Signaling Molecules of Human Skin Cells as the Targets for Injection Cosmetology.

INTRODUCTION: Skin aging is a natural process that cannot be stopped. However, there are many ways to help attenuate premature aging of the skin and reduce the signs that have already appeared. One of them is the subcutaneous administration of preparations containing a combination of hyaluronic acid, active amino acids, and peptides providing an anti-aging clinical effect. The purpose of this research is to study in vitro new signaling molecules with the anti-aging effects and influence of hyaluronic acid fillers on its expression. METHODS: The study was conducted using cell cultures of human facial skin: 1) mixed culture of human facial skin keratinocytes and fibroblasts, and 2) culture of human facial skin keratinocytes enriched with Merkel cells. Immunocytochemistry, confocal microscopy and Western blot were used to identify markers of aging. RESULTS: HA-Y and HA-S activated the expression of Klotho in the case of aging mixed culture of human skin keratinocytes and Merkel cells. The increase in expression of MTH-1 with aging of cultures provides evidence of activating defense mechanisms against reactive oxygen species that are accumulating with aging, under the action of HA-S and HA-Y. There was a statistically valid increase in the area of expression of melatonin receptor 1A and 1B markers when adding both HA-S and HA-Y to cultured cells. CONCLUSION: This investigation showed that the studied fillers have biological effects, testifying the stimulation of reparative processes in the skin under their control.

Maternal Melatonin Deficiency Leads to Endocrine Pathologies in Children in Early Ontogenesis.

The review summarizes the results of experimental and clinical studies aimed at elucidating the causes and pathophysiological mechanisms of the development of endocrine pathology in children. The modern data on the role of epigenetic influences in the early ontogenesis of unfavorable factors that violate the patterns of the formation of regulatory mechanisms during periods of critical development of fetal organs and systems and contribute to the delayed development of pathological conditions are considered. The mechanisms of the participation of melatonin in the regulation of metabolic processes and the key role of maternal melatonin in the formation of the circadian system of regulation in the fetus and in the protection of the genetic program of its morphofunctional development during pregnancy complications are presented. Melatonin, by controlling DNA methylation and histone modification, prevents changes in gene expression that are directly related to the programming of endocrine pathology in offspring. Deficiency and absence of the circadian rhythm of maternal melatonin underlies violations of the genetic program for the development of hormonal and metabolic regulatory mechanisms of the functional systems of the child, which determines the programming and implementation of endocrine pathology in early ontogenesis, contributing to its development in later life. The significance of this factor in the pathophysiological mechanisms of endocrine disorders determines a new approach to risk assessment and timely prevention of offspring diseases even at the stage of family planning.

The Role of Prenatal Melatonin in the Regulation of Childhood Obesity.

There is a growing awareness that pregnancy can set the foundations for an array of diverse medical conditions in the offspring, including obesity. A wide assortment of factors, including genetic, epigenetic, lifestyle, and diet can influence foetal outcomes. This article reviews the role of melatonin in the prenatal modulation of offspring obesity. A growing number of studies show that many prenatal risk factors for poor foetal metabolic outcomes, including gestational diabetes and night-shift work, are associated with a decrease in pineal gland-derived melatonin and associated alterations in the circadian rhythm. An important aspect of circadian melatonin's effects is mediated via the circadian gene, BMAL1, including in the regulation of mitochondrial metabolism and the mitochondrial melatoninergic pathway. Alterations in the regulation of mitochondrial metabolic shifts between glycolysis and oxidative phosphorylation in immune and glia cells seem crucial to a host of human medical conditions, including in the development of obesity and the association of obesity with the risk of other medical conditions. The gut microbiome is another important hub in the pathoetiology and pathophysiology of many medical conditions, with negative consequences mediated by a decrease in the short-chain fatty acid, butyrate. The effects of butyrate are partly mediated via an increase in the melatoninergic pathway, indicating interactions of the gut microbiome with melatonin. Some of the effects of melatonin seem mediated via the alpha 7 nicotinic receptor, whilst both melatonin and butyrate may regulate obesity through the opioidergic system. Oxytocin, a recently recognized inhibitor of obesity, may also be acting via the opioidergic system. The early developmental regulation of these processes and factors by melatonin are crucial to the development of obesity and many diverse comorbidities.

Reciprocal Interactions of Mitochondria and the Neuroimmunoendocrine System in Neurodegenerative Disorders: An Important Role for Melatonin Regulation.

Structural and functional alterations of mitochondria are intimately linked to a wide array of medical conditions. Many factors are involved in the regulation of mitochondrial function, including cytokines, chaperones, chemokines, neurosteroids, and ubiquitins. The role of diffusely located cells of the neuroendocrine system, including biogenic amines and peptide hormones, in the management of mitochondrial function, as well as the role of altered mitochondrial function in the regulation of these cells and system, is an area of intense investigation. The current article looks at the interactions among the cells of the neuronal-glia, immune and endocrine systems, namely the diffuse neuroimmunoendocrine system (DNIES), and how DNIES interacts with mitochondrial function. Whilst changes in DNIES can impact on mitochondrial function, local, and systemic alterations in mitochondrial function can alter the component systems of DNIES and their interactions. This has etiological, course, and treatment implications for a wide range of medical conditions, including neurodegenerative disorders. Available data on the role of melatonin in these interactions, at cellular and system levels, are reviewed, with directions for future research indicated.

Plurihormonal cells of normal anterior pituitary: Facts and conclusions.

INTRODUCTION: plurihormonality of pituitary adenomas is an ability of adenoma cells to produce more than one hormone. After the immunohistochemical analysis had become a routine part of the morphological study, a great number of adenomas appeared to be multihormonal in actual practice. We hypothesize that the same cells of a normal pituitary gland releases several hormones simultaneously. OBJECTIVE: To analyse a possible co-expression of hormones by the cells of the normal anterior pituitary of adult humans in autopsy material. MATERIALS AND METHODS: We studied 10 pituitary glands of 4 women and 6 men with cardiovascular and oncological diseases. Double staining immunohistochemistry using 11 hormone combinations was performed in all the cases. These combinations were: prolactin/thyroid-stimulating hormone (TSH), prolactin/luteinizing hormone (LH), prolactin/follicle-stimulating hormone (FSH), prolactin/adrenocorticotropic hormone (ACTH), growth hormone (GH)/TSH, GH/LH, GH/FSH, GH/ACTH, TSH/LH, TSH/FSH, TSH/ACTH. Laser Confocal Scanning Microscopy with a mixture of primary antibodies was performed in 2 cases. These mixtures were ACTH/prolactin, FSH/prolactin, TSH/prolactin, ACTH/GH, and FSH/GH. RESULTS: We found that the same cells of the normal adenohypophysis can co-express prolactin with ACTH, TSH, FSH, LH; GH with ACTH, TSH, FSH, LH, and TSH with ACTH, FSH, LH. The comparison of the average co-expression coefficients of prolactin, GH and TSH with other hormones showed that the TSH co-expression coefficient was significantly the least (9,5±6,9%; 9,6±7,8%; 1,0±1,3% correspondingly). CONCLUSION: Plurihormonality of normal adenohypophysis is an actually existing phenomenon. Identification of different hormones in pituitary adenomas enables to find new ways to improve both diagnostic process and targeted treatment.

Cosmeceutical product consisting of biomimetic peptides: antiaging effects in vivo and in vitro.

BACKGROUND: Biomimetic peptides are synthetic compounds that are identical to amino acid sequence synthesized by an organism and can interact with growth factor receptors and provide antiaging clinical effects. PURPOSE: The purpose of this study was to investigate the effects of biomimetic peptides on the repair processes in the dermis using a model of cell cultures and in vivo. PATIENTS AND METHODS: Five female volunteers were subjected to the injection of biomimetic peptides 1 month prior to the abdominoplasty procedure. Cell culture, immunocytochemistry, and confocal microscopy methods were used in this study. RESULTS: Biomimetic peptides regulate the synthesis of proteins Ki-67, type I procollagen, AP-1, and SIRT6 in cell cultures of human fibroblasts. They contribute to the activation of regeneration processes and initiation of mechanisms that prevent aging. Intradermal administration of complex of biomimetic peptides produces a more dense arrangement of collagen fibers in the dermis and increased size of the fibers after 2 weeks. The complex of biomimetic peptides was effective in the in vivo experiments, where an increase in the proliferative and synthetic activities of fibroblasts was observed. CONCLUSION: This investigation showed that the studied peptides have biological effects, testifying the stimulation of reparative processes in the skin under their control.

Morphofunctional and signaling molecules overlap of the pineal gland and thymus: role and significance in aging.

Deficits in neuroendocrine-immune system functioning, including alterations in pineal and thymic glands, contribute to aging-associated diseases. This study looks at ageing-associated alterations in pineal and thymic gland functioning evaluating common signaling molecules present in both human and animal pinealocytes and thymocytes: endocrine cell markers (melatonin, serotonin, pCREB, AANAT, CGRP, VIP, chromogranin А); cell renovation markers (p53, AIF, Ki67), matrix metalloproteinases (MMP2, MMP9) and lymphocytes markers (CD4, CD5, CD8, CD20). Pineal melatonin is decreased, as is one of the melatonin pathway synthesis enzymes in the thymic gland. A further similarity is the increased MMPs levels evident over age in both glands. Significant differences are evident in cell renovation processes, which deteriorate more quickly in the aged thymus versus the pineal gland. Decreases in the number of pineal B-cells and thymic T-cells were also observed over aging. Collected data indicate that cellular involution of the pineal gland and thymus show many commonalities, but also significant changes in aging-associated proteins. It is proposed that such ageing-associated alterations in these two glands provide novel pharmaceutical targets for the wide array of medical conditions that are more likely to emerge over the course of ageing.

Comparison of circadian characteristics for cytotoxic lymphocyte subsets in non-small cell lung cancer patients versus controls.

Lymphocyte subsets are major cellular components of the adaptive immune response and in most cases show 24-h (circadian) variations in health. In order to determine overall levels and circadian characteristics of cytotoxic natural killer (NK) and T and B lymphocyte subsets, blood samples were collected every 4 h for 24 h from eleven male controls (C) without neoplastic disease and nine men with untreated non-small cell lung cancer (NSCLC) and analyzed for 3 hormones (melatonin, cortisol, and interleukin 2 [IL2]) and for 11 lymphocyte subpopulations classified by cell surface clusters of differentiation (CD) and antigen receptors. Circadian rhythmicity for each variable was evaluated by ANOVA and 24 h cosine fitting and groups compared. Rhythms in melatonin and cortisol (peaks near 01:30 and 08:00 h) indicated identical synchronization to the light-dark schedule and probable persistent entrainment of rhythms for both groups in metabolism or proliferation of healthy tissues normally tightly coupled to the sleep-wake cycle. Twenty-four hours means were significantly higher in NSCLC for CD16, CD25, cortisol, and IL2 and lower for CD8, CD8bright, and γδTCR. A significant circadian rhythm was found in C with daytime peaks for CD8, CD8dim, CD16, Vδ2TCR, and cortisol and nighttime peaks for CD3, CD4, CD20, and melatonin, and in NSCLC, with daytime peaks for CD16, γδTCR, Vδ2TCR and cortisol, and nighttime peaks for CD4, CD25, and melatonin. Thus, NSCLC was associated with significant increases or decreases in proportions for several lymphocyte subsets that may reflect disease development, but peak times were nevertheless similar between C and NSCLC for each variable, suggesting that timed circadian administration (chronotherapy) of immunotherapy and other cancer treatments may improve efficacy due to persistent circadian entrainment of healthy tissues.

Hormonal function and proliferative activity of thymic cells in humans: immunocytochemical correlations.

OBJECTIVES: The immunocytochemical study of the localization of hormones in thymic cells has been performed to clarify possible correlations of their expression with proliferative activity of thymocytes. METHODS: We used commercial antibodies to serotonin, melatonin, somatostatin, glucagon, gastrin, beta-endorphin and histamine, and ABP or BSP kits for visualization of reaction. Computer image analysis was used to find correlations between hormone production and proliferative activity of thymocytes. RESULTS: Different subpopulations of thymocytes are able to produce hormones: precursors of T-lymphocytes (CD4-CD8-) contain serotonin and melatonin, immature cortical cells (CD4+CD8+) produce only serotonin, mature medullar cells (CD4+CD8-) show immunoreactivity to serotonin, melatonin, beta-endorphin and histamine. The expression of serotonin, somatostatin and gastrin is localized in thymic epithelial cells, formatting Gassal's bodies. Proliferative activity of thymocytes depends from the expression of serotonin and somatostatin in thymic cells. CONCLUSION: The data received testify the expression of different hormones in human thymic cells and showing by this fact high endocrine activity of thymus. The presence of correlations between hormonal expression and cell proliferative activity could be considered as the bright illustration of important role of neuroimmunoendocrine mechanisms in the regulation of local thymic homeostasis.

Gastrointestinal melatonin: cellular identification and biological role.

Melatonin, a pineal hormone, because of its wide activity spectrum, is a subject of much current interest for biologists and physicians. It has been demonstrated that pineal gland is not an exclusive source of melatonin synthesis. Melatonin synthesis has been found in different sites of the organism, and a major source of extrapineal melatonin is the gastrointestinal tract. The role of melatonin in gastrointestinal functions is considered in the present review.

Diffuse neuroendocrine system and mitochondrial diseases: molecular and cellular bases of pathogenesis, new approaches to diagnosis and therapy.

Structural and functional alterations of mitochondria have been shown to be responsible for a wide variety of clinical disorders that are referred to as "mitochondrial diseases." It is now obvious that many factors are involved in transport of mitochondrial proteins including cytokines, chaperones, chemokines, neurosteroids, ubiquitin and many others. At the same time the participation and the role of biogenic amines and peptide hormones (which are produced by the diffuse neuroendocrine system cells located in different organs) in endogenous mechanisms of mitochondrial diseases are still unknown. Taking into account the wide spectrum of biological effects of biogenic amines and peptide hormones, and especially their regulatory role for intercellular communication, it seems important to analyze the possible participation of these molecules in the pathogenesis of mitochondrial disorders as well as to draw up new ways for elaboration of new markers for lifetime diagnosis, definition of prognosis and efficiency of specific therapy in neurodegenerative diseases.

Tau-protein expression in human blood lymphocytes: a promising marker and suitable sample for life-time diagnosis of Alzheimer's disease.

OBJECTIVES: Taking into account the hypothesis that Alzheimer's disease (AD) might be a systemic disease that affects several tissues in the body, the aim of this study was to try to detect the expression of tau-protein in human peripheral blood lymphocytes (PBL) in patients with AD. MATERIAL AND METHODS: Blood samples were obtained from patients with AD (n=16, age 67-98) and from volunteers without psychoneurological pathology (n=10, age 65-78). PBL were isolated on Ficoll-Paque gradient centrifugation. For cell fixation and permeabilization we used a fixative solution (4% formaldehyde and 0.1% glutaraldehyde) and 0.03% Triton X-100. Immunocytochemical detection of tau-protein was carried out by biotin-streptavidin complex method with tau monoclonal antibody (1:100, clone TAU-2, ICN) and universal immunostaining kit IMMU-MARK (ICN). RESULTS: The expression of tau-protein was shown in PBL in absolute majority of AD patients studied. Only in two healthy volunteers a single lymphocyte from many cells (i.e. a smear) demonstrated a very weak-positive immunostaining to tau-protein CONCLUSION: This first demonstration of clear difference in localization of tau-protein in blood lymphocytes between healthy and sick people testifies to the fact that tau-protein could be considered as a promising marker and blood lymphocytes as a suitable sample for life-time diagnosis of AD.