Glycyrrhizin-induced changes in phospholipid dynamics studied by 1H NMR and MD simulation.

Phospholipid bilayer constitutes the basis of the cell membrane. Any changes in its structure and dynamics could significantly affect the properties and functions of the cell membrane and associated proteins. It could, in its turn, affect the mechanism and strength of drug-membrane interaction. Phase transitions in lipid bilayer play an important role in cell life and in transmembrane transport of ions and drug molecules. In the present study we have tried to clarify the mechanism of glycyrrhizin bioactivity by the study of its influence on the lipid dynamics and phase transition of the lipid bilayer. For this purpose, a combination of nuclear magnetic resonance (NMR) and molecular dynamic (MD) simulations was used. Glycyrrhizin is the saponin extracted from licorice root. It displays a wide spectrum of biological activity and is frequently used in traditional medicine since ancient times. Now glycyrrhizin attracts additional attention as a novel multifunctional drug delivery system. We have established that glycyrrhizin interaction with dipalmitoylphosphatidylcholine lipid bilayers leads to changes in lipid mobility and phase transition temperature. NMR and MD results demonstrated that a glycyrrhizin molecule is able to integrate into a lipid bilayer and form stable aggregates inside. We hypothesize that surface curvatures caused by local changes in the lipid composition and the presence of phase boundaries might affect the permeability of the cell membrane.

[Treating patients with acute myeloid leukemias (AML) according to the protocol of the AML-01.10 Russian multicenter randomized trial: the coordinating center's results].

AIM: To make a randomized comparison of 2 consolidation treatment options (two patient groups): 2 cycles of cytarabine in average (Ig/m2 in Group 2) and standard (100 mg/mi2 in Group 1) doses in combination with idarubicin (8-12 mg/m2) and mitoxantrone (10 mg/m2), after two 7+3 induction cycles of daunorubicin (60 mg/mi2) and subsequent 6 cycles of maintenance therapy. SUBJECTS AND METHODS: In January 2010 to October 2013, a Russian multicenter trial was conducted to treat patients with acute myeloid leukemias (AML) in accordance with the AML-01.10 protocol (ClinicalTrials.gov Identifier: NCT01587430). The trial enrolled 243 AML patients from 21 centers, including 71 patients (median age 38 years) from the State Hematology Center, Ministry of Health of the Russian Federation; 35 and 36 patients were randomized to Groups 1 and 2, respectively. The randomized groups were balanced by basic clinical and laboratory parameters. Favorable, intermediate, and high cytogenetic prognoses were in 14 (21.9%), 40 (62.5%), and 10 (15.6%) patients, respectively. RESULTS: Prior to treatment, 2 patients died; one patient refused treatment. Fifty-eight (85.3%) of the 68 patients achieved complete remission (CR); early deaths was in 2 (2.9%) and resistance in 8 (11.8%). Four (6.9%) patients died during CR. Protocol deviations (doses, intervals, and the number of cycles) were recorded in 12 (20.7%) of the 58 patients. Other 8 (11.8%) patients were switched to low-dose cytarabine because of complications, withdrawn from the protocol and not included into the analysis of randomized comparison. Twenty allogeneic bone marrow transplantations (allo-BMT) (7 related, 12 unrelated, and 1 haploidentical) were performed; of them 15 allo-BMTs were done during first CR. In the 68 patients, 3-year overall survival (OS) was 45.6%; relapse-free survival (RFS) was 41.5%. OS was 64.6% in Group 1 and 58.3% in Group 2; RFS was 62 and 38.8% in Groups 1 and 2, respectively (p>0.5). In the favorable, intermediate, and high prognosis groups, OS was 79.5, 60, and 31.1% and RFS was 81.8, 41.3, and 33.3%, respectively (p=0.1). The consolidation treatment option unchanged survival rates in the above risk groups. Unachieved CR after the first cycle considerably decreased RFS (33.9% versus 60%) and served as an indication for allo-BMT during first CP (RFS without BMT was 0; that with BMT was 78%). CONCLUSION: No differences were found between both consolidation options according to long-term results. Protocol deviations were recorded in one-third of the patients. While implementing the protocol, the efficiency of treatment was high. Allo-BMT during first CR substantially increased RFS if CP was not achieved after the first cycle.

Computational and experimental studies of size and shape related physical properties of hydroxyapatite nanoparticles.

In this work, the properties of hydroxyapatite (HAP) nanoparticles (NPs) have been studied both theoretically and experimentally focusing on computational analysis. HAP is widely used to fabricate implants, for drug delivery, etc. The physical properties of the nanosized HAP particles play an important role in the interaction with cells in the human body and are of great interest. Computer simulation was employed to understand the properties of HAP clusters (Ca(5)(PO(4))(3)OH) including formation energies, dipole moments and polarization (surface charges) by molecular mechanics (MM + , OPLS) and mostly by quantum semi-empirical Hartree-Fock (PM3) methods. The size of the simulated cluster is found to affect its dipole moment, polarization, and, finally, the electron work function- ϕ. These parameters depend on the concentration of hydrogen atoms H (or protons) at the surface. Values of ϕ were experimentally estimated via photoelectron emission measurements. The magnitude of ϕ was demonstrated to have a positive correlation on sizes. The NPs demonstrated a capability to be gathered within conglomerates. This property is confirmed by the calculated data for various sizes. Their sizes have a positive correlation on ϕ by the native particles. The main results show that the distributions of dipole moments have very different space orientations (along the OX, OY and OZ axes, the OZ axis is oriented along the OH column) and change with the addition of hydrogen atoms, which saturate the broken hydrogen bonds. This electrical property of NP leads to different behaviors and motions with consequent aggregation: (1) for the case of NPs having dipole moment oriented preferably perpendicular to the OZ axis (with more hydrogen bonds saturated by added H)-the HAP NP aggregates with hexagonal orientation and forms a wider and more spherical shape (sphere-like or bundle-like); (2) for the case of NPs having dipole moment oriented along the OZ axis (as is the case in the absence of added protons or non-saturated hydrogen bonds)-the NPs firstly rotated and oriented along this axis to form the most elongated cylindrical shape (rod-like).

Impact of hydrodynamics on oral biofilm strength.

Mechanical removal of oral biofilms is ubiquitously accepted as the best way to prevent caries and periodontal diseases. Removal effectiveness strongly depends on biofilm strength. To investigate the influence of hydrodynamics on oral biofilm strength, we grew single- and multi-species biofilms of Streptococcus oralis J22, Actinomyces naeslundii TV14-J1, and full dental plaque at shear rates ranging from 0.1 to 50 1/sec and measured their compressive strength. Subsequently, biofilm architecture was evaluated by confocal laser scanning microscopy. Multi-species biofilms were stronger than single-species biofilms, with strength values ranging from 6 to 51 Pa and from 5 to 17 Pa, respectively. In response to increased hydrodynamic shear, biofilm strength decreased, and architecture changed from uniform carpet-like to more "fluffy" with higher thickness. S. oralis biofilms grown under variable shear of 7 and 50 1/sec possessed properties intermediate of those measured at the respective single shears.

[Importance of the qualitative composition of dietary proteins in the dietotherapy of ischemic heart disease patients]. / Znachenie kachestvennogo sostava pishchevykh belkov v dietoterapii bol'nykh ishemicheskoi bolezn'iu serdtsa.

The effects of two isocaloric antiatherosclerotic diets (containing 120 g protein) differing in the amino acid composition of protein sources introduced were studied and compared in patients with coronary heart disease. Conventional protein sources were used in the first diet, whereas in the second diet, 15% of protein (by weight) was replaced by soybean protein isolate. A study was also made of the effect of dietetic management on lipid metabolism in blood serum. Hemocoagulation, capillary permeability, the kallikrein-kinin system, and immune responsiveness. An increase in the hypolipidemic effect of the diet was noted together with a decrease in the activity of the kallikrein-kinin system, capillary permeability, and body autosensitization upon introduction into the diet of soybean protein isolate. The increase of the protein quota as well as that attained by means of introducing in the diet of soybean protein isolate reduces the therapeutic effect of the diet on hemostasis.

[Effect of dietotherapy on the magnesium content of the blood serum of ischemic heart disease patients]. / Vliianie dietoterapii na soderzhanie magniia v syvorotke krovi bol'nykh ishemicheskoi bolezn'iu serdtsa.

Examination of patients with chronic coronary heart disease who suffered myocardial infarction has shown that most of them had a high blood serum content of magnesium. The magnesium content was lowered in 25% of the examined and was maximal in serum of the patients under 40 years. A positive correlation of the magnesium content to the serum content of beta-cholesterol and a negative one to the content of pre-beta-cholesterol and triglycerides were noted. After dietetic management a tendency was observed toward a 24% decrease in the magnesium content in obese patients and a 20% decrease in patients with normal body weight. Both groups demonstrated a reduction (but within normal) in the high magnesium content and a moderate elevation of the initially lowered content. The measurement of the magnesium content in blood serum cannot be regarded as an informative enough test for revealing the role of magnesium in the pathogenesis of coronary heart disease.

[Value of using dietary factors in the prevention and treatment of ischemic heart disease]. / Znachenie primeneniia alimentarnogo faktora v pofilaktike i lechenii ishemicheskoi bolezni serdtsa.

Influence of differentiated use of the alimentary factors on the lipemia level, hemocoagulation activity, arterial pressure level, carbohydrate tolerance and catecholamine content in the blood plasma of CHD patients was shown under the conditions of controlled dietotherapy. Incorporation of diet in multimodality therapy and prevention of this disease under inpatient, sanatorium-prophylactic and outpatient conditions was emphasized.

[Effect of diet therapy on indices of the activity of the plasma kallikrein-kinin system of young and middle-aged ischemic heart disease patients]. / Vliianie dietoterapii na pokazateli aktivnosti kallikrein-kininovoi sistemy plazmy krovi u bol'nykh ishemicheskoi bolezn'iu serdtsa molodogo i srednego vozrasta.

Young and middle-aged patients with coronary heart disease manifested an increase in the activity of kallikrein and BAEE-esterase together with a reduction in the levels of prekallikrein and alpha 2-macroglobulin. The maximal shifts were seen in young patients and in patients who sustained myocardial infarction less than a year before examination. High kallikrein level was associated with hypertriglyceridemia and disordered fibrinolytic activity. Dietetics promoted the normalization of the disordered parameters, particularly in patients whose diet included soybean.

[Status of the kallikrein-kinin system of the blood in young and middle-aged patients with ischemic heart disease]. / O sostoianii kallikrein-kininovoi sistemy krovi u bol'nykh ishemicheskoi bolezn'iu serdtsa molodogo i srednego vozrasta.

Increase in BAEE-esterase and kallikrein activities, simultaneously with decrease in alpha 2-macroglobulin and prekallikrein activities were found in blood plasma of young and middle age patients with heart ischemic disease. The maximal alterations were observed in young patients as well as in patients, subjected to heart infarction less than a year before the examination. Maximal activity of kallikrein was accompanied by deterioration of fibrinolytic activity, by hypertriglyceridemia and by increase in adrenaline excretion. Dietetics normalized partially the state of kallikrein-kinin system, especially, in patients ration of which contained soybean products.

[Comparative evaluation of the role of protein in the diet therapy of ischemic heart disease and rheumatism with a slight degree of activity]. / Sravnitel'naia otsenka roli belka v dietoterapil boly'nykh ishemicheskoi bolezn'iu serdtsa i revmatizmom s maloi stepen'iu aktivnosti protsessa.

The patients with chronic heart disease (265 subjects) and with little active rheumatic fever (145 subjects) received two variants of isocaloric diets which differed only in protein quota. The former diet contained the physiological norm of protein (100 g) and the latter one a higher quota (130 g). As a result of the treatment the subjective sensations and objective status of all the patients improved. Evaluation of the time course of lipid metabolism, the system of hemostasis, capillary permeability and immunological reactivity showed that the diet containing the physiological norm of protein appeared the most effective in patients with ischemic heart disease, whereas that with a higher protein quota turned out the most adequate in patients with rheumatic fever.

[Effect of a reducing diet on metabolic disorders in ischemic heart disease patients having excess weight]. / Vliianie redutsirovannoi diety na nekotorye metabolicheskie narusheniia u bol'nykh ishemicheskoi bolezn'iu serdtsa, imeiushchikh izbytochnuiu massu.

The paper concerns the effect of the diet with a strongly reduced content of carbohydrates, with a restriction of table salt and extractive substances on lipid and carbohydrate metabolism, on catecholamine secretion and exocrine pancreatic function in patients with ischemic heart disease accompanied by overweight and disturbed carbohydrate tolerance. Dietetics has a normalizing action on the body overweight, lipid composition and lipoproteid spectrum, as well as on the enhanced activity of serum trypsin. Moreover, it makes the blood content of immunoreactive insulin return partially to normal.

[Effect of diets with a varying protein content on fibrinolysis in ischemic heart disease]. / Vliianie diet s razlichnym soderzhaniem belka na fibrinoliz u bol'nykh ishemicheskoi bolezn'iu serdtsa.

A comparative influence of an antiatherosclerotic diet with a reduced proportion of protein (65--70 g) and of a diet with an amount of protein in line with the physiological standard (100--110 g) on the fibrinolysis and lipids spectrum of the blood was studied in 60 patients with ischemic heart disease. The antiatherosclerotic diet is shown to have most favourable effect both on the fibrinolytic system and on the lipids metabolism with the protein proportion of 100--110 g, i.e. in keeping with the physiological standards. A reduction of the protein content in the diet of patients with ischemic heart disease lowers the effect of treatment and does not have any positive influence on the function of the fibrinolytic system.