Analysis of the Effect of IL-1ß on Blood-Brain Barrier Permeability in M6 Glioma Mouse Model Using Intravital Microscopy.

We studied the effect of IL-1ß on the permeability of brain capillaries in healthy mice. Intravital microscopy demonstrated that parenteral administration of IL-1ß was followed by an increase in vascular permeability ensuring passage of free Alexa488 fluorescent label through the capillary walls, but not sufficient for penetration of liposomes. In addition, experiments on mice with intracranial M6 glioma showed penetration of liposomes through the walls of tumor capillaries after parenteral administration of IL-1ß in a concentration of 2 µg/ml. Thus, the use of proinflammatory cytokine IL-1ß in the therapy of brain tumors can significantly increase the therapeutic efficacy of drug delivery systems, in particular, for drugs poorly crossing the blood-brain barrier.

[Proinflammatory cytokine content in the saliva of children suffering from chronic tonsillitis]. / Soderzhanie provospalitel'nykh tsitokinov v sliune detei s khronicheskim tonzillitom.

INTRODUCTION: We have examined 92 children aged between 6 and 15, suffering from chronic tonsillitis (CT). Tumor necrosis factor (TNF-α) and interleukin 1ß and 6 (IL-1ß and IL-6) contents have been defined in saliva. The control set comprised 17 healthy children. Cytokine content was defined with the enzyme multiplied immunoassay sets (Vektor Best Ltd., Russia) by enzyme-linked immunosorbent assay. The statistic analysis and data processing were carried out with statistic analysis programs (version 3.2, R Foundation for Statistical Computing, Vienna, Austria). RESULTS: The content of cytokines TNF-α, IL-1, IL-6 in CT children's saliva was high against the healthy children, yet the statistically significant differences were only noted for IL-6. In the CT group the median value of this factor (12.5) was significantly higher than in the control set (6.72) (p=0.01 in Mann-Whitney assessment). IL-6 was chosen as the basic factor for the mathematic model; its combinations in the form of a multi-factor logistic regression were given consideration. From out of the three possible models there was just one that had all the coefficients statistically significantly different from zero (TNF-α - IL-6). It was chosen as the basic diagnostic model for chronic tonsillitis. The created model's sensitivity is 80.4%, while its specificity is 82.4%. DISCUSSION: The revealed IL-6 dominance in saliva at CT can be is attributable to permanent antigenic challenge characteristic of the toxic allergic CT since, as previously shown, there are living proliferating microorganisms in the palatal tonsil tissues and their blood- and lymph vessels at CT. CONCLUSION: The conducted ROC-analysis has demonstrated high sensitivity and specificity of the mathematical model, which enabled us to recommend determination of IL-6 in the saliva of the children suffering from CT as an additional diagnostic criterion.

The change in the circadian rhythm of macrophage colony-stimulating factor content in the blood of patients with essential hypertension.

The purpose of this research is to study the characteristics of the change in the circadian rhythm of macrophage colony-stimulating factor (M-CSF) content in the peripheral blood serum of patients with stage II essential hypertension (EH) based on 5 time points (8:00, 14:00, 20:00, 2:00, and 8:00) and analyze its connection with the frequency of cardiovascular events. MATERIALS AND METHODS: Identified levels of M-CSF in the peripheral blood serum of 60 patients with stage II EH, before and after 1 year of antihypertensive therapy using enzyme-linked immunoassays (at 8:00, 14:00, 20:00, 2:00, and 8:00). RESULTS: The research demonstrated that stage II EH patients with a medical case history lasting 10-14 years have a greater content of M-CSF in their peripheral blood serum (p > 0.001). Before the start of antihypertensive therapy, they also have an increased variability in the circadian rhythm of M-CSF content in the bloodstream (when compared with healthy individuals) due to an increase at 20:00, decrease at 2:00 and recovery at 8:00. In 70% of those patients taking antihypertensive medication and have reached their target arterial blood pressure, the cytokine decrease stabilizes at 2:00 but the increase at 20:00 remains unchanged. Thirty percent of patients retained the rhythm characteristics of M-CSF content in the blood serum typical of patients before the start of therapy. This is a predictor of an increase in the five-year risk of developing cardiovascular complications, particularly myocardial infarction and acute cerebrovascular accident, in individuals with a comparable risk of cardiovascular complications or death on the Framingham risk score.

Antimicrobial activity of the indolicidin-derived novel synthetic peptide In-58.

Natural peptides with antimicrobial activity are extremely diverse, and peptide synthesis technologies make it possible to significantly improve their properties for specific tasks. Here, we investigate the biological properties of the natural peptide indolicidin and the indolicidin-derived novel synthetic peptide In-58. In-58 was generated by replacing all tryptophan residues on phenylalanine in D-configuration; the α-amino group in the main chain also was modified by unsaturated fatty acid. Compared with indolicidin, In-58 is more bactericidal, more resistant to proteinase K, and less toxic to mammalian cells. Using molecular physics approaches, we characterized the action of In-58 on bacterial cells at the cellular level. Also, we have found that studied peptides damage bacterial membranes. Using the Escherichia coli luminescent biosensor strain MG1655 (pcolD'::lux), we investigated the action of indolicidin and In-58 at the subcellular level. At subinhibitory concentrations, indolicidin and In-58 induced an SOS response. Our data suggest that indolicidin damages the DNA, but bacterial membrane perturbation is its principal mode of action. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Behavioral, hormonal, and neurotransmitter reactions to stress in adult rats with a history of high IL-1ß content in the early postnatal ontogeny.

Behavioral, hormonal, and neurotransmitter reactions to foot shock were studied in adult rats treated with IL-1ß during week 3 of life. After stress, these animals differed from controls treated with saline by high levels of dopamine, serotonin, and 5-hydroxy-indolacetic acid in the hypothalamus. In contrast to controls, they developed a significant stress-induced increase of blood corticosterone level and exhibited lesser motor and exploratory activities in the open field test.

[PECULIARITIES OF ERYTHROPOIETIN SYNTHESIS CIRCADIAN RHYTHM IN PATIENTS WITH ESSENTIAL ARTERIAL HYPERTENSION].

Erythropoietin (ERO) is known to be the main regulator of proliferation and terminal dissociation of erythroid cells. Its receptors are expressed not only in hematopoietic cells but also in the tissues of the cardiovascular system. The aim of this work was to study specific features of circadian rhythm in erythropoietin synthesis and estimate the predictive informative value of serum ERO level variations as regards the risk of developing cardiovascular complications in patients with stage II essential arterial hypertension (EAH). ERO, neopterin, and interleukin-1 levels were measured in 200 such patients. It was shown that ERO levels increased (p < 0.001) compared with normal values (12.6 pg/ml, 95% CI 11.8-13.4 and 68 pg/ml, 95% CI 6.4-7.2 respectively). Analysis of circadian rhythm demonstrated that enhanced probability of complications in the absence of reduction of the ERO level at night time correlated with the decreased number of CD34 cells (p < 0.001) and the increased neopterin level (p < 0.001). It is concluded that these dependences suggest the necessity of further studies of yet unknown effects of ERO and ways of their application for the treatment of EAH.

[Influence of synthetic peptide of active GM-CSF center on hemopoiesis recovery in C57Bl/6 mice after exposure to fractionated radiation].

The research allowed evaluation of the influence exerted by synthetic peptide of the active center of granulocyte-macrophage colony-stimulating (GM-CSF) factor on hematopoiesis in mice both under normal physiological conditions of the animals, and during the period of post-exposure recovery of hematopoiesis. It has been demonstrated that a synthetic peptide of the active GM-CSF center is able to exert a stimulating effect on animals with radiation-induced hematopoiesis inhibition. A single injection of the preparation at a dose of 0.005 µg/g to female C57Bl/6 mice, which had been exposed to fractionated exposure at a dose of 10 Gy and developed inhibition of bone-marrow hematopoiesis and cytopenia, exerted a stimulating effect on the granulocyte and monocyte lineages of hemopoiesis. Injections of an active GM-CSF center peptide to irradiated animals did not influence the content of CFUs in thebone-marrow (BM), but they exerted a stimulating influence on the population of these cells in unexposed animals. No effect of the influence of the preparation on the development of extramedullary hematopoiesis in the spleen was observed in the irradiated mice. The study showed that a peptide active site GM-CSF is a promising drug in terms of its use for the treatment of radiation-induced myelosuppression.

[The influence of neonatal interleukin-1beta increase on the formation of adult rats' spatial memory].

Children's and adults' cognitive dysfunctions are frequently caused by various types of pathology such as birth injuries, hypoxias, and infections suffered in prenatal and early postnatal periods of ontogenesis. These abnormal conditions trigger high production of proinflammatory cytokines by the cells of nervous and immune systems. The role of interleukin-1 beta (IL-1beta), one of such proteins, in the formation of cognitive deficit in early ontogenesis is not sufficiently studied. In present research it was revealed that administration of IL-1beta during the third week of postnatal ontogenesis impaired the learning of adult rats in Morris Water Maze. The differences between rats of control and experimental groups were observed during the training of searching for hidden platform and during the alteration of formed reflex (when the platform was in a different place). Meanwhile the spatial extinction has not been disrupted. The nature of experimental rats' learning abnormalities allows us to assume that the mechanisms of long-term but not short-term spatial memory are damaged in this experimental situation.

[Impairments of conditioned behavior in adult rats induced by interleukine-1beta treatment in early postnatal ontogenesis].

Impairments of cognitive functions in children and adolescents are often consequences ofperinatal pathology (natal injuries, ischemia, hypoxia, infection and allergic diseases), which are accompanied by enhanced production ofproinflammatory cytokine interleukine-1beta. In this work it was shown that treatment with interleukine-1beta during the third week of life impaired active and passive avoidance conditioning in adult rats at the age of 60-70 days.

Effect of interleukin-1ß on lipid peroxidation in emotiogenic structures of the brain in rats during acute stress.

We studied the effects of immunomodulatory cytokine interleukin-1ß on lipid peroxidation in emotiogenic structures of the brain (hypothalamus, sensorimotor cortex, and amygdala) of behaviorally active and passive rats with different prognostic resistance to stress. Immobilization of animals with simultaneous electrocutaneous stimulation (1 h) served as the model of acute emotional stress. Intraperitoneal injection of IL-1ß (5 µg/kg) was followed by accumulation of malonic dialdehyde (end-product of lipid peroxidation) in all structures of the brain in passive rats, as well as in the hypothalamus of active animals. As differentiated from active rats, stress exposure in passive specimens was accompanied by a selective increase in malonic dialdehyde content in the sensorimotor cortex and amygdala. Pretreatment with IL-1ß prevented activation of lipid peroxidation in the studied structures of the brain in passive rats after stress exposure. Our results show the specific effect of IL-1ß on free-radical processes in the hypothalamus, sensorimotor cortex, and amygdala in rats with various behavioral parameters. Regional features of lipid peroxidation in emotiogenic structures of the brain in animals with different emotional reactivity probably contribute to the existence of significant variations in the individual resistance to emotional stress.

Blood cytokines in rats with various behavioral characteristics during emotional stress and treatment with interleukin-1beta.

We studied the effect of acute emotional stress and exogenous IL-1beta (5 microg/kg intraperitoneally) on the cytokine profile of blood serum in Wistar rats with various behavioral characteristics in the open-field test. Blood level of proinflammatory cytokine IL-1beta decreased in behaviorally passive rats, but increased in active animals after simultaneous immobilization and electrocutaneous stimulation. These changes reflect the opposite immune responses to a similar stress exposure in rats with different emotional reactivity. Poststress variations in the concentration of circulating IL-1beta differed in rats receiving exogenous IL-1beta. Blood cytokine concentration decreased in behaviorally active rats, but remained unchanged in passive animals that were exposed to immobilization and electrocutaneous stimulation after pretreatment with IL-1beta. Emotional stress and injection of IL-1beta had no effect on blood level of an anti-inflammatory cytokine IL-4 in rats. Our results indicate that rats with various behavioral parameters are characterized by significant differences in the cytokine profile of blood serum under conditions of emotional stress and treatment with IL-1beta. These data illustrate the specific functional features of immune mechanisms, which provide an individual resistance of rats to the same stress exposure.

Effect of interleukin-1beta on functional activity of lymphoid structures in the gastrointestinal tract of rats during acute emotional stress.

We studied the effect of interleukin-1beta on functional activity of lymphoid structures in the gastrointestinal tract of rats with various behavioral parameters during stress of simultaneous immobilization and electrocutaneous stimulation. Morphofunctional characteristics of lymphoid tissue were estimated by studying elimination of intraperitoneally injected Chinese ink particles into the mesenteric lymph nodes and wall of the jejunum. Intraperitoneal injection of interleukin-1beta (5 mug/kg, 10(8) U/mg) was accompanied by accumulation of Chinese ink in the mesenteric lymph nodes of unstressed passive and active rats. The observed changes reflect an immunostimulatory effect of this cytokine. Acute stress was followed by an increase in the number of ink particles in the mesenteric lymph nodes and wall of the jejunum in behaviorally active rats. Under these conditions, the number of ink particles was elevated only in the mesenteric lymph nodes of passive specimens. As differentiated from passive animals, pretreatment of active rats with interleukin-1beta before acute stress was followed by the increased elimination of Chinese ink (antigenic material) from the abdominal cavity to the lymph nodes and through the wall of the jejunum. These data illustrate specific features of immune mechanisms for the stress response in mammals with various behavioral characteristics.

Effect of interleukin-1beta on the behavior of rats during mild stress in the open-field test.

We studied the effect of interleukin-1beta on the behavior of rats with different individual typological characteristics during mild stress in the open-field test. Intraperitoneal injection of interleukin-1beta (5 microg/kg, 108 U/mg) was followed by a decrease in orientation and exploratory activity of passive and, particularly, of active animals in the open field. As differentiated from rats receiving physiological saline, the initial differences in behavioral characteristics of active and passive animals were not revealed in the repeated test after injection of interleukin-1beta. We conclude that interleukin-1beta abolishes the behavioral differences between active and passive specimens in the open field. These data suggest that administration of interleukin-1beta to rats leads to reorganization of the mechanisms for emotional evaluation of adverse emotiogenic factors under conditions of mild stress in the open-field test.

The psychomodulatory action of subpyrogenic doses of interleukin-1beta in conditions of chronic administration to rats.

The effects of interleukin-1beta at low, subpyrogenic doses on behavior were studied in rats. Signs of increased anxiety were evident by day 5 of treatment courses. These results provide evidence supporting the role of proinflammatory cytokines in the pathogenesis of emotional disorders.

[The psychomodulating effect of sub-pyrogenic doses of interleukin-1beta during chronic administration to rats].

Behavioral effects of low, sub-pyrogenic doses of IL-lbeta were investigated in rats. It was shown that increasing of anxiety level started to occur as of the 5th day of the administration course. The data obtained suggest importance of pro-inflammatory cytokines in pathogenesis of psycho-emotional disorders.

The effects of proinflammatory cytokines on the formation of behavior in early postnatal ontogenesis.

Studies were performed to investigate impairments to the formation of behavior arising as a result of increases in the proinflammatory cytokine interleukin-1beta in early postnatal ontogenesis. The cytokine was given at pyrogenic or subpyrogenic doses for one week (the first, second, or third week of life). Behavior was assessed at prepubertal age and in the adult state in the open field and elevated cross maze tests. The greatest changes were seen in adolescent rats given interleukin-1beta during the first or third weeks of life. Impairments were seen after administration of pyrogenic and subpyrogenic doses of cytokine and were identical in females and males. Changes consisted of partial substitution of acts, increases in motor activity and decreases in investigative activity. After sexual maturation, these behavioral impairments were no longer seen.

[The action of proinflammatory cytokines on formation of behavior during early postnatal ontogenesis].

The study is devoted to the role of proinflammatory cytokine-interleukin-1beta during early postnatal ontogenesis in formation of behavioral programs. Cytokine was injected in pyrogenic and subpyrogenic doses during 1 week (1, 2 or 3 weeks of life). The behavior was tested in the young (40-45 days) and adult (3 months) rats in the "open field" and "elevated plus maze". The greatest behavior disordes (elevation of act's number and of motor activity, the decrease of investigation activity) are revealed in the young animals treated with IL-Ib during 1 and 3 weeks of life. These behavioral changes were marked in rats injected with pyrogenic and subpyrogenic doses of cytokine. They had a similar tendency in male and female rats. At the age of 3 months, behavior changes revealed in juvenile rats were insignificant.

[Proinflammatory cytokines in the development of bacterial keratitis]. / Rol' povospalitel'nykh tsitokinov v razvitii bakterial'nykh keratitov.

The production of proinflammatory cytokines IL-1alpha, IL1 2b, TNF-alpha and IL8 in lachrymal fluid was dynamically determined in 134 patients with uncomplicated and complicated clinical courses of primary (at exacerbation of the cornea) and secondary (with dystrophic changes in the cornea) keratitis. The level of proinflammatory cytokines in lachrymal fluid was found to essentially affect the clinical course in different types of keratitis.

[Immunological changes in patients with pulmonary tuberculosis during glutoxim therapy]. / Dinamika immunologicheskikh pokazatelei u bol'nykh tuberkulezom legkikh pri lechenii glutoksimom.

The paper deals with the effect of glutoxim included into a preoperative preparation regimen on immunological parameters in patients with fibrocavernous pulmonary tuberculosis. On admission, all the patients had inadequate cellular immunity and activated humoral immunity. After termination of a course of glutoxim therapy, there was an increase in the baseline low values of lymphocytic proliferative activity, in the count of mature T lymphocytes, and in the production of IL-2 induced by phytohemagglutinin. At the same time the similar parameters remained unchanged in the control group. The drug exerted the most noticeable stimulating effect on cellular immunity in patients with a limited process. Glutoxim produced no noticeable effect on humoral immunity. The immunomodulating effect of glutoxim was followed by improvement of the clinical and X-ray pictures of the disease. In glutoxim-treated patients with baseline immunological disorders, progression was found to occur 1.5-2 times more infrequently than in the control group. Indications for the use of glutoxim in the treatment of tuberculosis are specified on the basis of the baseline immunological parameters of each patient.

Pine resin and biopin ointment: effects of water-soluble fractions on cytokine production by peripheral blood neutrophils.

We studied the effects of water-soluble fractions of pine resin and Biopin-10 and Biopin-20 ointments used for the therapy of burns, wounds, and purulent and inflammatory diseases on spontaneous and induced synthesis of tumor necrosis factor and interleukins 1, 2, and 8 by human peripheral blood neutrophils in vitro. These preparations contain various bioactive substances producing opposite and dose-dependent immunomodulatory effects. Our results indicate that the composition and doses of preparations should be selected to achieve the maximum therapeutic effect.