Pullulan-Based Hydrogels in Wound Healing and Skin Tissue Engineering Applications: A Review.

Wound healing is a complex process of overlapping phases with the primary aim of the creation of new tissues and restoring their anatomical functions. Wound dressings are fabricated to protect the wound and accelerate the healing process. Biomaterials used to design dressing of wounds could be natural or synthetic as well as the combination of both materials. Polysaccharide polymers have been used to fabricate wound dressings. The applications of biopolymers, such as chitin, gelatin, pullulan, and chitosan, have greatly expanded in the biomedical field due to their non-toxic, antibacterial, biocompatible, hemostatic, and nonimmunogenic properties. Most of these polymers have been used in the form of foams, films, sponges, and fibers in drug carrier devices, skin tissue scaffolds, and wound dressings. Currently, special focus has been directed towards the fabrication of wound dressings based on synthesized hydrogels using natural polymers. The high-water retention capacity of hydrogels makes them potent candidates for wound dressings as they provide a moist environment in the wound and remove excess wound fluid, thereby accelerating wound healing. The incorporation of pullulan with different, naturally occurring polymers, such as chitosan, in wound dressings is currently attracting much attention due to the antimicrobial, antioxidant and nonimmunogenic properties. Despite the valuable properties of pullulan, it also has some limitations, such as poor mechanical properties and high cost. However, these properties are improved by blending it with different polymers. Additionally, more investigations are required to obtain pullulan derivatives with suitable properties in high quality wound dressings and tissue engineering applications. This review summarizes the properties and wound dressing applications of naturally occurring pullulan, then examines it in combination with other biocompatible polymers, such chitosan and gelatin, and discusses the facile approaches for oxidative modification of pullulan.

Melatonin: Manager of psychosomatic and metabolic disorders in polymorbid cardiovascular pathology.

Objectives: To investigate the relationship between changes in circadian patterns of melatonin and clinical manifestations of polymorbid cardiovascular pathology (PCVP) in young men and to analyze the effectiveness of their complex treatment. Materials and methods: We made the immunohistochemical (IHC) analysis of epiphysis tissues from autopsies of 25 men aged 32-44 with PCVP and metabolic syndrome (MS) who had died as a result of ischemic cardiomyopathy (IC) and 25 persons after the car accident as a control group. Then, 93 young men aged 35-44 with PCVP, metabolic syndrome, and depressive spectrum disorders (DSD) were divided into three groups: (1) standard therapy; (2) standard therapy and psychotherapy sessions; (3) standard therapy in combination with psychotherapeutic and psychophysiological visual and auditory correction sessions. The control group included 24 conditionally healthy male volunteers. Before and after the treatment, we studied the anthropometric status, lipid and carbohydrate metabolism indicators, the level of urinary 6-hydroxymelatonin sulfate, the degree of nocturnal decrease in blood pressure (BP), and the relationship of these indicators with circadian variations of melatonin excretion. Results: Young polymorbid patients who died from IC have a lower expression of melatonin type 1 and 2 receptors. All patients with PCVP showed a decrease in the nocturnal melatonin excretion fraction and a correlation with higher severity of depressive (r = -0.72) and anxiety (r = -0.66) symptoms. Reduced values of the 6-hydroxymelatonin sulfate (6-SM) in the 1st (r = 0.45), 2nd (r = 0.39), and 3rd (r = 0.51) groups before treatment was associated with periods of increased BP. The achievement of melatonin excretion reference values and normalization of biochemical parameters of carbohydrate and lipid metabolism, daily BP profile, and psychophysiological state were noted in all three patients' groups, with a more pronounced effect in group 3. Conclusion: Low nocturnal melatonin excretion levels are associated with greater severity of clinical symptoms and a higher risk of death in patients with PCVP. Therefore, comprehensive therapy may be more effective for correcting this disease.

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.

Antiphase signalling in the neuroendocrine-immune system in healthy humans.

BACKGROUND: Any quantity varying in the spatial-temporal dimension may be considered as a signal. Human lymphocyte cell surface molecules and subsets present circadian variation and this variation may represent a kind of signalling in the neuroendocrine-immune system. We have analyzed the dynamics of variation of specific lymphocyte subsets in healthy humans. SUBJECTS AND METHODS: In our study, lymphocyte subpopulation analyses were performed and cortisol, melatonin, GH and TSH serum levels were measured on blood samples collected every 4h for 24 hours from eleven healthy men, ages 35-53 years (mean=44±6SD). RESULTS: A clear circadian rhythm was validated for CD8 and cortisol with acrophase during the day and for CD3, CD4, melatonin, GH and TSH with acrophase at night. Cross-correlation showed that CD3 correlated positively with CD4 (ρ=0.67, P<0.05) and negatively with CD8 (ρ=-0.41, P<0.05), CD4 correlated positively with melatonin (ρ=0.90, P<0.05), GH (ρ=0.92, P<0.05) and TSH (ρ=0.71, P<0.05), negatively with CD8 (ρ=-0.90, P<0.05) and cortisol (ρ=-0.18, P<0.05), CD8 correlated positively with cortisol (ρ=0.38, P<0.05). DISCUSSION: The different profiles of nyctohemeral changes of lymphocyte cell surface molecules and specific lymphocyte subsets realize different relationships with the neuroendocrine hormones and might represent a way of signal transmission among the multiple components of the neuroendocrine-immune system.

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.