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Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation-induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15-E2-isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria-targeted scavenger of isolevuglandins by conjugating 2-hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1 g/L) to lipopolysaccharide treated mice increased survival by 3-fold, improved complex I-mediated respiration, and histopathological analyses supported mito2HOBA-mediated protection of renal cortex from cell injury. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction.

Marathon running is a stressful event that can significantly affect virtually any of the physiologic systems of a runner. The goal of this study was to investigate effects of marathon running on human immune and neuroendocrine parameters and their interaction. Blood samples were collected from 15 male runners (38.3 +/- 6.9 years) 18 hours before finish time, then within 20 minutes (0h), 1 hour, 24 hours, 48 hours, 5 days, and 8 days after the marathon. Complete blood count, secretion of cytokines in mitogen-activated cell culture and plasma, and plasma concentration of beta-endorphin, Adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) were analyzed. Significant increase in granulocyte and MID-cell count and lymphopenia were seen immediately after the marathon. Secretion of interleukin (IL)-2 and interferon (IFN)-gamma significantly declined at 0 and 1 hour after the marathon. Secretion of TNF-alpha declined at 0 hours and remained suppressed until 5 days. Suppression in the secretion of IL-1beta was observed at 48hour and 5-day intervals. Activated secretion of IL-6 decreased at 24 and 48 hours. Peak concentrations of ACTH, cortisol, beta-endorphin, and GH were registered after the race (0 and 1 hour). We concluded that marathon-associated stress factors can alter physiologic balance of cell-mediated versus humoral and antiinflammatory versus proinflammatory cytokines. Results suggest that hypothalamic pituitary-adrenocortical axis hormones played a significant role in the regulation of the observed changes. This information may be beneficial for development of new stress countermeasures to preserve wellness in subjects undergoing intensive physiological stress. [ABSTRACT FROM AUTHOR]

Inflammation is a major cause of morbidity and mortality in Western societies. Despite use of multiple drugs, both chronic and acute inflammation still represent major health burdens. Inflammation produces highly reactive dicarbonyl lipid peroxidation products such as isolevuglandins which covalently modify and cross-link proteins via lysine residues. Mitochondrial dysfunction has been associated with inflammation; however, its molecular mechanisms and pathophysiological role are still obscure. We hypothesized that inflammation-induced isolevuglandins contribute to mitochondrial dysfunction and mortality. To test this hypothesis, we have (a) investigated the mitochondrial dysfunction in response to synthetic 15-E 2 -isolevuglandin (IsoLG) and its adducts; (b) developed a new mitochondria-targeted scavenger of isolevuglandins by conjugating 2-hydroxybenzylamine to the lipophilic cation triphenylphosphonium, (4-(4-aminomethyl)-3-hydroxyphenoxy)butyl)-triphenylphosphonium (mito2HOBA); (c) tested if mito2HOBA protects from mitochondrial dysfunction and mortality using a lipopolysaccharide model of inflammation. Acute exposure to either IsoLG or IsoLG adducts with lysine, ethanolamine or phosphatidylethanolamine inhibits mitochondrial respiration and attenuates Complex I activity. Complex II function was much more resistant to IsoLG. We confirmed that mito2HOBA markedly accumulates in isolated mitochondria and it is highly reactive with IsoLGs. To test the role of mitochondrial IsoLGs, we studied the therapeutic potential of mito2HOBA in lipopolysaccharide mouse model of sepsis. Mito2HOBA supplementation in drinking water (0.1 g/L) to lipopolysaccharide treated mice increased survival by 3-fold, improved complex I-mediated respiration, and histopathological analyses supported mito2HOBA-mediated protection of renal cortex from cell injury. These data support the role of mitochondrial IsoLG in mitochondrial dysfunction and inflammation. We conclude that reducing mitochondrial IsoLGs may be a promising therapeutic target in inflammation and conditions associated with mitochondrial oxidative stress and dysfunction., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aspects of immune system dysregulation associated with long-duration spaceflight have yet to be fully characterized and may represent a clinical risk to crewmembers during deep space missions. Plasma cytokine concentration may serve as an indicator of in vivo physiological changes or immune system mobilization. The plasma concentrations of 22 cytokines were monitored in 28 astronauts during long-duration spaceflight onboard the International Space Station. Blood samples were collected 3 times before flight, 3-5 times during flight (depending on mission duration), at landing, and 30 days after landing. Analysis was performed by bead array immunoassay. With few exceptions, minimal detectable mean plasma concentrations were observed at baseline (launch minus 180) for innate inflammatory cytokines or adaptive regulatory cytokines; however, interleukin (IL)-1ra and several chemokines and growth factors were constitutively present. An increase in the plasma concentration, tumor necrosis factor-α (TNFα), IL-8, IL-1ra, thrombopoietin (Tpo), vascular endothelial growth factor (VEGF), C-C motif chemokine ligand 2 (CCL2), chemokine ligand 4/macrophage inhibitory protein 1b (CCL4), and C-X-C motif chemokine 5/epithelial neutrophil-activating protein 78 (CXCL5) was observed associated with spaceflight. No significant alterations were observed during or following spaceflight for the inflammatory or adaptive/T-regulatory cytokines: IL-1α, IL-1β, IL-2, interferon-gamma (IFN-γ), IL-17, IL-4, IL-5, IL-10, G-CSF, GM-CSF, FGF basic, CCL3, or CCL5. This pattern of cytokine dysregulation suggests multiple physiological adaptations persist during flight, including inflammation, leukocyte recruitment, angiogenesis, and thrombocyte regulation.

The main objective of this study was to evaluate the antiviral properties of the glyproline Selank in both in vitro and in vivo against the influenza virus strain A/Aichi 2/68 (H3N2). The pronounced antiviral effect of the agent was detected in both systems. Selank added to the cell culture 24 hours before inoculation (a preventive use scheme) showed the highest efficiency, by completely suppressing viral reproduction. The in vivo studies also demonstrated that the highest survival of laboratory animals was observed when the agent was administered by the prevention scheme. The use of Selank in vivo induced the gene expression of interferon-alpha (IFN-alpha), without affecting that of interleukin (IL)-4, IL-10, or tumor necrosis factor-alpha (TNF-alpha). The findings suggest that the mechanism of the antiviral action of Selank may be due to its ability to modulate Th1/Th2/Treg cytokine equilibrium both directly and indirectly via the central nervous system. This is particularly promising if that the agent is synthesized on the basis of an endogenous peptide and that it has no negative effects is kept in mind.

The purpose of this article was to study the immunotropic effects of the new neurotrophic heptapeptide selank. The experiments in vitro revealed that the drug in concentration 10-7 M completely suppressed gene expression by peripheral blood IL-6 of patients with depression but not of the healthy controls. At the same time, the significant increase (p<0,05) of IL-6 concentration was observed in the cell culture of peripheral blood of patients in the presence of selank. The changes of the Th1/Th2 cytokine balance in vivo were found in the serum of patients with generalized anxiety disorder and neurasthenia who received Selank during 14 days. The dynamics of these changes had the significant inverse correlation dependence. The cytokine regulating effects revealed in the study suggest that selank can be used as a novel immunomodulator in patients with anxiety-asthenic disorders. Additionally, the adaptogenic properties of selank may be beneficial to its use in elderly people and people exposed to environmental stressors for the prevention of infectious diseases.

Close interaction between the immune and nervous systems is well documented. The ability of immunocompetent cells to express receptors to neuroendocrine mediators as well as secrete many of them is proved. The current literature suggests that the hormones of the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonodal axes play the most significant role in the regulation of immune responsiveness. On the other hand, the immune system communicates with the CNS directly through the cytokines that are able to cross the blood-brain barrier, or directly via the nervus vagus, as well as via secondary messengers. Receptors to a number of cytokines have been found in the nervous tissue. Moreover, glial cells are able to secrete cytokines in the amount significant enough for at least autocrine action. In this article, the authors review the role of the "major" stress hormones such as cortisol, DHEA, growth hormone in the regulation of immune response, as well as neuro- and psychotropic properties of two major groups of cytokines that support cell-mediated (Type 1) and humoral (Type 2) immune reactions. This review emphasizes neuro-endocrine-immune interactions in response to infection both under laboratory and clinical conditions.

Confinement is one of the stress-inducing factors which humans face in such terrestrial environments as those in polar winter-over expeditions, submarines, and is inevitable in space flights. Confinement regime (CR) itself includes a number of stress factors (e.g. psychological compatibility between crew members, microbiological contamination etc.), which have been shown to alter human immunity. Two groups of total seven subjects spent 110 days in closed-habitat chamber as part of SFINCSS (Stimulation of Flight of International Crew on Space Station) study. Distribution of T-cell subsets, NK-, B-cells, and monocytes in whole blood was assessed. Secretion of type I (IL-2, IFN-gamma, TNF-beta) and type II (IL-4, IL-10) cytokines in the LPS/PHA activated whole blood cell culture was assessed. Significant alterations in type I / type II cytokine equilibrium were observed during and after confinement. The data show that stress factors associated with confinement may lead to disbalance between cell-mediated and humoral immune reactions.

Antiorthostatic hypokinesia or head-down bed rest (HDBR), is a ground-based model system used to simulate some of the physioloical responses observed during space flight. Several studies involving humans and animals have demonstrated the effects of HDBR on different physioloical systems. HDBR produced a large thoracic fluid shift similar to that reported for space flight. Exposure to the combination of -6 degrees HDBR, emotional stress, and hypergravity led to an elevation of plasma histamine and serotinin and a dramatic decrease in the concentration of prostaglandins E, F2-alpha, and erthropoietin. These responses indicated the HDBR produces significant alterations in the neuroendocrine regulatory pathways. The proliferative response of immune cells in response to activators was significantly enhanced in antiorthostatically suspended mice; plasma corticosterone also was higher but splenic natural killer cell cytotoxicity remained unchanged after suspension. Bone-resporbing activity of supernatatants increased in mitogen-stimulated PBMC cultures of subjects exposed to -5 degrees HDBR for 370 days of HDBR. Proliferative activity of PBMCs had declined at the end of a 320-day HDBR and during the initial days of recovery, but the numbers of active rosette-forming T cells increased. These and other results suggest that most stress-induced immune changes are neuroendocrine modulated, and that corticosteroids play a significant role in this modulation. It is expected that HDBR-induced immune changes could result from similar mechanisms. In this study, we investigated the effect of 120 days of HDBR on Type-1 vs. Type-2 cytokine equilibrium in mitogen-activated PBMC culture, and how these reactions may correlate with changes in the neuroendocrine status.

During 120-day and 370 day hypokinesia the possibility has been shown of manifestation of mechanism of immunological regulation of osteoclast functions. Supernatants of mononuclear peripheral blood cells which were in vitro nitrogen-stimulated, had an increased potential for resorption in 45Ca-labelled mice fetus long bone organ cultures. Resorbing activity was increased in mononuclear supernatants from some of the subjects exposed to 120-day hypokinesia and from all subjects exposed to 370-day hypokinesia. This variable returned to base-line values after completion of the bed-rest period. Lymphocyte in vitro proliferative activity decreased at the end of hypokinesia and during the initial days of recovery, and the number of active T-rosetting cells was, on the contrary increased. This suggested a possible activation of part of immunocompetent cell population potentially producing humoral regulators of bone cell functions in vivo. A study of a group of healthy males performing their routine daily activity and of patients with local osteoporosis (paradontitis) showed significant differences between normal subjects and patients, confirming the informative value of the method used and allowed to establish approximate limits of physiological variations of the values.

During 370 days 10 healthy male subjects were exposed to antiorthostatic hypokinesia. The exposure enhanced the production of the osteoclast-activating factor (OAF) by blood mononuclear cells. The enhancement began after the 2nd month of hypokinesia and continued to increase thereafter. The index of resorption was: prior to hypokinesia--1.15 +/- 0.156, 8 months after onset--2.05 +/- 0.129, and 11.5 months after onset--2.37 +/- 0.296, the upper normal limit being 1.54. The changes were correlated with a greater amount of active T-lymphocytes in blood and a progressive increase of calcium negative balance. This investigation lends support to the previously formulated hypothesis (I. V. Konstantinova, 1986) that immunological mechanisms associated with the OAF production contribute to calcium metabolism disorders in human bone during prolonged space flights.