We studied the apoptotic death of peripheral blood lymphocytes in individuals chronically exposed to radiation with a history of obligate forms of precancerous conditions. The study included 242 ...subjects chronically exposed to low-intensity radiation in the range of low and medium doses (mean dose of irradiation of the red bone marrow 555±39 mGy). Of these, 121 subjects had obligate forms of precancerous conditions. In irradiated individuals with obligate forms of precancers, a statistically significant increase in the frequency of apoptosis of peripheral blood lymphocytes at an early and late stages was revealed. Correlation analysis revealed no dependence of the apoptotic death of peripheral blood lymphocytes on the dose of red bone marrow irradiation.
The cytokine network is an important integrative and regulatory mechanism of the immune, endocrine, and nervous systems. Disturbances of this mechanism could play a role in the development of ...long-term biological effects of ionizing radiation at the subcellular, cellular, and whole body levels. Changes in the immune system of chronically exposed people, including specific features of the cytokine profile, were noted decades after the onset of exposure and were more pronounced in prenatally exposed individuals. The aim of this study was to assess the concentrations of certain cytokines in the blood serum of chronically exposed residents of the riverside villages of the Techa River 65–68 years after the onset of radiation exposure and correlations of the revealed changes with the dose to red bone marrow (RBM) and certain nonradiation factors. 406 people from the Techa River cohort (main group) were examined. Mean cumulative dose estimated for RBM in this group was 950.4 mGy; the median age of the patients was 70.0 years. Mean cumulative dose to RBM for 149 unexposed people included in the comparison group was 23.5 mGy; the median age of patients in this group was 68.5 years. The groups did not have statistically significant differences in age, sex, ethnic composition, or socio-economic living conditions of the people. The concentrations of IL-1β, IL-1(RA), IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, IFNα, and IFNγ in the blood serum were assessed using enzyme-linked immunosorbent assay. Chronically exposed individuals were revealed to have a statistically significant increase in the content of three proinflammatory cytokines: IL-8 (3.12 pg/mL,
p
= 0.010), TNFα (4.40 pg/mL,
p
= 0.010), and IFNγ (10.67 pg/mL,
p
= 0.040) relative to unexposed people (2.28, 3.61 and 8.34 pg/mL, respectively) and a decrease in the concentration of the main anti-inflammatory cytokines. Thus, the content of IL-4 in the main group was 1.14 pg/mL versus 3.48 pg/mL in the comparison group (
p
= 0.010), and the level of IL-10 was 6.18 pg/mL relative to 7.52 pg/mL in unexposed people (
p
= 0.010). The serum concentrations of IL-1β, IL-1α, IL-1(RA), IL-2, IL-6, CSF-GM, CSF-G, and IFNα did not differ in either group. The content of TNFα in the blood serum was weakly positively correlated with the individual cumulative dose of RBM exposure (SR = 0.14,
p
= 0.003). The concentrations of IL-4, IL-10, and IFNγ showed a weak negative correlation with the age of the examined people of the main group (SR = ‒0.19,
p
< 0.001; SR = –0.12,
p
= 0.020 and SR = –0.16,
p
= 0.002, respectively). In the comparison group, IL-4 correlated with age weakly negatively (SR = –0.30,
p
< 0.001), and IFNγ correlated with it weakly positively (SR = 0.18,
p
= 0.040). The level of IL-8 in the comparison group correlated weakly negatively with sex (SR = –0.18,
p
= 0.030); in the main group such a relationship was not found. Chronically exposed people were revealed to have proinflammatory changes in the serum cytokine profile with signs of an imbalance 65–68 years after the start of exposure. These changes did not depend (for most parameters) or depended little of the dose of RBM exposure (TNFα concentration) and the age (IL-4, IL-10, and IFNγ concentrations) of patients.
Objective: Cerebral ischemia is accompanied by damage and death of a significant number of neurons due to glutamate excitotoxicity with subsequent a global increase of cytosolic Ca
2+
concentration ...(Ca
2+
i
). This study aimed to investigate the neuroprotective action of BDNF overexpression in hippocampal neurons against injury under ischemia-like conditions (oxygen and glucose deprivation) and glutamate-induced excitotoxicity (GluTox).
Methods: The overexpression of BDNF was reached by the transduction of cell cultures with the adeno-associated (AAV)-Syn-BDNF-EGFP virus construct. Neuroprotective effects were mediated by Ca
2+
-dependent BDNF release followed by activation of the neuroprotective signaling cascades and changes of the gene expression. Thus, BDNF overexpression modulates Ca
2+
homeostasis in cells, preventing Ca
2+
overload and initiation of apoptotic and necrotic processes.
Results:Antiapoptotic effect of BDNF overexpression is mediated via activation of phosphoinositide-3-kinase (PI3K) pathway and changing the expression of PI3K, HIF-1, Src and an anti-inflammatory cytokine IL-10. On the contrary, the decrease of expression of proapoptotic proteins such as Jun, Mapk8, caspase-3 and an inflammatory cytokine IL-1β was observed. These changes of expression were accompanied by the decrease of quantity of IL-1β receptors and the level of TNFα in cells in control, as well as 24 h after OGD. Besides, BDNF overexpression changes the expression of GABA(B) receptors. Also, the expression of NMDA and AMPA receptor subunits was altered towards a change in the conductivity of the receptors for Ca
2+
.
Conclusion: Thus, our results demonstrate that neuronal BDNF overexpression reveals complex neuroprotective effects on the neurons and astrocytes under OGD and GluTox via inhibition of Ca
2+
responses and regulation of gene expression.
With the aim of optimizing the technique for the synthesis of selenium nanoparticles stabilized with cocamidopropyl betaine, a multifactorial experiment with three input parameters and three levels ...of variation was carried out. The selenous acid, cocamidopropyl betaine, and ascorbic acid concentrations were considered as input parameters. The output parameters were the average hydrodynamic radius of the particles (
r
av
) and ζ-potential. Photon correlation spectroscopy analysis revealed monomodal size distribution in all the samples. It was shown that the average hydrodynamic radius is most strongly influenced by the concentrations of selenous and ascorbic acids. The minimal size of the selenium nanoparticles (
r
av
≤ 20 nm) is achieved at selenous acid concentration of 0.05 to 0.15 M and at ascorbic acid concentrations of 0.0332 to 0.5 M. Acoustic and electroacoustic spectroscopy examination showed that the technique proposed allows formation of both positively (ζ-potential = +29.71 mV) and negatively (ζ-potential = –2.86 mV) charged nanoparticles. It was found that the ζ-potential of the selenium nanoparticles depends very heavily on the concentrations of the stabilizer and of selenous acid. For obtaining positively charged selenium nanoparticles the selenous acid concentration should not exceed 0.15 M and the cocamidopropyl betaine concentrations should be greater than 0.12 M. Negatively charged selenium nanoparticles are formed at selenous acid concentrations above 0.15 M and at cocamidopropyl betaine concentration under 0.12 M. The micelle structure for the positively charged and negatively charged selenium nanoparticles was proposed.
We report here studies of the antitumor action of a 4
H
-aminochromene compound in a xenograft model of ALK-expressing lung adenocarcinoma in humanized
nude
BALB/c mice. These studies showed that ...intragastric administration of the compound produced dose-dependent reductions in tumor size and metastasis frequency, with increases in the survival of xenograft-carrying animals. The effect of the compound is based on suppression of the expression of receptor tyrosine kinase and β3-tubulin in tumor tissues and activation of caspase-3-dependent programmed tumor cell death. The results allow the 4
H
-aminochromene compound AKh-554 to be regarded as having potential for development of molecularly targeted drugs.
Transcriptional activity of genes involved in maintaining genetic homeostasis (genes for repair, cell cycle and apoptosis: TP53, MDM2, ATM, BAX, BCL-2, CDKN1A, OGG1, XPC, PADI4, MAPK8, NF-KB1, STAT3, ...GATA3) was studied in chronically exposed persons with an increased intensity of early and late stages of apoptosis and necrosis of peripheral blood lymphocytes. The object of this study was peripheral blood mononuclear cells obtained from 132 chronically exposed residents of the Techa riverside villages. The mean accumulated dose to red bone marrow was 426.4 ± 48.2 mGy (1.3-2930.0 mGy), to thymus and peripheral immune organs, 58.9 ± 7.9 mGy (0.1-489.0 mGy). The study was performed more than 60 years after the onset of exposure, the average age of exposed persons was 68 ± 0.6 years (55-86 years). The study of apoptotic and necrotic death of peripheral blood lymphocytes was based on the presence of phosphatidylserine on the cell membrane surface, as well as on its permeability for DNA-intercalating dye. Evaluation of the relative content of mRNA genes for repair, cell cycle, and apoptosis was carried out using real-time PCR. An increased relative content of PADI4 gene mRNA was registered in the group of chronically exposed persons with the increased intensity of early apoptosis (p = 0.006). Modulation of the relative content of mRNA of the TP53 (p = 0.013) and BCL-2 (p = 0.021) genes was detected in the group of chronically exposed individuals with the increased intensity of the late stage of apoptosis. A statistically signif icant increase in the transcriptional activity of the TP53 gene was observed in the group of chronically exposed persons with the increased intensity of peripheral blood lymphocyte necrosis in the long-term period (p = 0.015). In the course of the study it was noted that exposed people with increased intensity of apoptosis, f irst of all, demonstrate changes in the transcriptional activity of apoptotic genes. These data are consistent with current views on the activation of programmed cell death.
Aim. To assess the impact of autologous activated T-lymphocyte immunotherapy on clinical parameters and quality of life in patients with allergic bronchial asthma (BA) in comparison with patients ...with allergic BA who received standard therapy.Materials and methods. A non-randomized, pilot study included 19 patients with allergic BA of moderate severity (7 men and 12 women aged 23–61 years, average age – 38.5 ± 4.3 years) who received the T-cell vaccine (n = 12) and standard therapy with inhaled glucocorticoids, short- and long-acting β2-adrenergic agonists (n = 7). After signing an informed consent, the patients were subcutaneously injected with autologous activated T-lymphocytes with a frequency of 4 injections 1 time / week, and then 6 injections 1 time / month. The research methods included asthma control measurement according to the ACQ-5 questionnaire and quality of life assessment according to the AQLQ(S) questionnaire. Clinical data were collected during lung function tests and by measuring the total immunoglobulin E (IgE) level.Results. In the course of the study, the immunotherapy was well tolerated, no systemic adverse reactions were noted. The treatment approach in the patients who received the T-cell vaccine resulted in significant improvement of asthma control parameters (according to the ACQ-5 questionnaire) and parameters of the patients’ quality of life (according to the AQLQ(S) questionnaire) within all 4 categories. Besides, their lung function improved by the end of treatment, and the total IgE level decreased. No significant changes in these parameters were observed during the follow-up in patients who received standard therapy. The study was conducted before immunotherapy, after 2 months (after 5 injections), and after 7 months (after 10 injections).Conclusion. Evaluation of the impact of immunotherapy with autologous activated T-lymphocytes on the clinical parameters and quality of life in patients with BA indicates effectiveness of treatment in patients with allergic BA.
The association between single nucleotide polymorphisms of genes involved in the cell cycle control (
ATM
rs664677,
MDM2
rs2279744,
CDKN1A
rs1801270) and apoptosis (
BCL-2
rs2279115,
BAX
rs4645878,
...TNF
α rs361525,
CASP8
rs1045485) and the risk of solid cancer development in people of various ethnicities exposed to chronic radiation is studied. The study included 915 residents of the Techa riverside settlements belonging to two ethnic groups the Slavs and the Turkic people who were affected by chronic exposure of a low dose rate in the low to medium dose range. Of them 310 people had solid cancers. Genotyping of polymorphic regions of the genes regulating the cell cycle and apoptosis was performed by the real-time PCR method. The study showed that the rs2279744*C allele of the
MDM2
gene was associated with an increased risk of cancer development (OR = 2.29; 95% CI 1.23–4.28;
p
= 0.007), while the rs1801270*A allele of the
CDKN1A
gene showed a protective effect against cancer development (OR = 0.55; 95% CI 0.35–0.85;
p
= 0.01) in exposed individuals of the Turkic people. The combined effect of the identified polymorphisms and soft tissue exposure dose modifies statistically significantly the risk of cancer development in chronically exposed individuals of the Turkic ethnic group, with the greatest contribution being made by the carriage of the rs2279744*C allele of the
MDM2
gene.
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