ПОЛІПИ ЕНДОМЕТРІЯ У ЖІНОК РЕПРОДУКТИВНОГО ВІКУ – СУЧАСНИЙ ЕТІОПАТОГЕНЕТИЧНИЙ ПОГЛЯД НА ПРОБЛЕМУ: (ОГЛЯД ЛІТЕРАТУРИ)

Hyperproliferative diseases of the endometrium in patients of childbearing age is one of the main causes of decreased fertility and the risk of developing oncological pathology. This publication is devoted to an urgent problem, namely, local endometrial hyperplasia, that is, endometrial polyps, which today requires a thorough study and improvement of methods for diagnosing and treating this pathology in order to preserve reproductive function. The aim of the scientific search is to review the literature on risk factors, etiology and pathogenesis of endometrial polyps, the role of chronic endometritis in the development of local endometrial hyperplasia in women of reproductive age. The leading links in the etiopathogenesis of this pathology are estrogenic stimulation, which is combined with progesterone deficiency, hormone-independent proliferation, chronic inflammation, pathological neoangiogenesis, and impaired immune status in the endometrium. Study of markers of apoptosis, proliferation, receptor status and oxidative stress to determine the intensity of proliferative endometrial processes will improve tactics of patient management, and development on this basis of new forecasting methods, treatment and prevention of endometrial polyps will help prevention of recurrence of pathology and preservation of the reproductive health of women. In addition, information is presented on the role of microbial and viral agents in the development of atypical endometrial hyperplasia in women of fertile age, and on the features of the expression of steroid hormone receptors in the pathologically altered endometrium. The role of echographic and hysteroscopic methods for diagnosing endometrial polyps was evaluated. The assessment of the effect of endometrial polyps on reproductive function was carried out.Гиперпролиферативные заболевания эндометрия у пациенток детородного возраста являются одной из основных причин снижения фертильности и риска развития онкологической патологии. Данная публикация посвящена актуальной проблеме, а именно локальной гиперплазии эндометрия, то есть полипам эндометрия, что требует на сегодняшний день тщательного изучения и совершенствования методов диагностики и лечения данной патологии с целью сохранения репродуктивной функции. Целью научного поиска является обзор литературы, посвященной факторам риска, этиологии и патогенезу полипов эндометрия, роли хронического эндометрита в развитии локальной гиперплазии эндометрия у женщин репродуктивного возраста. Ведущими звеньями этиопатогенеза данной патологии являются эстрогенная стимуляция, которая сочетается с недостаточностью прогестерона, гормон-независимая пролиферация, хроническое воспаление, патологический неоангиогенез, а также нарушения иммунного статуса в эндометрии. Исследование маркеров апоптоза, пролиферации, рецепторного статуса и оксидативного стресса для определения интенсивности пролиферативных процессов эндометрия позволит усовершенствовать тактику ведения пациентов, а разработка на этой основе новых методов прогнозирования, кор­рекции и профилактики полипов эндометрия будет способствовать предотвращению рецидивирования патологии и сохранению репродуктивного здоровья женщин. Кроме того, представлена ​​информация о роли микробного и вирусного агентов в развитии неатипичной гиперплазии эндометрия у женщин фертильного возраста, особенности экспрессии рецепторов стероидных гормонов в патологически измененном эндометрии. Оценена роль эхографических и гистероскопических методов диагностики полипов эндометрия. Проведена оценка влияния полипов эндометрия на репродуктивную функцию.Гіперпроліферативні захворювання ендометрія у пацієнток дітородного віку є однією з основних причин зниження фертильності і ризику розвитку онкологічної патології. Дана публікація присвячена актуальній проблемі, а саме локальній гіперплазії ендометрія, тобто поліпам ендометрія, що потребує на сьогодні ретельного вивчення й удосконалення методів діагностики та лікування даної патології з метою збереження репродуктивної функції. Метою наукового пошуку є огляд літератури, присвяченої факторам ризику, етіології та патогенезу розвитку поліпів ендометрія, ролі хронічного ендометриту в розвитку локальної гіперплазії ендометрія у жінок репродуктивного віку. Провідними ланками етіопатогенезу даної патології є естрогенна стимуляція, що поєднується з недостатністю прогестерону, гормон-незалежна проліферація, хронічне запалення, патологічний неоваскулогенез, а також порушення імунного статусу в ендометрії. Дослідження маркерів апоптозу, проліферації, рецепторного статусу і оксидативного стресу для визначення інтенсивності проліферативних процесів ендометрія дозволить удосконалити тактику ведення пацієнтів, а розробка на цій основі нових методів прогнозування, корекції та профілактики поліпів ендометрія сприятиме попередженню рецидиву патології і збереженню репродуктивного здоров’я жінок. Крім того, досліджено роль мікробного та вірусного агентів у розвитку неатипової гіперплазії ендометрія у жінок фертильного віку, особливості експресії рецепторів стероїдних гормонів у патологічно зміненому ендометрії. Оцінено роль ехографічних та гістероскопічних методів діагностики поліпів ендометрія. Проведено оцінку впливу поліпів ендометрія на репродуктивну функцію

Ciliopathy is differentially distributed in the brain of a Bardet-Biedl syndrome mouse model

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous inherited human disorder displaying a pleotropic phenotype. Many of the symptoms characterized in the human disease have been reproduced in animal models carrying deletions or knock-in mutations of genes causal for the disorder. Thinning of the cerebral cortex, enlargement of the lateral and third ventricles, and structural changes in cilia are among the pathologies documented in these animal models. Ciliopathy is of particular interest in light of recent studies that have implicated primary neuronal cilia (PNC) in neuronal signal transduction. In the present investigation, we tested the hypothesis that areas of the brain responsible for learning and memory formation would differentially exhibit PNC abnormalities in animals carrying a deletion of the Bbs4 gene (Bbs4-/-). Immunohistochemical localization of adenylyl cyclase-III (ACIII), a marker restricted to PNC, revealed dramatic alterations in PNC morphology and a statistically significant reduction in number of immunopositive cilia in the hippocampus and amygdala of Bbs4-/- mice compared to wild type (WT) littermates. Western blot analysis confirmed the decrease of ACIII levels in the hippocampus and amygdala of Bbs4-/- mice, and electron microscopy demonstrated pathological alterations of PNC in the hippocampus and amygdala. Importantly, no neuronal loss was found within the subregions of amygdala and hippocampus sampled in Bbs4-/- mice and there were no statistically significant alterations of ACIII immunopositive cilia in other areas of the brain not known to contribute to the BBS phenotype. Considered with data documenting a role of cilia in signal transduction these findings support the conclusion that alterations in cilia structure or neurochemical phenotypes may contribute to the cognitive deficits observed in the Bbs4-/- mouse mode. © 2014 Agassandian et al

Oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in <i>Caenorhabditis elegans</i>

<div><p>The mechanisms by which the sensory environment influences metabolic homeostasis remains poorly understood. In this report, we show that oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. <i>C</i>. <i>elegans</i> oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for <i>C</i>. <i>elegans</i>. Under lower oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss to the availability of food and oxygen, and provides an interesting example of the myriad mechanisms underlying homeostatic control.</p></div

A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened

Many signaling proteins including G protein-coupled receptors localize to primary cilia, regulating cellular processes including differentiation, proliferation, organogenesis, and tumorigenesis. Bardet-Biedl Syndrome (BBS) proteins are involved in maintaining ciliary function by mediating protein trafficking to the cilia. However, the mechanisms governing ciliary trafficking by BBS proteins are not well understood. Here, we show that a novel protein, Leucine-zipper transcription factor-like 1 (LZTFL1), interacts with a BBS protein complex known as the BBSome and regulates ciliary trafficking of this complex. We also show that all BBSome subunits and BBS3 (also known as ARL6) are required for BBSome ciliary entry and that reduction of LZTFL1 restores BBSome trafficking to cilia in BBS3 and BBS5 depleted cells. Finally, we found that BBS proteins and LZTFL1 regulate ciliary trafficking of hedgehog signal transducer, Smoothened. Our findings suggest that LZTFL1 is an important regulator of BBSome ciliary trafficking and hedgehog signaling

The dynamic cilium in human diseases

Cilia are specialized organelles protruding from the cell surface of almost all mammalian cells. They consist of a basal body, composed of two centrioles, and a protruding body, named the axoneme. Although the basic structure of all cilia is the same, numerous differences emerge in different cell types, suggesting diverse functions. In recent years many studies have elucidated the function of 9+0 primary cilia. The primary cilium acts as an antenna for the cell, and several important pathways such as Hedgehog, Wnt and planar cell polarity (PCP) are transduced through it. Many studies on animal models have revealed that during embryogenesis the primary cilium has an essential role in defining the correct patterning of the body. Cilia are composed of hundreds of proteins and the impairment or dysfunction of one protein alone can cause complete loss of cilia or the formation of abnormal cilia. Mutations in ciliary proteins cause ciliopathies which can affect many organs at different levels of severity and are characterized by a wide spectrum of phenotypes. Ciliary proteins can be mutated in more than one ciliopathy, suggesting an interaction between proteins. To date, little is known about the role of primary cilia in adult life and it is tempting to speculate about their role in the maintenance of adult organs. The state of the art in primary cilia studies reveals a very intricate role. Analysis of cilia-related pathways and of the different clinical phenotypes of ciliopathies helps to shed light on the function of these sophisticated organelles. The aim of this review is to evaluate the recent advances in cilia function and the molecular mechanisms at the basis of their activity

Hyperactive Neuroendocrine Secretion Causes Size, Feeding, and Metabolic Defects of C. elegans Bardet-Biedl Syndrome Mutants

Bardet-Biedl syndrome, BBS, is a rare autosomal recessive disorder with clinical presentations including polydactyly, retinopathy, hyperphagia, obesity, short stature, cognitive impairment, and developmental delays. Disruptions of BBS proteins in a variety of organisms impair cilia formation and function and the multi-organ defects of BBS have been attributed to deficiencies in various cilia-associated signaling pathways. In C. elegans, bbs genes are expressed exclusively in the sixty ciliated sensory neurons of these animals and bbs mutants exhibit sensory defects as well as body size, feeding, and metabolic abnormalities. Here we show that in contrast to many other cilia-defective mutants, C. elegans bbs mutants exhibit increased release of dense-core vesicles and organism-wide phenotypes associated with enhanced activities of insulin, neuropeptide, and biogenic amine signaling pathways. We show that the altered body size, feeding, and metabolic abnormalities of bbs mutants can be corrected to wild-type levels by abrogating the enhanced secretion of dense-core vesicles without concomitant correction of ciliary defects. These findings expand the role of BBS proteins to the regulation of dense-core-vesicle exocytosis and suggest that some features of Bardet-Biedl Syndrome may be caused by excessive neuroendocrine secretion

The Role for HNF-1β-Targeted Collectrin in Maintenance of Primary Cilia and Cell Polarity in Collecting Duct Cells

Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1α, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1β and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to γ-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1β and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1β regulated genes

Pheromone-sensing neurons regulate peripheral lipid metabolism in <i>Caenorhabditis elegans</i>

It is now established that the central nervous system plays an important role in regulating whole body metabolism and energy balance. However, the extent to which sensory systems relay environmental information to modulate metabolic events in peripheral tissues has remained poorly understood. In addition, it has been challenging to map the molecular mechanisms underlying discrete sensory modalities with respect to their role in lipid metabolism. In previous work our lab has identified instructive roles for serotonin signaling as a surrogate for food availability, as well as oxygen sensing, in the control of whole body metabolism. In this study, we now identify a role for a pair of pheromone-sensing neurons in regulating fat metabolism in C. elegans, which has emerged as a tractable and highly informative model to study the neurobiology of metabolism. A genetic screen revealed that GPA-3, a member of the Gα family of G proteins, regulates body fat content in the intestine, the major metabolic organ for C. elegans. Genetic and reconstitution studies revealed that the potent body fat phenotype of gpa-3 null mutants is controlled from a pair of neurons called ADL(L/R). We show that cAMP functions as the second messenger in the ADL neurons, and regulates body fat stores via the neurotransmitter acetylcholine, from downstream neurons. We find that the pheromone ascr#3, which is detected by the ADL neurons, regulates body fat stores in a GPA-3-dependent manner. We define here a third sensory modality, pheromone sensing, as a major regulator of body fat metabolism. The pheromone ascr#3 is an indicator of population density, thus we hypothesize that pheromone sensing provides a salient 'denominator' to evaluate the amount of food available within a population and to accordingly adjust metabolic rate and body fat levels

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders are highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points towards DISC1 being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain