the DR of wild-type (WT) mice. However, in ovariectomized (OVX) WT and in ERβ−/− mice, there was a marked reduction in the number of TPH-positive normal-looking neurons and a marked increase in TPH-positive spindle-shaped cells. These neuronal changes were prevented in mice 1–3 weeks (but not 10 weeks) after OVX by the selective ERβ agonist, LY3201, given as continuous release pellets for 3 days. The ERβ agonist had no effects on glucose homeostasis. Thus, the onset of action of the ERβ agonist is rapid but there is a limited window in time after estrogen loss when the drug is useful. We conclude that, rather than estradiol, ERβ agonists could be useful pharmaceuticals in maintaining functional DR neurons to treat postmenopausal depression.

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERα and ERβ1 were widely distributed throughout the brain. Sucrose density gradient sedimentation followed by western blotting supported the histochemical evidence for high levels of both ERs at P7. Over the following 2 days, there was a rapid downregulation of ERs. At P9, ERα expression was visible only in the hypothalamic area. Decline in ERβ1 expression was slower than that of ERα, and ERα-negative, ERβ1-positive cells were observed in the dentate gyrus and walls of third ventricle. Between P14 and P35, ERs were undetectable except for the hypothalamic area. As before P7, the ovary does not produce estrogen but does produce 5α-androstane-3β, 17β-diol (3βAdiol), an estrogenic metabolite of dihydrotestosterone, we examined the effects of high levels of 3βAdiol in the postnatal period. We used CYP7B1 knockout mice which cannot hydroxylate and inactivate 3βAdiol. The brains of these mice are abnormally large with reduced apoptosis. In the early postnatal period, there was 1-week delay in the timing of the reduction in ER expression in the brain. These data reveal that the time when ERs might be activated in the brain is limited to the first 8 postnatal days. In addition, the importance of aromatase has to be reconsidered as the alternative estrogen, 3βAdiol, is important in neuronal function in the postnatal brain.

Effects of prolactin-releasing peptide microinjection into the ventrolateral medulla on arterial pressure and sympathetic activity in rats.

Prolactin-releasing peptide (PrRP), originally isolated from the hypothalamus, is highly localized in the cardiovascular regions of the medulla, and intracerebroventricular administration of PrRP causes a pressor response. In the present study we investigated the cardiovascular effects of PrRP applied to functionally different areas of the ventrolateral medulla (VLM), and to the nucleus tractus solitarius (NTS) and the area postrema (AP). In urethane-anesthetized rats, microinjection of PrRP into the pressor area of the most caudal VLM, recognized as the caudal pressor area in the rat, elicited dose-dependent increases in mean arterial pressure, heart rate, and renal sympathetic nerve activity. In the same injection area, neither thyrotropin-releasing hormone, corticotropin-releasing hormone nor angiotensin II affected these baseline cardiovascular variables. On the other hand, microinjection of PrRP into more rostral parts of the VLM, i.e. the depressor area of the caudal VLM and the pressor area of the rostral VLM, as well as the NTS and the AP, had no effect on these cardiovascular variables. Immunohistochemical analysis in the medulla revealed that the cardiovascularly PrRP-responsive region contained PrRP-immunoreactive cell bodies and nerve fibers. These results suggest that the most caudal VLM is an action site of PrRP to induce a pressor response, which is mediated, at least partly, by the increase in sympathetic outflow.

Poor performance on the Iowa gambling task in children with obsessive-compulsive disorder

BackgroundSeveral lines of evidence implicate orbitofrontal cortex dysfunction in the pathophysiology of obsessive-compulsive disorder (OCD). The purpose of this study was to investigate neuropsychological dysfunction of the orbitofrontal cortex in children with OCD.MethodsThe Iowa Gambling Task (IGT), which reflects orbitofrontal cortex function, and the Wisconsin Card Sorting Test (WCST), which is associated with functioning of the dorsolateral prefrontal cortex, were administered to 22 children with OCD and 22 healthy controls matched for gender, age, and intelligence.ResultsOCD patients displayed poor performance on the IGT. In contrast, performance on the WCST was not impaired in OCD patients compared to controls.ConclusionsThese findings are in line with previous studies demonstrating that OCD in childhood is associated with a dysfunction of orbitofrontal-striatal-thalamic circuitry.

What time periods of the day are concerning for parents of children with attention deficit hyperactivity disorder

Background/Aim The questionnaire-children with difficulties (QCD) is a parent-assessed questionnaire designed to evaluate a child’s difficulties in functioning during specific time periods of the day. In this study, the QCD was applied to determine the time periods of the day that are concerning for the parents of children with attention deficit hyperactivity disorder (ADHD). The results were compared with those for a community sample. Methods Elementary and junior high school students with ADHD (243 boys, 55 girls) and a community sample of children (518 boys, 618 girls) were enrolled in this study. Their behaviors were assessed by the QCD, the ADHD-rating scale (ADHD-RS), and the Oppositional Defiant Behavior Inventory (ODBI). The effects of gender (boy/girl) and diagnosis (ADHD/community sample) on the total QCD score were analyzed across each school grade (elementary/junior high school). Correlation coefficients between QCD and ADHD-RS/ODBI scores were analyzed. Results The QCD score for the ADHD group was significantly lower than that for the community sample (P < 0.001). There were significantly strong correlations between “evening” and ADHD-RS and ODBI scores for all children with ADHD (r > 0.41, P < 0.001) and between “night” and inattention and oppositional symptoms for the girls with ADHD (r > 0.40, P < 0.001). Conclusions Parents reported that children with ADHD faced greater difficulties in completing basic daily activities compared with the community controls, particularly in the evening. Furthermore, these difficulties were related to the severity of ADHD symptoms. The parents’ perceptions depended on the gender, ADHD and oppositional symptoms, and the time period of the day. This study determined that children with ADHD face greater difficulties in daily functioning compared with community sample children, that these difficulties are time-dependent, and that these difficulties were particularly experienced in the evening.

The reliability and validity of the Questionnaire - Children with Difficulties (QCD)

BackgroundThe aim of this study was to evaluate the reliability and validity of the Questionnaire-Children with Difficulties (QCD), which was developed for the evaluation of children’s daily life behaviors during specified periods of the day.MethodsThe subjects were 1,514 Japanese public elementary and junior high school students. For the examination of reliability, Cronbach’s alpha was calculated to assess the internal consistency of the questionnaire. With regard to validity, correlation coefficients were calculated to examine whether QCD scores correlated with those of the ADHD-Rating Scale (ADHD-RS) and the Oppositional Defiant Behavior Inventory (ODBI).ResultsCronbach’s alpha coefficient for the total score of the QCD was .876. The correlation coefficients of the QCD score with ADHD-RS and ODBI scores were -.514 and -.577, respectively.ConclusionsThe internal consistency and validity of the QCD were demonstrated. The QCD is a reliable and valid instrument for evaluating daily life problems for children during different time periods of the day.

Prion disease causes less severe lesions in human hippocampus than other parts of brain

Aim:  The hippocampus can be very sensitive to damage in the scrapie‐infected mouse, a well‐established animal model of prion diseases. Terminally ill scrapie‐infected animals exhibit nearly complete loss of cornu ammonis (CA) 1 pyramidal neurons, but few studies have focused on the neuropathological lesions of the human hippocampus in autopsied brain tissue; in particular, few findings on differences in severity of pathology between the hippocampal and parahippocampal formations have been obtained. The aim of the present paper is to evaluate the human hippocampus of prion disease through neuropathological examination.

Patterns of hippocampal atrophy differ among Alzheimer's disease, amnestic mild cognitive impairment, and late-life depression

This study investigated whether the characteristic changes in hippocampal atrophy seen in coronal scans are useful for differentiating Alzheimers disease (AD), amnestic mild cognitive impairment (aMCI), and major depressive disorder (MDD).

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Hormonal changes due to menopause can cause various health problems including weight gain and depressive symptoms. Multiple lines of evidence indicate that oestrogen receptors (ERs) play a major role in postmenopausal obesity and depression. However, little is known regarding the ER subtype-specific effects on obesity and depressive symptoms. To delineate potential effects of ERβ activation in postmenopausal women, we investigated the effects of a novel oestrogen receptor β-selective ligand (C-1) in ovariectomized mice. Uterine weight, depressive behaviour, and weight gain were examined in sham-operated control mice and ovariectomized mice administered placebo, C-1, or 17β-oestradiol (E2). Administration of C-1 or E2 reduced body weight gain and depressive-like behaviour in ovariectomized mice, as assessed by the forced swim test. In addition, administration of E2 to ovariectomized mice increased uterine weight, but administration of C-1 did not result in a significant increase in uterine weight. These results suggest that the selective activation of ERβ in ovariectomized mice may have protective effects against obesity and depressive-like behaviour without causing an increase in uterine weight. The present findings raise the possibility of the application of ERβ-ligands such as C-1 as a novel treatment for obesity and depression in postmenopausal women.