The effects of radio-frequency radiation (RFR) exposure on the analgesic efficacy of morphine in healthy rats and rats with inflammation.

OBJECTIVES: The aim of this study, conducted at the Military Institute of Hygiene and Epidemiology in Warsaw in 2017, was to evaluate the effects of a single (15 min) and repeated (5 times for 15 min) radio-frequency radiation (RFR) exposure of 1800 MHz frequency on the analgesic efficacy of morphine in healthy rats and rats with complete Freund's adjuvant (CFA) induced inflammation. MATERIAL AND METHODS: Rats were injected intraperitoneally with morphine (MF) in the dose of 8 mg/kg or drug vehicle 15 min before RFR exposure. The authors used the plantar analgesia meter and the radiant heat paw-withdrawal test to assess the pain threshold. RESULTS: A single RFR exposure slightly influenced paw withdrawal latency (PWL) in healthy rats in the single exposure baseline group, and influenced PWL, 30 and 60 min after morphine or vehicle injection, in the repeated exposure group. There were differences between the sham-exposed groups (vehicle), 30, 60 and 90 min after injection, both in the single and repeated RFR-exposure groups. The antinociceptive effect of morphine in healthy rats was slightly decreased by RFR exposure at 60 and 90 min, both in the single and repeated exposure groups. The PWL was slightly decreased, both in the single and repeated exposure groups with inflammation (CFA and CFA/MF), at 30, 60 and 90 min, and PWL was increased in the sham-exposed groups (CFA and CFA/MF), both in the single and repeated exposure groups, at 30, 60 and 90 min. The antinociceptive effect of morphine in healthy rats was significantly increased by RFR exposure at 30 min after drug injection in the single exposure group, and increased at 30 and 60 min in the repeated exposure group. CONCLUSIONS: The authors observed a minor influence of RFR exposure on the antinociceptive effects of morphine in healthy rats after repeated exposures and a statistically significant influence of repeated exposure on morphine mediated antinociceptive effects in the inflammation group. Int J Occup Med Environ Health. 2019;32(4):465-74.

The effect of 1800MHz radio-frequency radiation on NMDA receptor subunit NR1 expression and peroxidation in the rat brain in healthy and inflammatory states.

BACKGROUND: The aim of this study was to evaluate the effect of repeated exposure (5 times for 15min) of 1800MHz radio-frequency radiation (RFR) on N-methyl-d-aspartate receptor subunit NR1 (NMDA-NR1) expression in the brains of rats in a persistent inflammatory state. We also measured the effect of RFR combined with tramadol (TRAM) to determine the potential antioxidant capacity of this agent. METHODS: The effects of the Global System for Mobile Communication (GSM) modulated 1800MHz RFR exposure on the expression and activity of glutamate receptor channels with antioxidative activity in brain tissue was measured using oxygen radical absorbance capacity (ORAC) and electron spin resonance (ESR) detection of the hydroxyl radical generated by the Fenton reaction. NMDA-NR1 was measured in the cerebral tissue of rats with inflammation (complete Freund's adjuvent) and those injected with tramadol after RFR exposure (RFR, RFR/TRAM) and in non-exposed (baseline, TRAM) rats. RESULTS: No differences between the baseline group and the exposed group (RFR) were observed. NMDA-NR1 expression decreased after CFA injection and RFR exposure, and an elevated expression of NMDA-NR1 was observed in healthy control rats of both groups: TRAM/RFR and RFR. CONCLUSIONS: ORAC assessment revealed a robust effect of RFR, however the other experiments revealed equivocal effects. Further studies examining the combination of ORAC with NMDA are warranted to elucidate more clearly the effect of RFR on the brain.

Psychoneuroimmunological aspects of cardiovascular diseases: a preliminary report.

AIM OF THE STUDY: Due to their prevalence and negative social effects, cardiovascular diseases belong to a group of civilization diseases. Previous research suggests comorbidity of heart diseases, mood disorders and impaired cognitive functioning. The aim of this study was to evaluate the psychoneuroimmunological aspects of functioning in patients diagnosed with cardiovascular diseases. MATERIAL AND METHODS: Ten persons, mean age 48.2 years old, diagnosed with primary hypertension, were studied. All of them were treated with beta blockers and ACE inhibitors with unsuccessful therapeutic effect. This group also included 4 subjects with heart rate disturbances. The control group included 10 clinically healthy volunteers in mean age 46.8. All participants had 24-hour ECG monitoring with Holter method in order to evaluate the autonomic activity with time and frequency domain analysis (heart rate variability). Patients also underwent neuropsychological assessment of quality of life and personality traits (EQ-5D, NEO-PI-R, PSS10, SWLS, MHLC). Quantitative evaluation of immune system parameters included: TCD3, TCD4, CD8, CD16/CD56, CD19, HLA-DR+. RESULTS: The cardiovascular disease group showed significantly lower time and frequency domain parameters (p < 0.05) except low/high frequency (LF/HF) power ratio. The heart rhythm disorder group demonstrated significant relationships such as: Quality of life with Total Power of HRV and day-time LF/HF ratio, pNN50 and rMSSD - negative correlation. CONCLUSIONS: 1. In cardiovascular disease patients, activity of the autonomic nervous system is significantly reduced. 2. Impaired modulation of the autonomic nervous system activity affects mood and decreases quality of life. 3. In patients with heart rhythm disturbances, increased sympathetic nervous system activity affects prolonged tension and the immune response.

Influence of electromagnetic field (1800 MHz) on lipid peroxidation in brain, blood, liver and kidney in rats.

OBJECTIVES: The aim of this study is the evaluation of the influence of repeated (5 times for 15 min) exposure to electromagnetic field (EMF) of 1800 MHz frequency on tissue lipid peroxidation (LPO) both in normal and inflammatory state, combined with analgesic treatment. MATERIAL AND METHODS: The concentration of malondialdehyde (MDA) as the end-product of the lipid peroxidation (LPO) was estimated in blood, liver, kidneys, and brain of Wistar rats, both healthy and those with complete Freund's adjuvant (CFA)-induced persistent paw inflammation. RESULTS: The slightly elevated levels of the MDA in blood, kidney, and brain were observed among healthy rats in electromagnetic field (EMF)-exposed groups, treated with tramadol (TRAM/EMF and exposed to the EMF). The malondialdehyde remained at the same level in the liver in all investigated groups: the control group (CON), the exposed group (EMF), treated with tramadol (TRAM) as well as exposed to and treated with tramadol (TRAM/EMF). In the group of animals treated with the complete Freund's adjuvant (CFA) we also observed slightly increased values of the MDA in the case of the control group (CON) and the exposed groups (EMF and TRAM/EMF). The MDA values concerning kidneys remained at the same levels in the control, exposed, and not-exposed group treated with tramadol. Results for healthy rats and animals with inflammation did not differ significantly. CONCLUSIONS: The electromagnetic field exposure (EMF), applied in the repeated manner together with opioid drug tramadol (TRAM), slightly enhanced lipid peroxidation level in brain, blood, and kidneys.

Role of Fas/FasL signaling in regulation of anti-viral response during HSV-2 vaginal infection in mice.

Fas receptor-Fas ligand (FasL) signaling is involved in apoptosis of virus-infected cells but increasing evidence accumulates on Fas receptor as a mediator of apoptosis-independent processes such as induction of activating and pro-inflammatory signals. In this study, we examined the role of Fas/FasL pathway in regulation of anti-viral response to genital HSV-2 infection using a murine model of HSV-2 infection applied to C57BL6/J, B6. MRL-Faslpr/J and B6Smn.C3-Faslgld/J mice. HSV-2 infection of Fas- and FasL-deficient mice led to decreased migration of IFN-γ expressing NK cells and CD4+ T cells, but not of γδ T cells, into the vaginal tissue. The vaginal tissues of HSV-2 infected Fas- and FasL-deficient mice showed increased production of IL-10, followed by low expression of the early CD69 activation marker on CD4+ and CD8+ T cells and increased numbers of regulatory T cells (Tregs). Experiments in co-cultures of CD4+ T cells and bone marrow derived dendritic cells showed that lack of bilateral Fas-FasL signaling led to expansion of Tregs and increased production of IL-10 and TGF-ß1. Our results demonstrate that Fas/FasL can regulate development of tolerogenic dendritic cells and expansion of Tregs early during HSV-2 infection, which further influences effective anti-viral response.

Interactions of orphanin FQ/nociceptin (OFQ/N) system with immune system factors and hypothalamic-pituitary-adrenal (HPA) axis.

BACKGROUND: Brain-immune system interactions and neurohormonal changes which are induced by psychophysiological factors are growing areas of scientific interest. Central (CNS) and autonomic nervous-endocrine-immune system pathways are connected with a number of behavioral and physiological factors which may be linked to disease susceptibility and progression. METHODS: In this paper, influence of orphanin FQ/nociceptin receptor (OFQ/N) on the hypothalamic-pituitary-adrenal (HPA) axis and their influence on the immunological system was reviewed. CONCLUSIONS: The neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) axis, is closely connected with the cytokines. HPA axis activation by cytokines, via the release of glucocorticoids has, in turn, been found to play a critical role in restraining and shaping immune responses. Investigation of the OFQ/N system and G-proteins suggests a role for this receptor as a down-regulator of cytokine, chemokine and chemokine receptor expression.

Changes in antioxidant capacity of blood due to mutual action of electromagnetic field (1800 MHz) and opioid drug (tramadol) in animal model of persistent inflammatory state.

BACKGROUND: The biological effects and health implications of electromagnetic field (EMF) associated with cellular mobile telephones and related wireless systems and devices have become a focus of international scientific interest and world-wide public concern. It has also been proved that EMF influences the production of reactive oxygen species (ROS) in different tissues. METHODS: Experiments were performed in healthy rats and in rats with persistent inflammatory state induced by Complete Freund's Adjuvant (CFA) injection, which was given 24 h before EMF exposure and drug application. Rats were injected with CFA or the same volume of paraffin oil into the plantar surface of the left hind paw. Animals were exposed to the far-field range of an antenna at 1800 MHz with the additional modulation which was identical to that generated by mobile phone GSM 1800. Rats were given 15 min exposure, or were sham-exposed with no voltage applied to the field generator in control groups. Immediately before EMF exposure, rats were injected intraperitoneally with tramadol in the 20 mg/kg dose or vehicle in the 1 ml/kg volume. RESULTS: Our study revealed that single EMF exposure in 1800 MHz frequency significantly reduced antioxidant capacity both in healthy animals and those with paw inflammation. A certain synergic mode of action between applied electromagnetic fields and administered tramadol in rats treated with CFA was observed. CONCLUSIONS: The aim of the study was to examine the possible, parallel/combined effects of electromagnetic radiation, artificially induced inflammation and a centrally-acting synthetic opioid analgesic drug, tramadol, (used in the treatment of severe pain) on the antioxidant capacity of blood of rats. The antioxidant capacity of blood of healthy rats was higher than that of rats which received only tramadol and were exposed to electromagnetic fields.

Synthetic immunostimulatory oligonucleotides in experimental and clinical practice.

BACKGROUND: Oligonucleotides belong to a class of macromolecules with great potential for research and various therapeutic applications. Their mechanisms of action are extremely diverse, although they are rather homogeneous in composition. Single-stranded oligodeoxynucleotides are not only inhibitors of gene expression, but their CpG sequence motifs may activate the innate immune response. Recent progress made in preclinical and clinical testing, as well as the case of the most recently discovered RNA interference technology, will help to overcome efficacy problems of the previous approaches of the 'standard therapy' of such diseases as tumors and various infections. METHODS: The aim of this article is to present various therapeutic aspects of oligonucleotides, and to review the most significant therapeutic applications of synthetic oligonucleotides. This paper presents a comprehensive review of current literature on various therapeutic properties of synthetic oligonucleotides. CONCLUSIONS: The available results gathered from preclinical and clinical studies suggest that TLR9-targeted therapy of oligonucleotides can stimulate both innate and adaptive immunity. It also appears that CpG ODNs are generally safe, although moderate adverse effects, based on a backbone-related mechanism have been reported. The presented studies demonstrate that adjuvant CpG ODN can unify an immune response that leads to enhanced antigen-specific Ab formation. CpG ODN may therefore provide a unique approach to enhancing the efficacy of immunization, including the strengthening of antitumor immunity.

T-regulatory cells in severe atopic dermatitis: alterations related to cytokines and other lymphocyte subpopulations.

The changes in lymphocyte subpopulations in atopic dermatitis (AD) concern also T-regulatory cells. We investigated the expression of various surface receptors on CD3(+)CD4(+)CD25(high)FoxP3(+) T-regulatory cells and the activation CD28(+) receptor and the inhibitory CD152(+) receptor on helper/inducer as well as cytotoxic/suppressor T cells. Peripheral blood lymphocytes of 15 AD patients and 20 healthy subjects were analyzed by flow cytometry using monoclonal antibodies. The concentrations of IL-6, IL-10 and TGF-ß were determined in the serum and the supernatant of ConA-stimulated CD4(+) lymphocytes. In AD patients the percentage of CD4(+)CD25(high)FoxP3(+) as well as CD3(+)CD8(+) cells increased, which positively correlated with SCORAD index (r = 0.55, p = 0.03). The concentrations of IL-10 in the CD4(+) lymphocyte culture supernatants and the concentrations of TGF-ß in the sera and the supernatant negatively correlated with the severity of AD (p < 0.01, r = -0.63; p < 0.02, r = -0.64 and p < 0.03, r = -0.58, respectively), whereas the serum concentration of IL-6 correlated positively (p < 0.003, r = 0.71). The regulatory cells expressed more CD62L and CD134 surface markers but less CD95. Reduced expression of the apoptotic CD95 receptor suggests that survival time of these cells is prolonged. Since CD62L and CD134 were upregulated, the enhanced modulatory effect of CD4(+)CD25(high)FoxP3(+) cells seemed to be suggested, which may result in increased co-expression of CD28/CD152 on both CD4(+) and CD8(+) subpopulations.

Immunomodulatory properties of thalidomide analogs: pomalidomide and lenalidomide, experimental and therapeutic applications.

Thalidomide has a broad spectrum of anti-cancer activity. Antitumor activity of thalidomide may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic activities. The therapeutic potential of thalidomide provided motivation to develop more effective derivatives with considerably reduced toxicity. Thalidomide's immunomodulatory (IMiDs) analogs (lenalidomide, CC-5013; CC-4047, ACTIMID) represent a novel class of compounds with numerous effects on the immune system. Some of these analogs are thought to mediate the anticancer and anti-inflammatory effects observed in humans. Thalidomide is currently approved for the treatment of dermal reaction to leprosy and is currently in phase III trials for multiple myeloma (MM). IMiDs inhibit the cytokine's tumor necrosis factor-α (TNF-α), interleukins (IL) 1ß, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). The repression of the tumor necrosis factor-a (TNF-α) expression is the crucial factor of many of the anti-inflammatory properties of thalidomide. The mechanisms underlying many of the anti-inflammatory properties of thalidomide, including its ability to co-stimulate T cells, still remain unclear. Some recent patent are also summarized in this review.

Immunostimulatory oligonucleotides.

RNA-protein interactions have been characterized often. Above all, the proteins which are associated with the studied RNA should be precisely identified. The pharmaceutical compositions containing nucleic acids and/or other compounds can be administered by any suitable route for administering medications. The immunostimulatory oligonucleotides play the role of antisense drugs which are being researched to treat cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, Amyotrophic lateral sclerosis (ALS), and diseases such as asthma and arthritis with an inflammatory component. The immunostimulatory oligonucleotides may contain one or more natural or unnatural amino acid residues which are connected to the polymer by peptide (amide) linkages. The vaccine against cancer which has been produced during this work can be prophylactic or therapeutic. Since most studies so far have been performed with first-generation antisense oligonucleotides (ODNs), it is interesting to observe how second-generation immune stimulatory drug candidates with enhanced potency and efficacy can further improve the utility of this class of therapeutic agents. The aim of this article is to review most significant patents on immunostimulatory oligonucleotides.

Immunomodulatory effect of probiotic bacteria.

Probiotics are usually defined as live microbial food ingredients beneficial to health which comprise of normal commensally bacteria as a part of the healthy human gut micro flora. The gut microflora is an important component of the gut defense barrier and have been shown to induce and maintain oral tolerance in experimental animal models. Functional foods, including probiotic bacteria, are an attractive medium for maintaining the steady nutritional state of the host with defective gut barrier functions. The gut-associated lymphoid tissue (GALT) embraces a crucial component of the total immunological capacity of the host in recognizing and selectively handling alien antigens for the initiation of immune responses. Normalization of increased intestinal permeability and altered gut micro ecology can ensure improvement of the function of the gut barrier. Probiotics do modify the composition of the gut microflora and, as a consequence, they have been shown to influence both intestinal and body functions. This review also discussed some patent related to the field.

Influence of prebiotics on the human immune system (GALT).

Prebiotics have great potential to improve human health in specific intestinal disorders. The knowledge about the influence of prebiotics on the gut-associated lymphoid tissues (GALT) for the improvement of human health is still growing. This paper reviews the latest evidence for the immunity-enhancing effects of prebiotics. Prebiotics, include inulin, fructooligosaccharides, mannosoligosaccharides, and arabinogalactans, are a therapeutic nutritional preparation used for the gut function favoring growth of normal bacterial flora and impedes growth of pathogenic organisms. There is convincing preliminary data to suggest that the consumption of prebiotics can modulate immune parameters in GALT, secondary lymphoid tissues and peripheral circulation. There is increasing evidence that the newly described prebiotics and innovative means of administration can modulate various properties of the immune system, including those of the gut-associated lymphoid tissues (GALT). Authors of recently published patents showed new mechanisms for immuno-modulation, and the ultimate impact on immunological health of prebiotics.