[Myocardial Contractile Function in Patients with Liver Cirrhosis and Syndrome of Bacterial Overgrowth Syndrome].

OBJECTIVE: to study myocardial contractile function in patients with liver cirrhosis and ascites in the presence of bacterial overgrowth syndrome (BOS) and pathological bacterial translocation. MATERIALS AND METHODS: We included in this study 59 patients with Child-Pugh class B and C liver cirrhosis (LC) of various etiology and ascites. Control group comprised 12 patients with ischemic heart disease complicated by chronic heart failure (CHF). Examination included history taking and laboratory and instrumental investigation. LC was diagnosed basing on clinical symptoms and instrumental studies. Child-Pugh and MELD scores were used for assessment of LC severity and prognosis. International ascites club grading system was used for evaluation of severity of ascites. Hydrogen breath test was applied for diagnosing BOS. Syndrome of pathological bacterial translocation was established based on blood levels of lipopolysaccharide-binding protein and detection of bacterial DNA in ascitic fluid. Structural-functional parameters of the myocardium and hemodynamics were assessed by echocardiography. Brain natriuretic peptide (BNP) concentration was measured in blood serum and ascitic fluid. RESULTS: In 13 of 59 patients with LC the hydrogen breath test was negative, in 33 positive and in 13 patients the positive hydrogen test was combined with the presence of BOS and pathological bacterial translocation. Blood serum and ascitic fluid BNP concentrations in LC patients were low and within normal limits (62.5±4.1 and 53.3±4.9 rg / ml, respectively), what contrasted with high BNP concentrations in patients with CHF (1820±95.5 and 497.1±39.6 rg / ml, respectively). Total protein level in ascitic fluid also was significantly lower in patients with LC than in patients with CHF (1.77±0.1 and 4.43±0.35 mg / dL, respectively). The serum-ascitic albumin gradient (SAAG) in both groups of patients exceeded 1.1 (1.58±0.13 in patients with CHF and 1.88±0.19 in patients with LC). Conclusions. In patients with liver cirrhosis the presence of BOS and bacterial translocation did not produce a distinct negative impact on contractile function.

Differential diagnosis of ascites in internal medicine: clinical case.

Ascites and hydrothorax may be the symptoms of congestive heart failure and do not always reflects presense of the decompensated liver cirrhosis. Clinical examination of patient with chronic hepatitis C which cyanosis of the lips, cervival veins pulsation, a triple heart rhythm indicated on pathology of the heart (constrictive pericarditis), which was confirmed by instrumental methods. Congestive heart failure has lead to the congestive liver in a young female patient. Regression of all the symptoms of heart failure occurred after surgical treatment (pericardectomy).

Minibactenecins ChBac7.Nα and ChBac7. Nß - Antimicrobial Peptides from Leukocytes of the Goat Capra hircus.

Antimicrobial peptides (AMPs) of neutrophils play an important role in the animal and human host defenses. We have isolated two AMPs (average molecular masses of 2895.5 and 2739.3 Da), with potent antimicrobial activity from neutrophils of the domestic goat (Capra hircus). A structural analysis of the obtained peptides revealed that they encompass N-terminal fragments (1-21 and 1-22) of the proline-rich peptide bactenecin 7.5. The primary structure of caprine bactenecin 7.5 had been previously deduced from the nucleotide sequence, but the corresponding protein had not been isolated from leukocytes until now. The obtained caprine AMPs were designated as mini-batenecins (mini-ChBac7.5Nα and mini-ChBac7.5Nß), analogously to the reported C-terminal fragment of the ovine bactenecin 7.5 named Bac7.5mini [Anderson, Yu, 2003]. Caprine mini-ChBac7.5Nα and mini-ChBac7.5Nß exhibit significant antimicrobial activity against Gram-negative bacteria, including drug-resistant strains of Pseudomonas aeruginosa, Klebsiella spp., Acinetobacter baumannii at a range of concentrations of 0.5-4 µM, as well as against some species of Gram-positive bacteria (Listeria monocytogenes EGD, Micrococcus luteus). The peptides demonstrate lipopolysaccharide-binding activity. Similarly to most proline-rich AMPs, caprine peptides inactivate bacteria without appreciable damage of their membranes. Mini-ChBac7.5Nα and mini-ChBac7.5Nß have no hemolytic effect on human red blood cells and are nontoxic to various cultured human cells. Therefore, they might be considered as promising templates for the development of novel antibiotic pharmaceuticals. Isolation of highly active fragments of the antimicrobial peptide from goat neutrophils supports the hypothesis that fragmentation of cathelicidin-related AMPs is an important process that results in the generation of potent effector molecules, which are in some cases more active than full-size AMPs. These truncated AMPs may play a crucial role in host defense reactions.

[Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1].

In order to find novel inhibitors of 17a-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: 1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; 2) the localization of the steroid moiety of all compounds in the active site is basically the same; 3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; 4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; 5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; 6) oxazoline--and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.

Computer-aided design and discovery of protein-protein interaction inhibitors as agents for anti-HIV therapy.

Protein-protein interactions (PPI) are involved in most of the essential processes that occur in organisms. In recent years, PPI have become the object of increasing attention in drug discovery, particularly for anti-HIV drugs. Although the use of combinations of existing drugs, termed highly active antiretroviral therapy (HAART), has revolutionized the treatment of HIV/AIDS, problems with these agents, such as the rapid emergence of drug-resistant HIV-1 mutants and serious adverse effects, have highlighted the need for further discovery of new drugs and new targets. Numerous investigations have shown that PPI play a key role in the virus's life cycle and that blocking or modulating them has a significant therapeutic potential. Here we summarize the recent progress in computer-aided design of PPI inhibitors, mainly focusing on the selection of the drug targets (HIV enzymes and virus entry machinery) and the utilization of peptides and small molecules to prevent a variety of protein-protein interactions (viral-viral or viral-host) that play a vital role in the progression of HIV infection.

[Computer-based substrate specifity prediction for cytochrome P450].

Cytochrome P450 is important class of enzymes metabolizing numerous drugs. The composition and activity of these enzymes are determined the drug distribution in organism, its pharmacological and toxic effect. Thus the prediction of the behaviour of compounds in organism is essential for discovery and development of new drugs in the early stages of this process. The different isoforms of cytochrome P450 can oxidized wide range of chemical compounds and their substrate specifity do not correlate with their taxonomical classification. The main methods of cytochrome P450 substrate specifity prediction is reviewed. These methods divided based on primary informations that used: prediction based on amino acid sequences, ligand-based (pharmacophore and QSAR models) and structure-based (molecular docking, affinity prediction) methods. The common problem of cytochrome P450 substrate prediction and advantage and disadvantages of these methods are discussed.

Human serum gamma-globulin binds copper cations.

Binding of copper cations to human serum gamma-globulin was studied using molecular ultrafiltration. The content of free metal in the filtrate was evaluated by the reaction with sodium diethyldithiocarbamate. Conformation characteristics of the protein were evaluated by UV spectrophotometry. gamma-Globulin molecule has several copper-binding sites differing by binding constants and filled one-by-one as the content of bound metal increased.

Biphasic interaction of gamma-globulin with copper cations.

Interactions of human serum gamma-globulin with copper cations in solution were studied by differential ultraviolet spectrophotometry. Copper in supraphysiological concentrations increases optical density of protein solution, reflecting the effect of gamma-globulin saturation with metal. In physiological and lower concentrations of copper cations we observed hypochromia in the protein absorption spectrum. Conformational changes in g-globulin molecule during interactions with copper by the surface and intramolecular binding sites and possible role of bivalent metal cations in the maintenance of certain conformations of immunoactive serum proteins are discussed.

Formation of supramolecular aggregations of gamma-globulin as a metal-dependent process.

The presence of copper cations in the solution of human serum gamma-globulin induced the formation of supramolecular forms of the protein. The intensity of this reaction increased with increasing copper concentration. The mechanisms of g-globulin aggregate formation under normal conditions and the possible role of bivalent metal cations in the regulation of protein effector functions are discussed.