Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.

A (series) range of potential dimorpholinoquinazoline-based inhibitors of the was synthesized. Several compounds exhibited cytotoxicity towards a panel of cancer cell lines in the low and sub-micromolar range. Compound with the highest activity and moderate selectivity towards MCF7 cells which express the mutant type of PI3K was also tested for the ability to inhibit PI3K-(signaling pathway) downstream effectors and associated proteins.

Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins.

The PARP family consists of 17 members with diverse functions, including those related to cancer cells' viability. Several PARP inhibitors are of great interest as innovative anticancer drugs, but they have low selectivity towards distinct PARP family members and exert serious adverse effects. We describe a family-wide study of the nicotinamide (NA) binding site, an important functional region in the PARP structure, using comparative bioinformatic analysis and molecular modeling.

Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies.

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.

[Cardiovascular syphilis (current state of the problem and analysis of own observations)].

A description of two cases of cardiovascular syphilis is presented. The introduction discusses the relevance of visceral syphilis. The literary review is constructed in a chronological format and reflects the stages of studying the problem of cardiovascular syphilis.

[The Experience of Use Triple Antithrombotic Therapy in Patients With Acute Coronary Syndrome and Atrial Fibrillation].

Aim: In real life to evaluate the effectiveness and safety of apixaban with double antiplatelet therapy for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and the recent episode of acute coronary syndrome without ST segment elevation.

Materials And Methods: 8 patients with atrial fibrillation and the recent (8-14 days after the onset of symptoms of ACS) episode of acute coronary syndrome without ST segment elevation were involved into the research. The effectiveness (deaths, stroke and systemic embolism) and the safety (major clinically significant and not significant bleeding) were investigated within 3 months.

[Clinical and metabolic features of nonalcoholic fatty liver disease in men and women].

To evaluate clinical features and metabolic disorders in men and women with non-alcoholic fatty liver disease (NAFLD).

Tankyrase Activity in Organs and Tissues of Mice.

Tankyrase, one of the NAD+ ADP-ribosyltransferases, is a target for drugs developed for their anticancer and other pharmacological activities. We designed an assay for estimation of the inhibition or activation of the enzyme in preclinical studies. In mice, the highest specific activity of tankyrase was observed in thymus, spleen, pancreas, and bone marrow.

NON-ALCOHOLIC FATTY LIVER DISEASE IN ELDERLY.

Aim: The study of the clinical course and metabolic disorders in patients nonalcoholic fatty liver disease (NAFLD) elderly.

Subjects And Methods: 153 patients with NAFLD was investigated, including 97 men and 56 women. In comparative terms we studied clinical manifestations of NAFLD.

[ALLELES C282Y AND H63D HFE GENE, INSULIN RESISTANCE AND SUSCEPTIBILITY TO DISTURBANCE OF PORPHYRIN METABOLISM IN NON-ALCOHOLIC FATTY LIVER DISEASE].

The Purpose Of The Study: The aim of the present work was to study the frequency of genotypes and alleles of C282Y and H63D HFE gene that may be associated with impaired porphyrin metabolism, as well as possible reasons for the formation of dysmetabolism porphyrins with NAFLD.

Materials And Methods: The study involved 65 patients (52 men and 13 women) aged 21 to 69 years (mean age 48.5±1.

[Porphyrin metabolism in women with metabolic syndrome].

A total of 47 women with metabolic syndrome (MS) were examined with the fractional determination of porphyrins in urine (uroporphyrin and coproporphyrin) and feces (coproporphyrin and protoporphyrin) as well as their precursors (5-aminolevulinic acid and porphobilinogen). Disorders of porphyrin metabolism were documented in 29 (61.7%) women All patients had elevated levels of porphyrin precursors.

[Coenzyme q10 in complex therapy of patients with ischemic heart disease].

The paper contains results of assessment of clinical efficacy and safety of coenzyme Q10 in patients with ischemic heart disease. Coenzyme Q10 (60 mg/day for 8 weeks) added to basic treatment of patients with stable class II-III angina significantly improved clinical status of these patients without clinically significant side effects.

[Dynamics of changes of blood inflammatory-oxidative biomarkers in acute coronary syndrome].

Some inflammatory cytokines and parameters of low density lipoproteins (LDL) oxidative modification were studied in blood of 250 acute coronary syndrome (ACS) patients--Siberian inhabitants, men and women with myocardial infarction (MI) or unstable angina on first, tenth and thirtieth days of disease. The inflammatory biomarkers in men and women with MI are: increased concentrations of interleukin (IL)-6, IL-8 and C-reactive protein (CRP), especially on the first day of disease. The most significant inflammatory biomarker of ACS is increased CRP level, especially in women.

Poly(ADP-ribosyl)ation of mannose-binding lectin out of human kidney cells.

Mannose-binding lectin was identified as a substrate of tankyrase 2, an enzyme that catalyzes poly(ADP-ribosyl)ation. The endogenous tankyrase 2 was isolated out of cytoplasm of human embryonic kidney cells. It was bound to a soluble complex of at least two other proteins; they were identified using specific antibodies and other approaches as keratin 1 and mannose-binding lectin.

Interaction of afobazole with sigma1-receptors.

In vitro radioligand assay revealed interaction of afobazole with sigma(1)-receptors (Ki=5.9x10(-6) M). Translocation of sigma(1)-receptors from the endoplasmic reticulum to the outer membrane was demonstrated by confocal microscopy.

[Non-medicamentous correction of metabolic and functional disorders in the biliary tract of patients with metabolic syndrome].

This study included 49 patients with coronary heart disease (CHD) and arterial hypertension (AH) in whom comprehensive medical examination revealed metabolic syndrome (MA). The objective of the work was to ascertain the possibility of therapy courses using chloride-hydrocarbonate-sodium mineral water and to evaluate its corrective effect on metabolic processes and functional disturbances of the biliary tract. It was shown that mineral water has beneficial effect in patients with functional incompetence of the biliary tract.

[Porphirin metabolism in non-alcoholic steatohepatitis].

Aim: To study porphirin metabolism in non-alcoholic steatohepatitis (HASH).

Material And Methods: The trial enrolled 66 patients with verified diagnosis of HASH. Patients with chronic viral hepatitis and chronic alcohol intoxication were not included in the trial.

Isolation and physicochemical properties of tankyrase of human embryonic kidney cells of line 293.

We have isolated and purified endogenous cytosolic tankyrase from human embryonic kidney cells of line 293. Our data confirm a model of De Rycker and Price who consider that tankyrase is a master scaffolding protein capable of regulating assembly of large protein complexes. We have also studied kinetic characteristics of tankyrase in the complex, pH dependence of the enzyme activity, and its physicochemical properties.

[Use of chloride-hydrocarbonate sodium mineral water in the combined therapy of cardiovascular diseases].

Ability and efficiency of use of chloride-hydrocarbonate sodium mineral water Karachinskaya in the combined therapy of coronary heart disease (CHD) and arterial hypertension (AH) were studied. Mineral water was used in regimen of 1000 ml in a day for 10 days. This intake of mineral water did not have a negative influence on the course of CHD and AH.

[The prospectivity of permanent cardiostimulation for prevention of atrial fibrillation].

Possibility of prevention of atrial fibrillation in patients with permanent pacemakers was analyzed taking into account induction mechanisms. Patients with bradicardiac and ectopic mechanisms of atrial fibrillation induction seem to be optimal candidates for pacemaker therapy. Right ventricular pacing was an independent predictor of arrhythmic events.

[Porphyrin metabolism in men with metabolic syndrome].

Forty-three patients with metabolic syndrome (MS) were examined. The urinary (uroporphyrin--UP and coproporphyrin--CP) and fecal (CP and protoporphyrin) fractions of porphyrin, as well as the urinary excretion of porphyrin precursors (S-aminolevulinic acid and porphobilinogen) were measured. Porphyrin metabolic disturbances were registered in 33 (76.

[Differential diagnosis of specific gastric lesions in early syphilis patients with helicobacter infection].

Aim: To evaluate differential-diagnostic significance of different clinical signs, endoscopic and serological studies in making diagnosis of early gastric syphilis (EGS) in patients with helicobacter infection.

Material And Methods: Thirty patients were hospitalized with diagnosis of gastric and/or duodenal ulcer. Helicobacter pylori was identified morphologically or with a rapid urease test.

[The combination of carbohydrate and porphyrinic exchange disturbances: is it a chance or regularity?].

The subjects of the study were 399 patients with internal diseases and metabolic disturbances. Carbohydrate exchange parameters (fasting level of capillary blood glucose and glucose tolerance test), and porphyrin fractions in urine (uroporphyrin, coproporphyrin), and feces (protoporphyrin, coproporphyrin) were measured. Hepatic type of porphyrinic dysmetabolism was registered in 201 (50.

Immunohistochemical detection of tankyrase 2 in human breast tumors and normal renal tissue.

Tankyrase, which functions at telomeres and other cellular compartments, is thought to be a positive regulator of telomerase; its isoenzyme tankyrase 2 has been cloned as a putative cancer antigen. This pilot immunohistochemical study was designed to examine whether tumors overexpress tankyrase 2. An antibody was generated by using synthetic peptide specific for tankyrase 2 and was tested by Western blot and immunocytochemically; no cross-reaction with isoenzyme 1 was revealed.