[Results of a multicenter observational program to evaluate the effectiveness of complex therapy of patients with chronic cerebrovascular pathology with cognitive impairment with Cortexin and Neuromexol (CORNELia study)]. / Rezul'taty mnogotsentrovoi nablyudatel'noi programmy otsenki effektivnosti kompleksnoi terapii patsientov s khronicheskoi tserebrovaskulyarnoi patologiei s kognitivnymi narusheniyami preparatami Korteksin i Neiromeksol (issledovanie KORNElii).

OBJECTIVE: To evaluate the effectiveness of complex therapy with Cortexin and Neuromexol in patients with chronic cerebral ischemia (CCI) and cognitive impairment (CI). MATERIAL AND METHODS: We examined 801 patients with CCI on the background of arterial hypertension and atherosclerosis with confirmed CI: 329 (41.1%) men and 472 (58.9%) women aged 30 to 80 years (mean age 64±10 years), who were examined. Cortexin and Neuromexol. Examination - Mini-Mental State Examination (MMSE) scale, hour-long drawing test (HDT) and severity of depressive states (Brief Geriatric Depression Scale, Mini Geriatric Depression Scal, MGDS). In 30 patients receiving Cortexin and Neuromexol (main group, MG) and 30 patients in the comparison group (CG), biomarkers of ischemic brain damage (NSE, antibodies to NR2, VEGFA) were determined. The examination was carried out before the start of treatment and after 30 days. RESULTS: During therapy with Cortexin and Neuromexol, characteristic signs of a decrease in the severity of CI were noted (p<0.05). A positive correlation was revealed between the performance indicators of the MMSE and TFC tests, both before and after treatment (r=0.5 and r=0.6, respectively; p<0.05). A positive effect of therapy on the emotional background of patients was noted, in particular, a decrease in the severity of depressive symptoms on the MGDS scale. During therapy, a 2-fold decrease in the NSE level (p<0.05) was detected in the MG, which indicates a decrease in the structural and functional parameters of biomembrane neurons in the brain. The concentration of antibodies to NR2 decreased compared to the baseline level in both groups (p<0.05), and VEGFA decreased only in the MG (p<0.05). CONCLUSION: The results of the study allow us to recommend the complex prescription of Cortexin 10 mg/day for 10 days and Neuromexol tablets 125 mg (375-750 mg/day) for 30 days for chronic CVD. Complex therapy with Cortexin and Neuromexol is effective and safe in patients with CCI and CI.

[Evaluation of the effectiveness of the drug Cytoflavin in patients with dyscirculatory encephalopathy who have undergone a new coronavirus infection]. / Otsenka effektivnosti preparata Tsitoflavin u patsientov s distsirkulyatornoi entsefalopatiei, perenesshikh novuyu koronavirusnuyu infektsiyu.

OBJECTIVE: To evaluate the effectiveness of the Cytoflavin in patients with dyscirculatory encephalopathy (DE) who had a new coronavirus infection. MATERIAL AND METHODS: 82 patients were examined: 16 (19.5%) men and 66 (80.5%) women aged 58 to 80 years, mean age 69±6 years and 70±6 years, respectively. All patients had moderate vascular cognitive impairment (less than 26 points according to the MoCA test), a history of COVID-19 in the period from 3 to 12 months before the start of the study. Patients before COVID-19 were registered with a neurologist with chronic cerebrovascular diseases with non-demented cognitive impairment of vascular origin. Patients of the main group (MG) received the Cytoflavin from the 1st to the 25th day of observation, inclusive, 2 tablets 2 times a day against the background of standard basic therapy. Patients in the comparison group received only standard basic therapy. RESULTS: It was found that during therapy with Cytoflavin, patients noted a positive trend in the form of a decrease in the symptoms of cognitive impairment, improved orientation and working memory, concentration of attention and counting. Also, patients in MG noted a decrease in fatigue and depressive disorders, an increase in motivation and a positive attitude, the emergence of interest in life, an improvement in the emotional background of mood, an increase in physical activity and working capacity. Comparing the mechanisms of development of vascular dysfunction, a pathogenetic commonality between DE and the development of consequences in the form of cognitive impairment caused by COVID-19 was noted. CONCLUSION: Cytoflavin therapy at a dosage of 2 tablets 2 times a day for 25 days can be recommended as part of complex therapy for patients with DE and a COVID-19.

[The influence of laser radiation of the infrared range with a wavelength of 1270 nm on mice Balb/cNude]. / Vliianie lazernogo izlucheniia infrakrasnogo diapazona s dlinoi volny 1270 nm na myshei Balb/cNude.

BACKGROUND: The effects of low-intensity laser radiation (LILR) on the skin depend on the wavelength and density of the irradiation flux. Moreover, the vast receptor field of the skin facilitates the systemic influence of irradiation on the body. AIMS: The objective of the present study was to evaluate the effects of low-intensity laser irradiation (LIRI) of the infrared range with a wavelength of 1270 nm on the skin of mice Balb/cNude. MATERIAL AND METHODS: The study was carried out with the use of the linear immunodeficient mice Balb/c nude obtained from the animal house of the Pushchino branch of the Academicians M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Biorganic Chemistry. The animals were irradiated once with a fiber laser of stimulated Raman scattering with a wavelength (λ) of 1270 nm, a power of 1.96 mW during the 2 min exposure at an intensity of 10 mW/cm2, and an energy flux density of 1.2 J/cm2. The histological studies and morphometry of the skin autoptate were performed. In adition, the expression of microRNA-21, -31, -130a, -191, -200c, -205, -218 was determined in the skin. Reverse transcription and real-time PCR reactions with Taq-Man probes and primers were performed on the nucleic acid amplifier CFX96 ('BioRad', USA).MicroRNA-191 was chosen as the reference gene. The bioinformation analysis of signaling pathways involving the studied microRNAs was performed using the DJANA miRPath database v.3.0. RESULTS: A significant increase in the amount of keratinocytes of the basal layer was documented together with diffuse lymphoid-leukocyte infiltration of the interlobular connective tissue of the subcutaneous fat and endomysium after LILR. The pattern of microRNA expression was tissue-specific. An increase in the expression of micro-RNA-31 and-21 in the skin and a multidirectional change in miRNA-200 and -218 levels were shown. The bioinformation analysis showed that miR21 and miR31 were involved in the regulation of such signaling pathways as PI3K-Akt, Jak-STAT, MAPK, and mTOR of importance for carcinogenesis. Also, they have a signaling significance in the development of melanoma, kidney cancer, prostate cancer and malignant glioma. CONCLUSION: The data obtained in this study suggest activation of the tumor cell-specific and basic processes in the skin of immunodeficient Balb/cNude mice under the influence of low-intensity laser radiation with a wavelength of 1270 nm applied at a dose of 1.2 J/m2.

[The vascular endothelial growth factor in patients with advanced ovarian cancer on the background of chemotherapy according to the AP scheme.]

Antiangiogenic therapy requires to search for molecular markers of angiogenesis in ovarian cancer (OC). The diagnostic and prognostic role of VEGFA in OC is controversial today. The aim of the study was to compare the serum level of VEGF, the cytoplasmic protein content and VEGF transcript in the tumor tissue of primary patients with advanced ovarian cancer and to analyze the relationship between these parameters and the response to standard polychemotherapy using the AP scheme. 82 primary patients with advanced OC were incladed in the study. The control group included 30 healthy women. All patients received adjuvant chemotherapy according to the AP scheme after surgery. The serum VEGF-A level was determined by direct immunoassay analysis "Human VEGF ELISA Kit" ("RayBiotech", USA). Analysis of the VEGF transcript in tumor tissue was performed by PCR-RT using TaqMan® Gene Expression Assay (Thermo Scientific) probes, and for the data normalization the 18S and GAPDH referee genes were used. To calculate the IHC score of cytoplasmic expression of VEGF, immunohistochemical reactions were performed in paired samples of OC patients using antibodies (GeneTex, USA). For the genotyping of patients' DNA, test systems for the analysis of functional polymorphisms of the VEGF-A C12143A, G634C (LLC "Sintol", Moscow) were used. The level of VEGF-A in the serum of patients with OC was increased in comparison with the norm and depended on the response to chemotherapy according to the AP scheme. However, the specificity of this indicator is insufficient for use in prognostic purposes. There are no significant differences in the cytoplasmic expression of VEGF-A, depending on the response to chemotherapy. VEGF mRNA level was increased in 58% of patients. There was no correlation between serum VEGF levels and the transcript in the tumor tissue. Genotyping showed that the combination of genotypes of CC / GG reduces the risk of recurrence by 2.6 times. The results obtained make it possible to question the value of studying the serum level of VEGF for evaluating the sensitivity of patients with OС to anti-angiogenic drugs.

[The characteristics of redox-status of peripheral part of erythron under various localizations of neoplasm of organs of female reproductive sphere.]

The study was carried out to evaluate characteristics of redox-status in erythrocytes of peripheral blood of patients with ovarian cancer, uterine body cancer and cervix cancer using evaluation of products of peroxide oxidation of lipids: diene conjugates, ketodienes, Schiff's bases by Volchegorskii, malonic di-aldehyde by L.I. Andreieva, content of products of oxidizing modification of proteins by E.E. Dubinina; activity of anti-oxidant enzymes: superoxiddismutase by Nishikimi, catalase, glutathione-S'-transferase, glutathionereductase and level of reduced glutathione by A.I. Karpischenko. The evaluation of architectonics of erythrocytes and rigidity of membrane was implemented using a scanning probing microscope SolverPro (NT-MDT, Zelenograd, Russia). The statistical processing of obtained data was implemented using non-parametric Mann-Whitney U-test. The increasing of products of initial stages of peroxide oxidation of lipids - diene conjugates and malonic di-aldehyde and decreasing of level of interim (ketodienes) and tertiary ( Schiff's bases) products of peroxide oxidation of lipids have been established. Against this background a multi-directional alteration of superoxiddismutase and decreasing of catalase occurred. Simultaneously, increasing of activity of glutathione-transferase and level of reduced glutathione under all analyzed localizations of neoplasm were noted. The level of products of oxidizing modification of proteins depended on localization of primary tumor and it was minimal in case of cervix cancer. Also such an alteration of cyto-architectonics of erythrocytes was established as development of reversible deformed echinocytes in patients in case of ovarian cancer and irreversible deformed spherocytes in patients with cervix cancer and uterine body cancer and also abrupt increasing of rigidity of membrane of erythrocytes. The obtained data permits to surmise as a capacity of para-neoplastic processes development of oxidative and carbonyl stress in erythrocytes of peripheral blood of patients with ovarian cancer, cervix cancer and uterine body cancer at extensive stage of disease. The mentioned stress is accompanied by formation of echinocytes and spherocytes and significant increasing of rigidity of membrane. However, intensity of these processes is determined by localization of primary neoplasm and it can be applied for characteristic of biological portrait of tumor in case of consideration of schemes of anti-oxidant therapy.

[PHENOTYPE OF PERIPHERAL BLOOD NEUTROPHILS IN THE INITIAL STAGE OF ENDOMETRIAL CANCER].

We have examined peripheral blood neutrophils from 123 patients with primary endometrial cancer at stage Ia. Receptor system and the ability of neutrophils to form extracellular traps were assessed by fluorescence microscopy, the spontaneous production of cytokines IL-2, IFN-γ, g-CSF, matrix metalloproteinases-1,9,13 by the method of enzyme-linked immunosorbent assay, phagocytic activity, myeloperoxidase activity, the level of cationic proteis activity in NBT-test were evaluated by cytochemical methods, activity of neutrophils in the spontaneous NBT-test was used to evaluate the oxygen-dependent bactericidal action of neutrophils. The topology and the rigidity of the membrane of neutrophils were assessed by scanning probe microscopy. We have shown that the increase in the relative number of neutrophils lead to a change in their receptor system, aerobic and anaerobic cytotoxicity and ability to phagocytosis are enchanced while reducing NET-activity. We have observed a change in the secretory activity of neutrophils, which is characterized by increased level of MMP-1, possibly initiated by enhanced production of reactive oxygen species, by a reduction in the IL-2 level (inductor of cytotoxic activity) and a sharp increase in the level of the G-CSF. Architectonics of neutrophils in the case of endonetrial cancer at stage Ia is characterized by changing the shape and loss of grit. The rigidity of the cell membrane decreased. Changes in the morphology of neutrophils on the background of the continuing hyperactivity suggests that a state of balance between the immune system and the tumor is already in stage Ia endometrial cancer.

Effects of CAR-regimen autohemochemotherapy on redox-dependent processes in erythrocytes of tumor-bearing organism in experimental ovarian cancer.

The purpose: The purpose of the study was to investigate the effect of the scheme autohemochemotherapy ATS on redox-dependent processes in red blood cells of tumor-bearing organism at an experimental ovarian cancer. Methods: We studied the dynamics of redox-dependent processes in red blood cells of rats with experimental ascitic ovarian tumor during CAP-regimen autohemochemotherapy (cyclophosphamide, doxorubicin and cisplatin). We assessed the indicators of oxidative modification of proteins in erythrocytes - carbonyl derivatives at l = 346 nm, 370 nm, 430 nm and 530 nm, the parameters of lipid peroxidation - malondialdehyde, ketodienes, diene conjugates, Schiff bases; the enzymatic part of antioxidant system - the activity of catalase, glutathione transferase and superoxide dismutase biochemically. Results: The red blood cells of tumor-bearing animals were found having increased the products of lipid peroxidation and oxidative modification of proteins while reducing the activity of antioxidant enzymes, suggesting a state of oxidative and carbonyl stress. Conclusion: We showed that extracorporeal incubation of cytotoxic drugs used in the CAP scheme with autoblood prior to infusion - the method of autohemochemotherapy - either in monochemotherapy, or in CAP-regimen, decreases the levels of lipid peroxidation, oxidative modification of proteins and increases activity of first line antioxidant defense enzymes - catalase and superoxide dismutase in circulating red blood cells. Such dynamics of redox-dependent processes suggests a stabilizing effect of autohemochemotherapy on circulating erythrocytes in a tumor-bearing organism.

[THE MODE OF CLARIFYING DIAGNOSTIC OF PROGRESSING FORMS OF OVARIAN CARCINOMA].

The ovarian carcinoma is the most frequent cause of death because of malignant neoplasins in women. At that, there is no pathognomonic symptoms permitting diagnosing stage of process with sufficient degree of confidence. This is a determinative not only for choosing treatment regimen but also for correlation of expected results of treatments with economic factors with purpose to evaluate cost effectiveness under monitoring of these patients. The study was carried out to develop mode of clarifying diagnostic of progressing forms of ovarian carcinoma on the basis of evaluation of oxidative modification of proteins in blood plasma. In 100 female patients with primary ovarian carcinoma (stage III and IV according FIGO,) in blood plasma 21 indicators were determined in blood plasma using standardized techniques: absolute number of leukocytes, absolute and relative number of neutrophils, products of oxidative modification of proteins of basic and ketonic character (under wavelength of 356, 370, 430, 530 nm), Her-2/neu CA-125, matrix metalloproteinase 2 and 9 in blood serum and neutrophils, interleukin-6, interleukin-10, interleukin-1ß, interferon-γ, tumor necrosis factor-α, malonic dialdehyde, catalase, glutaihione transferase, glutathione reductase. The least squares method was applied to every parameter to appmximnate relative rates by density of Rayleigh distribution. For every indicator likelihood ratio functions of likelihood ratio were constructed and intervals at every stage were determined. The reliability of approximation was proved under testing with Pirson criterion hypothesis of compliance of practical values of parameters to theoretical law of density of distribution. The results permit to assert that level of oxidative modification of proteins cab be used as a reliable indicator for differentiated diagnostic of stage III and IV of ovarian carcinoma.

[Matrix metalloproteinases and clinical and functional status in smokers with persistent asthma].

AIM: To assess the role of matrix metalloproteinases (MMP) in the clinical and functional status of smoking patients with persistent asthma. SUBJECTS AND METHODS: Examinations were made in 16 healthy smokers (a control group), 22 healthy nonsmoking volunteers (a volunteer group), and 16 patients with endogenous (n = 6) and mixed (n = 10) persistent asthma (a study group) with varying disease control. The investigators used the following techniques: spirometry; determination of airway resistance and FeCO in the expired air; 30-minute percutaneous monitoring of blood oxygenation and 6-minute walk test; enzyme immunoassay for matrix metalloproteinase levels. RESULTS: The longer duration and higher intensity of smoking increase airway inflammation in the asthmatic patients and the length of blood oxygenation within the very low range. The combined negative influence of tobacco smoking and the underlying disease leads to a clinically significant decrease in pulmonary ventilation ability and basic levels of blood oxygenation, the occurring asthma control reduction being correlating with the longer duration of treatment. The investigators revealed the predictors of lowering the mean level of blood oxygenation (MMP-9, FeCO, and airway resistance), as well as the factors that negatively influence the level of dyspnea and fatigue in asthmatic smokers. CONCLUSION: The serum levels of FeCO and MMP-9 may serve as markers reflecting the intensity of airway inflammation in smokers with persistent asthma.

Dynamics of proinflammatory cytokine levels and their role in the development of local and systemic effects during progressing cervical cancer.

In order to evaluate the role of cytokines in the development of polymodal local and distant effects in patients with stages I-IV cervical cancer, the following parameters were measured: serum concentrations of TNF-α, IFN-γ, IL-1ß, IL-6, and IL-10; levels of malondialdehyde, activities of catalase, superoxide dismutase, glutathione reductase, and glutathione-S-reductase in the plasma, erythrocyte, and cervix uteri homogenate. The expression of p53, Bcl-2, VEGF, and Ki-67 in tumor tissue was evaluated. High levels of malondialdehyde in tumor tissue and erythrocyte were paralleled by low levels of superoxide dismutase and catalase and high activities of glutathiones. Medium correlations between Ki-67, Bcl-2, and p53 and the levels of IL-6, IL-10, and TNF-α at stages Ib-IIa were detected. The results indicated that the progress of cervical cancer was associated with the neoplasm integration in the host homeostasis by using the regional and systemic cytokine functions. These effects, amplifying the biological potential of the tumor, were the most significant at stages Ib-IIa.

[Redox-dependent processes in blood plasma, neutrophils and erythrocytes of patients with ovary cancer after polychemotherapy by CAP scheme].

The dynamics of the redox-dependent processes in blood plasma, neutrophils and erythrocytes of the patients with ovary cancer of the IIIrd clinical stage by FIGO after polychemotherapy according to the CAP scheme is considered. In the blood plasma and erythrocytes there were estimated the values of protein oxidative modification: carbonyl derivatives at λ = 346 nm, 370 nm, 430 nm and 530 nm; the lipid peroxidation parameters: malonic dialdehyde, dienic conjugates, ketodiens, shiff's bases; the fermentative chain of the antioxidant system: activities of catalase, glutationtransferase and superoxide dismutase. In the peripheral blood neutrophils there were cytochemically determined the myeloperoxidase activity and the number of the active neutrophils in the spontaneous NBTR-test. After the polychemotherapy there were detected higher levels of the protein oxidative modification products and the products of the lipid peroxidation in the blood plasma and erythrocytes of the patients. Simultaneous increase of the activity of the antioxidant enzymes in the blood plasma could be evident of a high level of the lipid antioxidants peroxidation system functioning, whereas the simultaneous decrease of the activity of the antioxidant enzymes in the erythrocytes was indicative of passible development of oxidative stress in them. After the chemotherapy there was observed a significant and reliable decrease of the total number of the neutrophils. After the second course of the chemotherapy the activity of myeloperoxidase in them in the spontaneous NBTR-test as well decreased. Such a dynamics of the redox-depended processes in various components of the blood in the tumour carrier was characteristic of the tumor biological picture and required the use of differential multicomponent antioxidant therapy in patients with ovary cancer.

[Cytokines profile and metabolic activity of neutrophils of peripheral blood when progressing neoplasma].

The neutrophil is considered as the peculiar monocelled sekretorny gland realizing the effector potential including by secretion of soluble products - cytokines and for today. Influence of a tumor on functional activity of neutrophils depends on type, localization and a stage of its development. In our research dynamics of metabolic and of neutrophils of peripheral blood, the contents in a lysate and serums of blood of cytokines of IL-1ß, 1Ra, 2, 6, 10, 18, TNF-α, IFN-γ and is studied when progressing a cervical cancer. Cytokines and metabolism indicators - activity of, determined by an immunofermental method, level of cationic proteins, a share of active cages in the spontaneous NST-test were cytochemical. It is shown that when progressing cervical cancer against increase in total of neutrophils significant decrease in their, aerobic and anaerobic bacterial action, decrease in the IL-1ß and IL-1 Ra level, and also IFN-γ takes place at TNF-α increase, increase of production of matrix metalloproteinas-2 on Ib-IIa of a stage of a disease that allows to assume emergence at this stage of cervical cancer of pro-tumoral effect of neutrophils.

[Cytokine status and neutrophil phenotype in the progression of cervical cancer].

There were assessed morphofunctional state of peripheral blood neutrophils and cytokine status in the serum of primary patients with progression of cervical cancer in the dynamics. Against the background of increasing the total number of neutrophils, a significant reduction occurred in the phagocytic activity, aerobic and anaerobic bactericidal activity, an increase of the rigidity of the membrane and the change of cell cytoarchitectonics at Ib-IIa stage of the disease. At the same stage, in neutrophils there were reduced the level of IL-1ß and its receptor IL-1Ra as well as the number of IFN-γ. Wherein there was increased the level of pro-inflammatory cytokine TNF-α. Cytokine status of the serum, characterized by sig- nificant boosting of IL-1Ra and IL-18 while lowering TNF-α, IFN-γ and IL-2, was advantageous for tumor progression and was detected at Ib-IIa stage of cervical cancer. The observed changes of cytokine status in the serum and morphofunctional state of neutrophils were discussed in the light of connection with the possibility of potential pro-tumor effect of the latter.