Досліджено екзогенні та ендогенні регуляторні впливи на стан ліпідного метаболізму за допомогою вивчення жирнокислотного складу їжі та експресії регуляторного протеїну L-FABP у 43 осіб без діабету (23 із підвищенням вмісту глюкози та/або холестерину крові, 20-група контролю) та у 76 пацієнтів з ускладненим цукровим діабетом 2-го типу (ЦД2). Основною відмінністю ліпідного обміну пацієнтів з ЦД2 та осіб без діабету виявлено суттєву різницю перерозподілу вмісту жирних кислот (ЖК) у мембранах еритроцитів у вигляді підвищення в 1,5 раза вмісту насичених і відповідне зниження ненасичених ЖК за рахунок поліненасичених (ПНЖК), а також підвищення вмісту сироваткового протеїну L-FABP в 1,5 раза. Вживання в їжу продуктів-джерел указаних типів ЖК за показником «раціональності споживання продуктів», отриманим на основі аналізу анкет харчування,не відрізнялося в групах осіб без діабету та з ЦД2. У осіб без діабету, але з підвищеним вмістом глюкози крові та/або холестерину, виявили зменшений індекс маси тіла, незначне підвищення вмісту ПНЖК у мембранах еритроцитів, концентрацію L-FABP в 1,2 раза меншу, ніж у відносно здорових осіб і вдвічі меншу, ніж у пацієнтів з ЦД2. Можна припустити, що за певних умов, саме зменшення експресії L-FABP на тлі підвищення вмісту ПНЖК у клітинах, не погіршує стан метаболічних зсувів, а запобігає розвитку ожиріння і діабету. Відсутність прямої залежності між екзогенним впливом у вигляді вживання продуктів-джерел ЖК та перерозподілом вмісту цих кислот у мембранах еритроцитів, що є ознакою розвитку діабету, але наявністьзв'язку експресії внутрішньоклітинного регуляторного протеїну L-FABP із вмістом ЖК, дає підставу вважати ендогенні клітинні механізми основою глибокого порушення ліпідного гомеостазу.

Background. The aim was to investigate the influence of propionic acid (PA) on the endoplasmic reticulum (ER), unfolded protein response (UPR) state, and astrocyte/microglia markers in rat ventromedial hypothalamus (VMH) after type 2 diabetes mellitus (T2DM). Methods. Male Wistar rats were divided: (1) control, (2) T2DM, and groups that received the following (14 days, orally): (3) metformin (60 mg/kg), (4) PA (60 mg/kg), and (5) PA+metformin. Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed. Results. We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA—by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin—by 4.98-fold, PA—5.64-fold, and metformin+PA—3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values. Conclusions. T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH.

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The state of antitumor immunity of patients with oral cavity and oropharyngeal cancer during treatment (radiation and chemoradiation therapy), which additionally included α/β-defensin immunotherapy, was studied. In all three study groups, where preparation α/β-defensins was used, there was a more pronounced dose-dependent decrease in the relative number of lymphocytes in the blood than among those receiving cytostatic therapy in mono mode. Patients of group I received radiation therapy and immunotherapy, group II - chemoradiation and immunotherapy, group III - radiation therapy with immunotherapy in increased doses, VI - radiation, V - chemoradiation. Thus, in group І the decrease in the absolute number of lymphocytes was by 0.6×109/l, in group II - by 0.82×109/l, and in group III - by 0.93×109/l; by 8.51% there was a decrease in the relative number of lymphocytes in group I, by 15.52% in group II and in group III - by 14.32%. A significant decrease in the absolute number of CD3+ T cells in the blood was registered with a combination of radiation- and immunotherapy: in group I from 1141×106/l to 682×106/l and in group III - from 871×106/l to 309×106/l. At the same time, there was an increase in the relative number of natural killers in the blood of patients undergoing radiation therapy in combination with immunotherapy, also with a dose-dependent effect, the growth in group I is from 16 to 17% and group III - from 13.4 to 19.5%. Among patients undergoing cytostatic therapy, there were significant differences in the absolute number of NKT cells in the combination of radiation and immunotherapy, groups I and III, by reducing the number of these lymphocytes in the blood from 86 to 57 and from 62 to 31, respectively. α/β-defensins have been shown to have a dose-dependent adjuvant effect on cytostatic treatment – radiation, and chemoradiation of patients with cancer of the oral cavity and oropharynx. Simultaneously with the use of the drug α/β-defensins associated additional immunomodulatory effect in the form of the restructuring of the subpopulation of lymphocytes due to an increase in the relative number of natural killers in the blood.

Relevance. When modeling experimental type 2 diabetes mellitus (T2DM), various schools and research groups receive significant variability in tissue changes, which is difficult to compare and extrapolate as a specific pathogenic or pharmacological effect. The lack of standard operating procedures agreed upon in the scientific community greatly complicates the interpretation of the result. Therefore, the creation of a uniquely pathogenetic animal model of CD2 in animals is an urgent task. Objective. Determination of the complex of exogenous effects for the most efficient reproduction of the experimental model of T2DM in rats and the pathogenetic justification of the changes in the body to study the central mechanisms of homeostasis regulation and their pharmacological correction. Materials and methods. T2DM was model in rats by feeding a high-fat diet (HFD) with additional streptozotocin induction. The model was evaluated by anthropometric measurements, studies of biochemical parameters, an insulin tolerance test, analysis of the spectrum of fatty acids in the composition of tissues. Statistical data processing was performed with using the IBM SPSS Statistics 23. Results. The obtained data were compared with our studies of the lipid metabolism of patients with varying degrees of diabetic retinopathy on the background of T2DM and analysis of the information content of biochemical markers to assess lipid metabolic disturbances on the background of hyperglycemia in patients. It was found that the simulation in rats of experimental T2DM by a food load of HFD (45%) + fructose 20% for 3 months followed by a single induction of streptozotocin (25 mg/kg) causes changes in lipid and carbohydrate metabolism in animals similar changes which are in the human with a diagnosed long-term diabetes and the development of microvascular complications. Conclusion. We determined the optimal combination of effects and developed a consistent experimental load scheme that allows us to obtain a symptom model of type 2 diabetes in an animal experiment. Using the diagnostic algorithm, which includes physiological and laboratory methods, the degree of damage to organs and systems was determined, a comparison was made with the level of metabolic disorders in patients with T2DM and people without diabetes. The given model is a pathogenetically grounded approach for further study of the central mechanisms of homeostasis regulation and their pharmacological correction

We examined the neuronal activity of hypothalamic neurons in acute experiments on cats under ketamine anesthesia. Using glass microelectrodes, we extracellularly recorded the impulse activity (IA) of neurons of the anterior hypothalamus in the absence of controlled influences (background IA, BIA) and after stimulation of evolutionary heterogeneous zones of the brain cortex projecting to the hypothalamus (hippocampal СА3 area, pyriform, cingular, and proreal gyri). Electrical 5-sec-long stimuli were applied with frequencies of 12, 30, or 100 sec -1 . In another experimental series, we recorded changes in the IA of hypothalamic neurons induced by visceral stimuli (heating or cooling by 7°С of the foot pad, cooling of the body of the animal, and infusions of 5% glucose, 0.2% NaCl, 3.0% NaCl, or phenylephrine in the carotid artery), modeling in such a way shifts of the constants of homeostasis within physiological limits. We also compared the parameters of neuronal BIA and stimulation-influenced IA in equal epochs of the analysis and classified the types of BIA. About 50% of the cells of the total studied sampling of hypothalamic neurons responded by a considerable modulation of their BIA with a significant change in the frequency in the course of and after stimulations of the abovementioned modalities. In some neurons after cortical or visceral stimulation, a significant transformation of the temporal structure of the IA with no changes in the mean frequency occurred. We hypothesize that stimulation-induced transformation of the IA pattern with preservation of the mean discharge frequency can be one of the modes of encoding of information necessary for triggering of one efferent reaction or another, which are controlled by the hypothalamus. Examination of the BIA parameters of subcortical neurons, as well as comparison of the parameters of such an activity with the localization of cells and with the modality of stimulation that leads to modification of the IA, should allow one to reveal reasons for the formation and modification of the IA on neurons of the anterior hypothalamus. Since functional peculiarities of the neurons correlate with their BIA pattern, such data can provide an insight into the functional bases of the neurophysiological mechanisms underlying regulatory functions of the hypothalamus.

While virus-specific antibodies are broadly recognized as correlates of protection, virus-specific T cells are important for direct clearance of infected cells. Failure to generate hepatitis B virus (HBV)-specific antibodies is well-known in patients with end-stage renal disease. However, whether and to what extent HBV-specific cellular immunity is altered in this population and how it influences humoral immunity is not clear. To address it, we analyzed HBV-reactive T cells and antibodies in hemodialysis patients post vaccination. 29 hemodialysis patients and 10 healthy controls were enrolled in a cross-sectional study. Using multiparameter flow cytometry, HBV-reactive T cells were analyzed and functionally dissected based on granzyme B, interferon-γ (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2), and IL-4 expression. Importantly, HBV-reactive CD4 + T cells were detected not only in all patients with sufficient titers but also in 70% of non-responders. Furthermore, a correlation between the magnitude of HBV-reactive CD4 + T cells and post-vaccination titers was observed. In summary, our data showed that HBV-reactive polyfunctional T cells were present in the majority of hemodialysis patients even if humoral immunity failed. Further studies are required to confirm their in vivo antiviral capacity. The ability to induce vaccine-reactive T cells paves new ways for improved vaccination and therapy protocols.

aspects of pathogenesis of gout in light of recent scientific discoveries as a key for development of informative biomarkers and innovative therapeutic strategies.