Disruption of Intranasal GnRH Neuronal Migration Route into the Brain Induced by Proinflammatory Cytokine IL-6: Ex Vivo and In Vivo Rodent Models.

Maternal immune activation results in altered levels of cytokines in the maternal-fetal system, which has a negative impact on fetal development, including the gonadotropin-releasing hormone (GnRH) system, which is crucial for the reproduction. Suppression of GnRH-neuron migration may be associated with cytokine imbalances, and primarily with proinflammatory cytokine interleukin (IL)-6. This study aimed to determine the effects of IL-6 and monoclonal antibody to IL-6 or IL-6R or polyclonal IgG on the formation of migration route of GnRH-neurons in ex vivo and in vivo rodent models on day 11.

Disruptions in Hypothalamic-Pituitary-Gonadal Axis Development and Their IgG Modulation after Prenatal Systemic Inflammation in Male Rats.

The development of the neuroendocrine system, including the hypothalamic-pituitary-gonadal (HPG) axis, is sensitive to environmental impacts during critical developmental periods. Maternal immune system activation by bacterial or viral infection may be one of the negative impacts. This study focused on the effect of systemic inflammation induced by lipopolysaccharides (LPS ) on the HPG axis development in male rat offspring, corrected by the anti-inflammatory action of polyclonal IgG and monoclonal anti-interleukin (IL)-6 receptor antibodies (IL-6RmAbs).

IgG modulation in male mice with reproductive failure after prenatal inflammation.

Sexual performance in adult male rats is highly sensitive to prenatal stress which can affect the functionality of the reproductive system and various brain structures involved in modulating sexual behavior. The immunomodulatory effect of mouse IgG on reproductive maturity in male offspring after LPS exposure in vivo and in vitro was studied. Prenatal IgG injection (20 µg/mouse) had a positive impact on the puberty of male mice whose mothers were exposed to LPS (100 µg/kg) on the 12th day of pregnancy.

Mechanisms of Reciprocal Regulation of Gonadotropin-Releasing Hormone (GnRH)-Producing and Immune Systems: The Role of GnRH, Cytokines and Their Receptors in Early Ontogenesis in Normal and Pathological Conditions.

Different aspects of the reciprocal regulatory influence on the development of gonadotropin-releasing hormone (GnRH)-producing- and immune systems in the perinatal ontogenesis and their functioning in adults in normal and pathological conditions are discussed. The influence of GnRH on the development of the immune system, on the one hand, and the influence of proinflammatory cytokines on the development of the hypothalamic-pituitary-gonadal system, on the other hand, and their functioning in adult offspring are analyzed. We have focused on the effects of GnRH on the formation and functional activity of the thymus, as the central organ of the immune system, in the perinatal period.

Perinatal Inflammation Reprograms Neuroendocrine, Immune, and Reproductive Functions: Profile of Cytokine Biomarkers.

Viral and bacterial infections causing systemic inflammation are significant risk factors for developing body. Inflammatory processes can alter physiological levels of regulatory factors and interfere with developmental mechanisms. The brain is the main target for the negative impact of inflammatory products during critical ontogenetic periods.

Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation.

This review provides information on the structure of estrogen receptors (ERs), their localization and functions in mammalian cells. Additionally, the structure of proteasomes and mechanisms of protein ubiquitination and cleavage are described. According to the modern concept, the ubiquitin proteasome system (UPS) is involved in the regulation of the activity of ERs in several ways.

Gonadotropin-Releasing Hormone in Regulation of Thymic Development in Rats: Profile of Thymic Cytokines.

An increasing body of recent experimental data confirms the impact of neurohormones on fetal development and function of different body systems. The synthesis of many neurohormones starts in fetal tissues before the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal systems are formed, and their high levels are detected in the bloodstream. Here, we studied the role of gonadotropin-releasing hormone (GnRH) in rat thymus development and tried to reveal possible mechanisms underlying the GnRH effects in early development.

Abolition of prenatal lipopolysaccharide-induced reproductive disorders in rat male offspring by fulvestrant.

During prenatal and early postnatal periods of development, multiple environmental factors have profound and long-lasting effects on the immune and reproductive functions. The aim of this study was to investigate the effects of maternal lipopolysaccharide (LPS) exposure (50 mg/kg, i.p.

Prenatal Programming of Neuroendocrine System Development by Lipopolysaccharide: Long-Term Effects.

Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be a powerful programming factor of fetal development. Studies of the molecular mechanisms controlling the formation and functioning of physiological systems are in the pilot stage.

Transplantation of Epigenetically Modified Adult Cardiac c-Kit+ Cells Retards Remodeling and Improves Cardiac Function in Ischemic Heart Failure Model.

Unlabelled: Cardiac c-Kit+ cells have a modest cardiogenic potential that could limit their efficacy in heart disease treatment. The present study was designed to augment the cardiogenic potential of cardiac c-Kit+ cells through class I histone deacetylase (HDAC) inhibition and evaluate their therapeutic potency in the chronic heart failure (CHF) animal model. Myocardial infarction (MI) was created by coronary artery occlusion in rats.

Anti-Fibrotic Effects of Class I HDAC Inhibitor, Mocetinostat Is Associated with IL-6/Stat3 Signaling in Ischemic Heart Failure.

Background: Recent studies have linked histone deacetylases (HDAC) to remodeling of the heart and cardiac fibrosis in heart failure. However, the molecular mechanisms linking chromatin remodeling events with observed anti-fibrotic effects are unknown. Here, we investigated the molecular players involved in anti-fibrotic effects of HDAC inhibition in congestive heart failure (CHF) myocardium and cardiac fibroblasts in vivo.

Lipopolysaccharide-induced maternal inflammation affects the gonadotropin-releasing hormone neuron development in fetal mice.

Recent studies provide evidence that prenatal immunological stress may affect the programming of reproductive health and sexual behavior in adult animals. The aim of this study was to investigate the influence of maternal inflammation, induced by an intraperitoneal (i.p.

Retrograde coronary vein infusion of cardiac explant-derived c-Kit+ cells improves function in ischemic heart failure.

Background: Progenitor cells isolated from cardiac explant-derived cells improve cardiac function after myocardial infarction (MI). To fully realize the therapeutic potential of these cells, it is essential to develop a safe and efficient delivery method. Therefore, the objective of this study was to determine the efficacy of our newly developed approach to retrograde coronary vein (RCV) infusion of cardiac c-Kit(+) cells in a small-animal model of congestive heart failure (CHF).

Chronic heart failure is associated with transforming growth factor beta-dependent yield and functional decline in atrial explant-derived c-Kit+ cells.

Background: Cardiac c-Kit+ cells isolated from cardiac explant-derived cells modestly improve cardiac functions after myocardial infarction; however, their full potential has not yet been realized. For instance, the majority of potential candidates for cell therapy suffer from chronic heart failure (CHF), and it is unclear how this disease affects the explant-derived progenitor cells. Therefore, the objective of this study was to determine the effect of CHF on the number and phenotype of cardiac explant c-Kit+ progenitors and elucidate mechanisms of their regulation.

Cardiac explant-derived cells are regulated by Notch-modulated mesenchymal transition.

Background: Progenitor cell therapy is emerging as a novel treatment for heart failure. However the molecular mechanisms regulating the generation of cardiac progenitor cells is not fully understood. We hypothesized that cardiac progenitor cells are generated from cardiac explant via a process similar to epithelial to mesenchymal transition (EMT).

Pattern of MHC class I and immune proteasome expression in Walker 256 tumor during growth and regression in Brattleboro rats with the hereditary defect of arginine-vasopressin synthesis.

Dynamics of the expression of MHC class I, immune proteasomes and proteasome regulators 19S, PA28, total proteasome pool and proteasome chymotrypsin-like activity in Walker 256 tumor after implantation into Brattleboro rats with the hereditary defect of arginine-vasopressin synthesis was studied. The tumor growth and regression in Brattleboro rats were accompanied by changes in the proteasome subunit level unlike the tumor growth in WAG rats with normal expression of arginine-vasopressin gene. In the tumor implanted into Brattleboro rats the immune proteasome level was maximal between days 14 and 17, when the tumor underwent regression.

Ontogenesis of rat immune system: Proteasome expression in different cell populations of the developing thymus.

Immune proteasomes in thymus are involved in processing of self-antigens, which are presented by MHC class I molecules for rejection of autoreactive thymocytes in adults and probably in perinatal rats. The distribution of immune proteasome subunits LMP7 and LMP2 in thymic cells have been investigated during rat perinatal ontogenesis. Double immunofluorescent labeling revealed LMP7 and LMP2 in thymic epithelial and dendritic cells, as well as in CD68 positive cells - macrophages, monocytes - at all developmental stages.

Transplantation of cardiac progenitor cell sheet onto infarcted heart promotes cardiogenesis and improves function.

Aims: Cell-based therapy for myocardial infarction (MI) holds great promise; however, the ideal cell type and delivery system have not been established. Obstacles in the field are the massive cell death after direct injection and the small percentage of surviving cells differentiating into cardiomyocytes. To overcome these challenges we designed a novel study to deliver cardiac progenitor cells as a cell sheet.

Endogenous Jmjd6 gene product is expressed at the cell surface and regulates phagocytosis in immature monocyte-like activated THP-1 cells.

A jumonji domain containing gene 6 (Jmjd6), previously referred to as phosphatidylserine receptor (PSR) gene, plays an important role in cell differentiation and development of multiple organs, although mechanisms of its action are not known. The Jmjd6 gene product was initially identified as a membrane protein that participates in phagocytosis. However, the later findings that recombinant Jmjd6 in expression systems was targeted to the nucleus challenged the role of Jmjd6 as a membrane receptor.

New approach to study of T cellular immunity development: parallel investigation of lymphoid organ formation and changes in immune proteasome amount in rat early ontogenesis.

The expression pattern and distribution of proteasome immune subunits LMP7 and LMP2 in the developing rat spleen and liver as well as the periarterial lymphoid sheath formation were investigated. LMP7 and LMP2 were detected by immunoblotting in the spleen on the 21st embryonic day and during the first postnatal days in equal amounts. Their levels increased by the 8th and 18th postnatal days.

Store-operated Ca2+ influx causes Ca2+ release from the intracellular Ca2+ channels that is required for T cell activation.

The precise control of many T cell functions relies on cytosolic Ca(2+) dynamics that is shaped by the Ca(2+) release from the intracellular store and extracellular Ca(2+) influx. The Ca(2+) influx activated following T cell receptor (TCR)-mediated store depletion is considered to be a major mechanism for sustained elevation in cytosolic Ca(2+) concentration ([Ca(2+)](i)) necessary for T cell activation, whereas the role of intracellular Ca(2+) release channels is believed to be minor. We found, however, that in Jurkat T cells [Ca(2+)](i) elevation observed upon activation of the store-operated Ca(2+) entry (SOCE) by passive store depletion with cyclopiazonic acid, a reversible blocker of sarco-endoplasmic reticulum Ca(2+)-ATPase, inversely correlated with store refilling.

T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor.

Activated T lymphocytes release vesicles, termed exosomes, enriched in cholesterol and exposing phosphatidylserine (PS) at their outer membrane leaflet. Although CD4(+) activated T lymphocytes infiltrate an atherosclerotic plaque, the effects of T cell exosomes on the atheroma-associated cells are not known. We report here that exosomes isolated from the supernatants of activated human CD4(+) T cells enhance cholesterol accumulation in cultured human monocytes and THP-1 cells.