Progesterone Signaling and Mammary Gland Morphogenesis

Progesterone was identified as a mammogenichormone several years ago but until now its precise rolein mammary development has remained obscure. Recentlywith the generation of several transgenic mouse models and development of reagents for analysisof progesterone receptor expression, the role ofprogesterone signaling in mammary development isbecoming more clear. The most significant observationsto emerge from these studies are (1) progesteronereceptors (PR)4 are present in a heterogeneous manner inthe epithelial cells and undetectable in the surroundingfat pad; (2) they are essential for lobuloalveolar and not for ductal morphogenesis; (3)progesterone signaling through progesterone receptors,leading to lobuloalveolar development, is initiated inthe epithelium and may occur through paracrinemechanisms; and (4) a regulated expression of the twoisoforms of progesterone receptor is critical formaintaining appropriate responsiveness to progesteroneand hence, epithelial cell replicative homeostasis.These studies also reveal that the consequences ofprogesterone signaling through progesterone receptor maydepend on the cell context, cell-cell andcell-extracellular matrix interactions, the dynamics ofPR turnover and the fate of PR positivecells.     

Ranitidine and Nizatidine Stimulate Antral Smooth Muscle Contractility via Excitatory Cholinergic Mechanisms

Histamine type 2 receptor antagonists (H2RAs)have been found to alter gastric motility. The aims ofthis study were to determine if H2RAs affect antralcontractility in vitro and the mechanism of this effect. Guinea pig antral muscle strips werepinned in an organ bath after removing the mucosa, andcircular muscle tension was measured using an isometricforce transducer. Gastric myocytes were isolated from guinea pig stomach using collagenasedigestion, and cell lengths were measured using an imageanalysis system. In muscle strips, ranitidine andnizatidine increased the amplitude of spontaneous phasic antral contractions in aconcentration-dependent fashion with thresholdconcentrations of 5 M. The order of potency for theH2RAs was ranitidine = nizatidine cimetidine >famotidine. The contractile effects of ranitidine and nizatidine werereduced, but not abolished, by tetrodo- toxin andomega-conotoxin GVIA and nearly abolished by atropine.In isolated cells, ranitidine and nizatidine, but notfamotidine or cimetidine, induced concentration-dependentcell shortening, with maximal shortening at 10 M.These contractile effects of ranitidine and nizatidinein isolated cells were inhibited by atropine. Ranitidine and nizatidine increase antral contractility;this effect appears to be mediated by an interactionbetween ranitidine and nizatidine on cholinergicpathways with both direct effects on smooth musclecholinergic receptors and indirect effects by increasingcholinergic neurotransmission.     

Estrogen Responsiveness and Control of Normal Human Breast Proliferation

Our understanding of the hormonal control of theproliferation of normal human breast epithelium is stillsurprisingly meager. However, the results of a number ofrecent studies have confirmed that estrogen is the major steroid mitogen for the luminalepithelial cell population (the usual targets forneoplastic transformation). Estrogen seemingly exertsits effects on cell division indirectly as there iscomplete dissociation between the population of luminalepithelial cells expressing the estrogen receptor (ER)4and those that proliferate. We suggest that theER-negative proliferating cells represent a precursor or stem cell population that differentiates toER-containing, nonproliferative cells. In turn, theseER-positive cells act as 'estrogen sensors' and transmitpositive or negative paracrine growth signals to the precursor cells depending on theprevailing hormonal environment.As yetthere is nodirectevidence supporting this hypothesis but we suggestways in which it may be obtained. The implication ofthese studies is that inhibition of luminalepithelial proliferation with tamoxifen or pureantiestrogens or by preventing ovarian steroid secretionshould be an effective strategy for the prevention ofbreast cancer. In addition, we may be able to predictthe risk of breast cancer in an individual by measuringthe intrinsic estrogen sensitivity of her breastepithelium. Finally, study of the paracrine mechanisms of growth control in the normal human breastmay provide new, more specific, therapeutic targets forbreast cancer prevention.     

Epithelial Transcytosis of Immunoglobulins

Transcytosis plays a central role in theimmunological functions of epithelia, including thesampling of antigens that enter the body via thedigestive, respiratory and urogenital tracts and theirpresentation to underlying lymphoid tissues, the secretionof specific immunoglobulins required for the immuneprotection of mucosal surfaces and the transfer ofmaternal immunoglobulins to the fetus or newborn,providing the latter with passive immunity for the firstweeks of independent life.     

Klotho Lacks an FGF23‐Independent Role in Mineral Homeostasis

Fibroblast growth factor‐23 (FGF23) is a bone‐derived hormone regulating vitamin D hormone production and renal handling of minerals by signaling through an FGF receptor/αKlotho (Klotho) receptor complex. Whether Klotho has FGF23‐independent effects on mineral homeostasis is a controversial issue. Here, we aimed to shed more light on this controversy by comparing male and female triple knockout mice with simultaneous deficiency in Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23/Klotho/VDR) with double (Fgf23/VDR, Klotho/VDR, and Fgf23/Klotho) and single Fgf23, Klotho, and VDR mutants. As expected, 4‐week‐old Fgf23, Klotho, and Fgf23/Klotho knockout mice were hypercalcemic and hyperphosphatemic, whereas VDR, Fgf23/VDR, and Klotho/VDR mice on rescue diet were normocalcemic and normophosphatemic. Serum levels of calcium, phosphate, and sodium did not differ between 4‐week‐old triple Fgf23/Klotho/VDR and double Fgf23/VDR or Klotho/VDR knockout mice. Notably, 3‐month‐old Fgf23/Klotho/VDR triple knockout mice were indistinguishable from double Fgf23/VDR and Klotho/VDR compound mutants in terms of serum calcium, serum phosphate, serum sodium, and serum PTH, as well as urinary calcium and sodium excretion. Protein expression analysis revealed increased membrane abundance of sodium‐phosphate co‐transporter 2a (NaPi‐2a), and decreased expression of sodium‐chloride co‐transporter (NCC) and transient receptor potential cation channel subfamily V member 5 (TRPV5) in Fgf23/Klotho/VDR, Fgf23/VDR, and Klotho/VDR mice, relative to wild‐type and VDR mice, but no differences between triple and double knockouts. Further, ex vivo treatment of live kidney slices isolated from wild‐type and Klotho/VDR mice with soluble Klotho did not induce changes in intracellular phosphate, calcium or sodium accumulation assessed by two‐photon microscopy. In conclusion, our data suggest that the main physiological function of Klotho for mineral homeostasis in vivo is its role as co‐receptor mediating Fgf23 action. © 2017 American Society for Bone and Mineral Research.     

Development of dentition: From initiation to occlusion and related diseases

BackgroundThe development of dentition begins in the embryonic oral cavity and progresses in the branchial arches and alveolar bone. Continuous cellular and molecular crosstalk occurs during crown formation, after which the tooth germ begins to migrate apically through the alveolar process into the oral cavity. It eventually comes in contact with its antagonist in the contralateral jaw to establish functional occlusion. Any defect in either step can result in delayed tooth development, the spectrum of which varies from a congenitally missing tooth to an impacted tooth (infraocclusion) with an eruption problem, both of which can impair oral function.HighlightCongenitally missing teeth or eruption problems may result from genetic mutations. Several different mutations have been identified, each causing a distinct phenotype. Thus, it is imperative that medical providers understand the fundamentals of these genetic principles that govern such dental diseases.ConclusionIn this review, we focus on several diseases, including congenitally missing teeth and tooth eruption problems. We review these diseases with aspect to their association with a particular syndrome, as well as independently in a non-syndromic capacity. We also review previously identified genetic mutations and discuss the possible mechanisms that cause individual phenotypes by analyzing previous investigations. We also discuss future prospects of how genetic diagnosis and precision medicine could impact the clinical environment in the field of dentistry.Ethical approvalPresent study has been carried out in accordance with The Code of Ethics of the World Medical Association and approved by Institutional Review Board of Osaka University Graduate School of Dentistry.     

Distribution of Glucocorticoid Receptor Immunoreactivity in Gastric Mucosa of Normal and Adrenalectomized Rats

Glucocorticoids have many effects in thestomach. It is well known that glucocorticoids functionvia the glucocorticoid receptor (GR). In this study, GRimmunoreactivity in the gastric mucosa of normal and adrenalectomized (ADX) rats was examinedimmunohistochemically by using specific polyclonalantibodies against rat GR. In the gastric mucosa ofnormal rats, GR immunoreactivity was observed in thenuclei of morphologically identified parietal cells.Double immunohistochemical staining for GR and parietalcell, anti-parietal cell antibody-positive cells alsohad positive immunoreactions for GR. In the gastric mucosa of ADX rats, GR immunoreactivity wasdiminished in the nuclei of parietal cells but weakimmunoreactivity was still observed. These resultssuggest that parietal cells in the gastric mucosa ofrats are directly regulated by glucocorticoids viaits receptors. Nuclear GR immunoreactivity in gastricparietal cells is thought to depend on the circulatingligands.     

术后抗炎汤对白内障晶体植入术患者白细胞介素2及其受体的影响

[目的]探讨具有补益肝肾、益气活血、祛风清热作用的术后抗炎汤(主要由黄芪、当归、枸杞、生地、防风、白 术、桑叶、菊花、钧藤等中药组成)对白内障患者手术后血清与泪液白介素2(IL-2)和可溶性白介素2受体(SIL-2R)的 影响及其临床意义。[方法]将47例行超声乳化加人工晶体植入术的白内障患者随机分为对照组(26例)和中药组(21 例),对照组给予常规手术和滴眼液,中药组在对照组的药物治疗基础上加用术后抗炎汤。另选15例门诊体检的健康老年 人为正常组。检测白内障患者手术前后血清和泪液IL-2和SIL-2R水平的变化。[结果]对照组和中药组术后血清SIL-2R均 比术前升高(均P<0.01),而中药组术后泪液SIL-2R与术前相比差异无统计学意义(P>0.05),对照组术后血清和泪液 IL-2和SIL-2R水平高于中药组和正常组(P<0.05或P<0.01)。[结论]术后抗炎汤通过调节眼局部免疫功能,能有效减 轻白内障术后的炎症反应。     

Brain endocannabinoid system is involved in fluoxetine-induced anorexia

Abstract

In order to describe the effects of chronic fluoxetine administration on the brain endocannabinoid system in lean and obese Zucker rats, brain immunostaining for the CB1 and CB1-phosphorylated cannabinoid receptors was carried out. Obese Zucker rats showed significantly increased the numbers of neural cells positively immunostained for the CB1-phosphorylated receptor in the striatum, compared to their lean litter-mates. Chronic fluoxetine administration decreased the number of neural cells immunostained for CB1-phosphorylated receptor in several striatal and hippocampal regions of obese Zucker rats, compared to controls treated with saline. In contrast, no change in CB1-phosphorylated receptor immunostaining was observed in fluoxetine-treated lean rats, with respect to controls. Taken together, these results suggest the involvement of the hippocampal and striatal endocannabinoid receptor system in fluoxetine-induced anorexia in lean and obese Zucker rats.