[Botulinum toxin type A (Relatox) in transition from medication overuse to non-overuse status in patients with chronic migraine: a subgroup analysis of phase IIIb randomized single-blind multicenter active-controlled parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v preodolenii lekarstvennogo zloupotrebleniya u patsientov s khronicheskoi migren'yu: podgruppovoi analiz rezul'tatov mnogotsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the effect of Relatox, the first Russian botulinum toxin type A, in patients with chronic migraine (CM) and medication overuse (MO). MATERIAL AND METHODS: In phase IIIb single-blind randomized multicenter active-controlled parallel-group study, patients with CM were randomized to once intramuscular injections of Relatox (n=101) or onabotulinumtoxin A injections - Botox (n=108). This subgroup analysis evaluated the percentage of patients who transition from medication overuse to non overuse status from baseline; mean changes in the number of headache days, migraine headache days, acute headache medication intakes days, headache intensity, proportion of patients who had a ≥50% reduction in headache days, proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score in a 28-day periods in each treatment among patients with baseline acute medication overuse via repeated measures. RESULTS: Of 209 patients with CM, 100% met medication overuse criteria. Relatox and Botox demonstrated significant improvement for overall least squares mean change in headache days, migraine headache days, headache intensity; and headache-related disability and quality of life in CM patients with baseline MO, without differences between the groups. 75% and 70% patients in the Relatox and Botox groups, respectively, achieved ≥50% reduction in headache days from baseline (OR 1.58, CI 95% 0.84; 3.02, p=0.155). Furthermore, Relatox and Botox significant reduced average medication overuse rates in patient with CM and MO at baseline. 62% of patients in the Relatox group and 48% of patients in the Botox group transitioned from medication overuse to non overuse status compared from baseline (OR 2.07, CI 95% 0.91; 4.62, p=0.044). Relatox group had greater reductions than the Botox group in the percentage of patients with acute migraine-specific medication (triptan) overuse (p=0.050). CONCLUSION: The results demonstrate highly prevalent of medication overuse among individuals with CM. This analysis provides evidence that the Russian botulinum toxin type A Relatox significantly improves measures of headache symptoms, quality of life and headache-related disability, and also significantly greater, compared to Botox, reduces migraine-specific medication consumption in patients with chronic migraine who overuse acute medications.

[Experience of using rhythmic transcranial magnetic stimulation, extracorporeal shock wave therapy and botulinotherapy in individual motor recovery programs in patients with spastic paresis of the lower limb]. / Opyt ispol'zovaniya v individual'nykh programmakh dvigatel'nogo vosstanovleniya ritmicheskoi transkranial'noi magnitnoi stimulyatsii, ekstrakorporal'noi udarno-volnovoi terapii i botulinoterapii u patsientov so spasticheskim parezom nizhnei konechnosti.

Walking disorder is one of the most frequent consequences of stroke and traumatic brain injury, occurring in 80% of cases. Spastic paresis of the muscles of the lower extremity is the cause formed in 20-40% of patients within a few weeks after brain damage. In this case, a complex of symptoms occurs: motor deficiency (muscle paresis), increased muscle tone (spasticity), biomechanical changes in muscles, joints and surrounding tissues, contractures. Recovery of walking is a difficult task due to the peculiarities of its organization in the norm. At the same time, changes occurring in the muscles of the lower limb after a stroke, their modular reorganization, the formation of various pathological patterns, violation of the regulation of movements by the central nervous system, rapidly occurring changes in muscles, ligaments, complicate this process. Improving walking is one of the most important priorities of rehabilitation. Already at the second (stationary) stage of rehabilitation, patients have a lack of proper support on the lower limb, which inevitably leads to excessive load on the second limb, a change in the body scheme, incorrect foot placement, violation of the mechanics of walking (moving from heel to toe) due to plantar flexion / turn of the foot, etc. All this makes patients dependent on outside help, and walking unsafe, increases the risk of falls and complications (arthropathy, contracture, etc.). In this regard, it is important to timely diagnose the totality of changes in the lower limb and create optimal comprehensive rehabilitation programs using highly effective treatment methods aimed at reducing the severity of the motor defect, reducing spasticity and preventing complications. The article discusses the place of rhythmic transcranial magnetic stimulation, extracorporeal shock wave therapy and botulinum therapy during rehabilitation in patients with spastic paresis of the lower limb after a stroke. The results of the protocol of clinical approbation «Complex rehabilitation of patients with lower limb spasticity after focal brain damage at the second stage of medical rehabilitation¼ are presented.

[Botulinum toxin type A (Relatox) in the treatment of chronic migraine in adults: results of phase IIIb, randomized, one-blind, multicenter, active-controlled, parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v lechenii khronicheskoi migreni u vzroslykh: rezul'taty mul'titsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the efficacy and safety of the first Russian botulinum toxin type A (Relatox) as a headache prophylaxis in adult with chronic migraine (CM). MATERIAL AND METHODS: The randomized, one-blind, multicenter, active-controlled, parallel-group trial study involved 209 patients with CM aged from 19 to 65 years. The patients were randomized to injections of the Russian botulinum toxin type A - Relatox (n=101) or onabotulinumtoxinA injections - Botox (n=108). The duration of the study was 16 weeks, which included five visits of patients every 4 weeks. Relatox and Botox were injected once into seven muscle groups of the head and neck at a dose of 155-195 units. Primary efficacy variable was mean change from baseline in frequency of headache days after 12 weeks. Secondary efficacy variables were mean changes from the baseline to week 12 in frequency of migraine days, acute headache pain medication intakes days; headache intensity; proportion of patients achieving ≥50% reduction from baseline in headache days, the proportion of the patients with medication overuse, the proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score. RESULTS: Analyses demonstrated a large mean decrease from baseline in frequency of headache days, without statistically significant between-group differences Relatox vs Botox at week 12 (-10.89 vs -10.06; p=0.365) and at other time points. Significant differences from baseline were also observed for all secondary efficacy variables at all time points without differences between the groups. The proportion of patients achieving ≥50% reduction from baseline in headache days was 75.0% and 70% in the Relatox and Botox groups, respectively (OR, CI 95% 1.58 [0.84; 3.02], p=0.155). Adverse events (AE) occurred in 15.8% of Relatox patients and 15.7% of Botox patients (p=1.000). No unexpected AE were identified. CONCLUSION: The results demonstrate that the first Russian botulinum toxin type A (Relatox) is an effective prophylactic treatment for CM in adult patients. Relatox led to significant improvements from baseline in multiple measures of headache symptoms, headache-related disability and quality of life. For the first time, a comparative analysis of two botulinum toxin type A products in parallel groups showed no less (not inferior) efficacy and safety of Relatox relative to Botox in the treatment of CM in adults.

Computer-aided Evaluation of Polyvalent Medications' Pharmacological Potential. Multiphytoadaptogen as a Case Study.

Many human diseases including cancer, degenerative and autoimmune disorders, diabetes and others are multifactorial. Pharmaceutical agents acting on a single target do not provide their efficient curation. Multitargeted drugs exhibiting pleiotropic pharmacological effects have certain advantages due to the normalization of the complex pathological processes of different etiology. Extracts of medicinal plants (EMP) containing multiple phytocomponents are widely used in traditional medicines for multifactorial disorders' treatment. Experimental studies of pharmacological potential for multicomponent compositions are quite expensive and time-consuming. In silico evaluation of EMP the pharmacological potential may provide the basis for selecting the most promising directions of testing and for identifying potential additive/synergistic effects. Multiphytoadaptogen (MPhA) containing 70 major phytocomponents of different chemical classes from 40 medicinal plant extracts has been studied in vitro, in vivo and in clinical researches. Antiproliferative and anti-tumor activities have been shown against some tumors as well as evidence-based therapeutic effects against age-related pathologies. In addition, the neuroprotective, antioxidant, antimutagenic, radioprotective, and immunomodulatory effects of MPhA were confirmed. Analysis of the PASS profiles of the biological activity of MPhA phytocomponents showed that most of the predicted anti-tumor and anti-metastatic effects were consistent with the results of laboratory and clinical studies. Antimutagenic, immunomodulatory, radioprotective, neuroprotective and anti-Parkinsonian effects were also predicted for most of the phytocomponents. Effects associated with positive effects on the male and female reproductive systems have been identified too. Thus, PASS and PharmaExpert can be used to evaluate the pharmacological potential of complex pharmaceutical compositions containing natural products.

[Safety and efficacy of the Relatox in the treatment of patients with cervical dystonia (results of a multicenter simple blind comparative randomized study)]. / Bezopasnost' i effektivnost' preparata Relatoks v lechenii patsientov s tservikal'noi distoniei (rezul'taty mul'titsentrovogo prostogo slepogo sravnitel'nogo randomizirovannogo issledovaniya).

OBJECTIVE: The analysis of evaluation of the efficacy and safety of Relatox in patients with cervical dystonia (CD). MATERIAL AND METHODS: Russian multicenter simple comparative randomized clinical trial. The study involved 180 patients of both sexes aged 18-65 years from 3 research centers of the Russian Federation. All patients had previously established diagnosis of CD and were randomized to one of two groups at 1 visit after the inclusion procedure and signing of informed consent. Patients in group 1 (n=90) got injections of Relatox, in group 2 (n=90) - injections of Botox for the first time or no earlier than 4 months after the previous injection of Dysport 500 units, Botox 200 units or Xeomin 200 units. The assessment of changes in cervical dystonia followed, including of determination of changes in the severity of CD, assessed on the TWSTRS scale by the total score and by the defining values of the blocks, as well as on the scales: the Patient Global Impression of Improvement (PGI-I) and of adverse events (local and systemic reactions). Based on the form of cervical dystonia (torticollis, laterocollis, etc.), the drug was injected under electromyographic control into the target muscles: sternocleidomastoid, belt, trapezoidal, shoulder-lifting muscle. RESULTS: Equal efficacy, good tolerability and safety comparable to the comparison drug Botox was demonstrated in 12 weeks after injection of Relatox. The number of registered local and systemic reactions in both groups was insignificant and did not differ significantly (p>0.05). There were no significant differences in the results of laboratory parameters in patients of both groups (p>0.05). Serious adverse events were also not detected during the study. CONCLUSION: Obtained results indicate the safety, good tolerability and efficacy of Relatox in patients with CD comparable to Botox and can be recomemded for using by practitioners.

Efficient electron cyclotron current drive regime for plasma current start-up in fusion reactors.

An accessibility enhanced efficient fundamental X-mode electron cyclotron heating (ECH) current start-up regime was identified for a reactorlike toroidal magnetic field range which has more than 100 times higher current drive efficiency compared to more conventional ECH methods for the relevant start-up temperature range. Very high current drive efficiency is possible due to the strong cyclotron interaction only with unidirectional passing electrons constrained by the wave accessibility conditions. This efficient electron cyclotron current drive regime may help facilitate the design of innovative economical solenoid-free tokamak fusion reactor systems.

[Specific features of the pathology of the respiratory system in SARS-CoV-2 (Coronaviridae: Coronavirinae: Betacoronavirus: Sarbecovirus) infected Syrian hamsters (Mesocricetus auratus)].

INTRODUCTION: Verification of histological changes in respiratory system using Syrian (golden) hamsters (Mesocricetus auratus) as experimental model is an important task for preclinical studies of drugs intended for prevention and treatment of the novel coronavirus infection COVID-19.The aim of this work was to study pathological changes of pulmonary tissue in SARS-CoV-2 (Coronaviridae: Coronavirinae: Betacoronavirus; Sarbecovirus) experimental infection in Syrian hamsters. MATERIAL AND METHODS: Male Syrian hamsters weighting 80-100 g were infected by intranasal administration of culture SARS-CoV-2 at dose 4 × 104 TCID50/ml (TCID is tissue culture infectious dose). Animals were euthanatized on 3, 7 and 14 days after infection, with gravimetric registration. The viral load in lungs was measured using the polymerase chain reaction (PCR). Right lung and trachea tissues were stained with hematoxylin-eosin and according to Mallory. RESULTS AND DISCUSSION: The highest viral replicative activity in lungs was determined 3 days after the infection. After 7 days, on a background of the decrease of the viral load in lungs, a pathologically significant increase of the organ's gravimetric parameters was observed. Within 3 to 14 days post-infection, the lung histologic pattern had been showing the development of inflammation with a succession of infiltrative-proliferative, edematousmacrophagal and fibroblastic changes. It was found that initial changes in respiratory epithelium can proceed without paranecrotic interstitial inflammation, while in the formation of multiple lung parenchyma lesions, damage to the epithelium of bronchioles and acinar ducts can be secondary. The appearance of epithelioid large-cell metaplastic epithelium, forming pseudoacinar structures, was noted as a pathomorphological feature specific to SARS-CoV-2 infection in Syrian hamsters. CONCLUSION: As a result of the study, the specific features of the pathology of the respiratory system in SARSCoV-2 infected Syrian hamsters were described. These findings are of practical importance as reference data that can be used for preclinical studies to assess the effectiveness of vaccines and potential drugs.

Synthesis of Deuterium-Labeled Pyrrolylcarnosine.

The effect of temperature on the effectiveness of the incorporation of deuterium into pyrrolylcarnosine (PC) was studied. Deuterium gas and heavy water were used as a source of deuterium. Isotope exchange was carried out using solid-phase and liquid-phase methods. It was found that it is better to use isotope exchange with deuterated water to obtain preparative amounts of labeled pyrrolylcarnosine. When using y solid-phase method, the main label is in pyrrole. The incorporation of deuterium at a higher temperature occurs more evenly. In addition, the use of deuterated water made it possible to reduce the amount of unlabeled isotopomer to almost 0% and to obtain a product with a yield of 70% and a content of more than seven deuterium atoms. It was established that the content of deuterium in the compound can be increased by pretreating the reaction mixture with deuterium gas. This approach opens up additional opportunities for the synthesis of labeled compounds.

Assessment of the Cytotoxicity of Peptide Modifications of Doxorubicin on Tetrahymena pyriformis.

The cytotoxicity of doxorubicin (Dox) and its peptide modifications Z-Gly-Pro-Dox and Boc-Gly-Pro-Dox were studied. Tetrahymena pyriformis was used as a test system, which made it possible, due to the short life cycle and high reproduction rate of ciliates, to trace their response to the effects of toxicants over several generations. It was found that peptide modification of the Dox molecule markedly reduces its cytotoxic and cytostatic effect. The Z-Gly-Pro-Dox modification has less cytotoxic and cytostatic effect compared to Boc-Gly-Pro-Dox. When determining the ability of drugs (at a concentration of 100 µM) to prevent bacterial contamination of samples, it was shown that the smallest degree of overgrowth was recorded in the presence of Dox (OD600nm 81.1). Boc-Gly-Pro-Dox also had a bacteriostatic effect, though less pronounced (OD600nm 93.8). The degree of overgrowth in the presence of Z-Gly-Pro-Dox was close to that of distilled water. The results obtained on ciliates did not contradict the data obtained in similar studies on mice.

[Study of stability of proline-containing derivatives of dopamine and serotonin in the biological media in vitro experiments]. / Issledovanie ustoichivosti prolinsoderzhashchikh proizvodnykh dofamina i serotonina v biologicheskikh sredakh v éksperimentakh in vitro.

Boc-Gly-Pro-DP, Z-Gly-Pro-DP, LA-Gly-Pro-DP, Boc-Gly-Pro-Srt, Z-Gly-Pro-Srt were synthesized for the first time. The stability of these compounds in the presence of leucine aminopeptidase, carboxypeptidase Y, carboxypeptidase B and proline endopeptidase (PEP) was determined. It turned out that the compounds are stable in the presence of aminopeptidases and carboxypeptidases. In the presence of PEP, dopamine (DP) and serotonin (Srt) are cleaved from the synthesized preparations. Thus, new proline-containing Srt and DP derivatives were obtained, Srt and DP could be gradually released from them. This suggest the possibility of a prolonged action of these biologically active compounds on the vital activity of cells and, consequently, of the whole organism.

Efficiency of Penetration of Dopamine and Serotonin Peptide Derivatives through the Artificial Membranes.

A mass spectrometric method has been developed for determining the content of dopamine and serotonin derivatives, which allows evaluating the efficiency of their penetration through artificial membranes depending on the structure of their peptide fragment. In this case, the diffusion of dopamine and serotonin derivatives through the membrane occurred as a result of competitive interactions. It was shown which compounds in this mixture more easily penetrate through artificial membranes. It was found that the most promising in terms of overcoming the BBB are Boc-Pro-Srt and Boc-Pro-DOPA.

[Stability of prolin-containing peptides in biological media]. / Ustoichivost' prolinsoderzhashchikh peptidov v biologicheskikh sredakh.

New data on peptide drugs have been summarized; their high stability is due to both the introduction of Pro-Gly-Pro in various amino acid sequences and the modification of the glyproline fragment itself. Pro-Gly-Pro-Leu, ACTH(6-9)Pro-Gly-Pro, 5-oxo-Pro-Arg-Pro and 5-oxo-Pro-His-Pro-NH2 were used as proline-containing peptides. Tritiated peptides were obtained: Pro-Gly-Pro-Leu with specific radioactivity of 135 Ci/mmol, ACTH(6-9)Pro-Gly-Pro - 26 Ci/mmol, 5-oxo-Pro-Arg-Pro - 60 Ci/mmol and 5-oxo-Pro-His-Pro-NH2 - 75 Ci/mmol. The concentration of Pro-Gly-Pro-Leu, ACTH(6-9)Pro-Gly-Pro, 5-oxo-Pro-Arg-Pro and 5-oxo-Pro-His-Pro-NH2 in the blood was found to be about 200 times more than in the brain for intranasal administration, and in average 600 times more for intravenous administration. The stability of proline-containing peptides in vitro experiments was determined using different commercially available peptidases (leucine aminopeptidases, dipeptidases, carboxypeptidases B and Y), and using nasal mucus, microsomal fraction of the rat brain (IMPC) and rat blood plasma. During peptidase hydrolysis of Pro-Gly-Pro-Leu, the main metabolites were Gly-Pro-Leu, Pro-Gly-Pro, Gly-Pro and Pro-Gly. For ACTH(6-9)Pro-Gly-Pro, the main metabolites were Phe-Arg-Trp-Pro-Gly-Pro and Trp-Pro-Gly-Pro. In peptidase hydrolysis of 5-oxo-Pro-His-Pro-NH2, the major metabolite was 5-oxo-Pro-His-Pro. It was shown that with different methods of peptides administration the composition of the metabolites formed is different. Based on the data obtained, resistance to enzymatic cleavage of peptides and their metabolic pathways were evaluated. Thus, these new data have shown that the above approaches can be used to prolong the action of glyprolines in living objects. In this case, the degradation of proline-containing peptides occurs mainly not due to the action of proteases, but due to other ways of degradation. In general, the data presented in the review indicate the promise of intranasal way of introducing biologically active peptides into the brain of living organisms.

[Quantitative targeted screening of proteins associated with lung adenocarcinoma cancer by the method of selected reaction monitoring]. / Napravlennyi kolichestvennyi skrining markerov adenokartsinomy legkogo metodom monitoringa vybrannykh reaktsii.

In the present study, we applied selected reaction monitoring (SRM) to a group of proteins that were previously reported to be associated with lung cancer (Novikova S.E. et al. (2017) Biomeditsinskaya khimiya, 63, 181-210. [1]). Measurements were performed on 59 plasma samples. These samples included: 23 samples of plasma of patients diagnosed with lung adenocarcinoma (LAC), 11 samples of plasma of patients diagnosed with squamous cell lung carcinoma (SqCC), 25 samples of donors with no previous history of oncological diseases, and one pooled sample from each of the above group. As a result of the SRM measurements 52 proteins were detected at least in one individual plasma sample. Statistical analysis showed that there were two groups confidently differentiated by the concentration value of 8 proteins wherein 5 proteins displayed increased level (P00738, P26639, P21926, P08603, P51149) in LAC group and 3 proteins (P51884, O15162, Q8N2K0) indicated diminishing the concentration level towards the control level. Data on protein concentrations obtained for LAC and SqCC did not distinguish the samples by statistical clustering analysis. These potential biomarkers can be used for further development of methods for early diagnostics of lung cancer.

[Antegrade approach for cholangiolithiasis complicated by mechanical jaundice]. / Vozmozhnosti antegradnogo dostupa v lechenii kholangiolitiaza, oslozhnennogo sindromom mekhanicheskoi zheltukhi.

AIM: To improve an efficiency of surgical treatment of patients with cholelithiasis complicated by obstructive jaundice through antegrade interventional approach. MATERIAL AND METHODS: 166 patients aged from 23 to 92 years with cholangiolithiasis complicated by mechanical jaundice were enrolled. Patients were divided into 2 groups: group I (136) - retrograde endoscopic method, group II (30) - antegrade interventional approach. RESULTS: In the first group surgical efficacy was 79.4%. Morbidity and mortality were 13% and 2% respectively. In the second group these values were 96.7%, 10% and 3% respectively. CONCLUSION: Antegrade interventional approach for minimally invasive procedures is technically feasible, has the same effectiveness as the retrograde endoscopic method and also all advantages of minimally invasive techniques.

Synthesis of N-acyl derivatives of Pro-Gly-Pro-Leu peptide: Proteolytic stability in vitro and effects on mouse macrophage cells RAW264.7.

Acetyl, oleoyl, arachidonoyl, and docosahexaenoyl derivatives of the Pro-Gly-Pro-Leu peptide with a chemical purity of 99.8% were synthesized. The degradation kinetics of the Pro-Gly-Pro-Leu derivatives under the action of leucine aminopeptidase, nasal mucus, and microsomal fraction of the brain and blood of rats was studied. It was shown that the N-acyl derivatives of Pro-Gly-Pro-Leu proved to be more resistant to the action of leucine aminopeptidase and other enzyme systems. The study of the cytotoxic and anti-inflammatory activity of preparations on the mouse macrophage cell line RAW264.7 showed that acylation with oleic and arachidonic acid makes the peptide cytotoxic with LC50 in the range of 70-15 µM and gives it anti-inflammatory properties with EC50 of 32 and 36 µM, respectively.

Is myelin basic protein a potential biomarker of brain cancer?

Myelin basic protein is a potential biomarker for the central nervous system diseases in which the myelin sheath is destroyed. Using pseudo-selected reaction monitoring and the method of standard additions, we have measured the myelin basic protein level in the cerebrospinal fluid of patients with neurotrauma (n = 6), chronic neurodegenerative diseases (n = 2) and brain cancer (n = 5). Myelin basic protein was detected only in four out of five cerebrospinal fluid samples of patients with brain cancer. The cerebrospinal fluid myelin basic protein level ranged from 3.7 to 8.8 ng ml-1. We suggest that monitoring of myelin basic protein in cerebrospinal fluid can serve as a diagnostic test for the brain cancer.

[Polymorphisms in Genes of Cytokines and Matrix Metalloproteinases Associated With Ischemic Heart Disease in Patients With Type 2 Diabetes].

OBJECTIVE: To examine associations between ischemic heart disease (IHD) and polymorphisms in cytokine genes (IL-1B, IL-4, IL-6, IL-10, TNFA, VEGF) and matrix metalloproteinase genes (MMP2, MMP3, MMP9) in patients with type 2 diabetes. MATERIAL AND METHODS: We studied 232 Caucasian diabetic subjects (33 men and 199 women aged 50-70 years). In 93 patients IHD was verified by treadmill test and/or coronary angiography (86 subjects with stable angina, 19 with previous myocardial infarction). Thirteen polymorphisms localized in the promoters of IL-1B (rs1143627), IL-4 (rs2243250), IL-6 (rs1800795), IL-10 (rs1800872, rs1800896), TNFA (rs361525, rs1800629, rs1800630), VEGF (rs699947, rs3025039), MMP2 (rs243865), MMP3 (rs3025058) and MMP9 (rs3918242) were investigated. RESULTS: Prevalence of G-allele and GG-genotype at -308 position of TNFA (rs1800629), as well as C-allele and CC-genotype at position +936 of VEGF (rs3025039) was higher in patients with IHD as compared to patients without IHD (OR=2.0, OR=2.2, OR=2.1, OR=2.4, respectively, all p=0.02). In logistic regression analysis, TNFA -308 A/G and VEGF +936 C/T polymorphisms showed associations with IHD (both p=0.009). These polymorphisms along with age, body mass index, duration of diabetes, low density and high density lipoprotein cholesterol were associated with IHD in multivariate models (p=0.0002 and p=0.00008, respectively). Nine combinations of TNFA -308 GG-genotype and variants of other genes demonstrated associations with IHD (p≤0.002). CONCLUSION: The polymorphisms in promoter regions of TNFA (rs1800629) and VEGF (rs3025039) are associated with IHD in patients with type 2 diabetes.

Horizontal Transfer of Tamoxifen Resistance in MCF-7 Cell Derivates: Proteome Study.

Using estrogen-dependent MCF-7 breast cancer cells and tamoxifen-resistant MCF-7/T subline we have shown that their co-cultivation lead to increase in tamoxifen resistance in the parent MCF-7 cells. The proteome analysis of MCF-7/T cells and new-generated resistant cells revealed 21 common proteins differently expressed in both the resistant cell lines, among them - 6 proteins were associated with the drug or hormonal resistance. Both resistant lines were characterized with suppression of estrogen receptor and activation of SNAIL1-signaling - mesenchymal pathway playing an important role in the down-regulation of estrogen receptor and maintaining of the estrogen-independent phenotype.

The penetration of 5-oxo-Pro-Arg-Pro into the brain and the major metabolic pathways of this peptide in the rat brain and blood at the intranasal and intravenous administration.

It was shown that the neuroactive peptide 5-oxo-Pro-Arg-Pro (5-oxo-PRP) is detected in the brain in the time interval of 5-120 min after it was intravenously or intranasally administered to rats; the maximum concentration of labeled tripeptide in these modes of administration was observed after 30 and 10 min, respectively. A significant difference in the concentrations of 5-oxo-PRP in the blood and brain (the latter was 50 times lower) during intravenous administration indicates a relatively low permeability of the peptide across the blood-brain barrier. Pharmacokinetic data analysis showed that, when administered intranasally, approximately 45% of the total number of 5-oxo-PRP detectable in the brain in the entire period of study enters via transport from the nasal cavity, and the rest of the peptide enters through the blood-brain barrier from the blood stream. It was found that 5-oxo-PRP in rats is rapidly metabolized forming proteolytic products, mainly amino acids, and degradation products, presumably oxidized these amino acids.