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The mechanism of an antioxidant action of water-soluble polyol - methanofullerenes C 60 [C 9 H 10 O 4 (OH) 4 ] 6 and C 60 [C 13 H 18 O 4 (OH) 4 ] 6 as the mild uncouplers of an oxidative phosphorylation and respiration is postulated. According to this mechanism, hydroxyl group of methanofullerenols can be protonated under excess of protons in the intermembrane space of hyperpolarized mitochondria. Protonation of fullerene derivatives is confirmed by the decrease in their negative Zeta potential in the pH below 5.4. Heavily protonated methanofullerenols become positively charged and move into the mitochondrial matrix. As a consequence, the proton gradient is dissipated, which causes a decrease in mitochondrial transmembrane potential (ΔΨ m ) and reduction in ROS production., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hepatoprotective properties of a new pyrimidine derivative - L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropyrimidine-2-one, synthesized on the basis Xymedon, were assessed in white rats exposed to CCl4. The compound under study administered prior to exposure to CCl 4 reduced the deviation of biochemical parameters from reference values and severity of structural and morphological changes in liver, when compared to the control. Hepatoprotective properties of the studied compound were more pronounced than those of Xymedon.

Gastroduodenitis caused by H. pylori , often acquired in early childhood, is found in about 50% of the adult population. Although H. pylori infections can remain asymptomatic, its virulence factors usually trigger epithelial vacuolization and degeneration, loss of microvilli, disintegration of cytoplasm, and leukocyte accumulation. It is believed that leukocyte infiltration is driven by cytokines produced locally in infected tissue. However, so far little is known about changes in serum cytokines in juvenile patients infected with H. pylori . Serum cytokine profiles were analyzed in 62 juvenile patients diagnosed with gastroduodenitis using the Bio-Plex multiplex assay. H. pylori infection was confirmed in 32 patients, while 30 patients were H. pylori -free. Cytokines CXCL5 and CXCL6, potent neutrophil chemoattractants, were upregulated in all patients diagnosed with gastroduodenitis. Serum levels of IL8, a prototype neutrophil attractant, remained unchanged in subjects with gastroduodenitis relative to controls. Therefore, our data suggest that CXCL5 and CXCL6 play a role in directing neutrophil trafficking into inflamed gastroduodenal tissue. In addition, the CCL25/GM-CSF ratio differed significantly between H. pylori -positive and -negative juveniles. Further, study is needed to evaluate the role of CCL25 and GM-CSF in the pathogenesis of the different etiologies of gastroduodenitis.

Here, we report for the first time on two novel water-soluble polyol-methanofullerenes which uncouple respiration and oxidative phosphorylation. A cytofluorimetric JC-1-based ratiometric assay was used to quantify mitochondrial potential Ψm in Yarrowia lipolytica cells exposed to the fullerenes tested. Both methanofullerenes significantly downregulated Ψm, thereby decreasing the subset of cells with high mitochondrial potential compared with intact control cells. The Ψm-low subset of Yarrowia lipolytica cells resulted from methanofullerenes exposure preserved physiological cell size and granularity patterns., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The iron metabolism was studied in serum blood samples collected from 26 professional sportsmen undergoing intensive physical exercises using EPR combined with haematological and biochemical laboratory tests. Only 23% of EPR spectra (n = 6) were practically normal while in the rest spectra additional abnormal absorption lines were detected. Presumably, the significant portion of new signals may be caused by different cytochromes. Moreover, the anisotropic signals with g1 approximately equal to 2.02; g2 approximately equal to 1.94 and g3 approximately equal to 1.86 registered in some spectra pointed to the sulfur-iron centers. There was nearly linear correlation between the concentration of Fe3+ in transfferin (Fe(3+)-Tf) obtained from the EPR spectra and the serum iron concentration measured by absorption photometry both for sportsmen and controls (healthy individuals and patients with different diseases). At equal serum iron concentrations the Fe(3+)-Tf level was higher in sportsmen than that in controls. The Pearson correlation coefficient (r) for Fe(3+)-Tf and serum iron values was equal to 0.89 in sportsmen versus r = 0.97 in controls. Additional new lines in serum EPR spectra of professional sportsmen prove the suitability of EPR assay for scheduled medical exams since routinebiochemical and haematological tests are insufficient to discover all abnormalities in iron metabolism under intensive physical exercises.

The exact mechanism by which cytotoxic ribonucleases reach the cytosol of tumor cells remains unclear. The interaction of ribonucleases with a lipid bilayer is involved in the translocation of ribonucleases across the endosomal membrane. Here, we aimed to study the hydropathy character of toxic antitumor ribonucleases (bovine seminal ribonuclease and binase) and two non-toxic ribonucleases (bovine pancreatic ribonuclease and human pancreatic ribonuclease) by sliding-window hydrophobicity analysis. Comparative hydropathy plot analysis of the non-toxic pancreatic ribonucleases and their toxic variants was also performed. The data obtained indicate that some cytotoxic ribonucleases have a hydrophobic segment, which is sterically available for the hydrophobic interaction with a tumor cell membrane and endosomal membrane. After dissociation, subunits of dimeric ribonucleases are probably capable of thermodynamically favorable interaction with the interfacial region of a lipid bilayer. Remarkably the hydrophobic segment is not identified in the amino acid sequences of non-toxic ribonucleases. The paper describes the hydrophobic properties of toxic RNases that are essential for both the model of a lipid-protein interaction and the cytotoxicity mechanism unraveling., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Changes in Fe(3+)-transferrin (Fe(3+)-Tf) and Cu(2+)-ceruloplasmin (Cu(2+)-Cp) concentrations in venous blood sampled from anemic patients with urinary bladder and kidney cancer in I-IV stages were investigated using electron paramagnetic resonance spectroscopy. It was established that at malignancy-associated anemia the paramagnetic Fe3+ ion concentration in transferrin is below a norm, while in anemic non-oncology patients the Tf iron saturation is normal. Moreover, in patients with malignancy-associated anemia the Cu(2+)-Cp average value is nearly twice as large as that for healthy volunteers (confidence probability P). It was shown that simultaneous EPR measuring of paramagnetic centers (such as Fe(3+)-Tf and Cu(2+)-Cp) in blood of anemic patients can be used as a biomarker for urological cancer diagnosis even at early stages of the growth of a malignant tumor.

The magnitude of transmembrane potential delta psi in cells of Escherichia coli K12 was determined by the method of flow cytofluorometry for different phases of growth. It was large in the log phase, whereas in the lag and stationary phases, the population was shown to consist of two subpopulations with low and large values of delta psi in cells. In the presence of 2,4,6-trinitrotoluene (TNT), this bimodal distribution of delta psi over the population was observed during the entire growth period until TNT was almost completely eliminated from the cultivation medium (to a concentration of 18-20 mg/l). The mean value of delta psi in cells of the population grown in the presence of TNT was substantially smaller than that in controls due to the larger size of the subpopulation with a low value of delta psi. Upon elimination of TNT, the distribution of delta psi in cells of the culture became unimodal and close to that in the control culture in the early log phase of growth. These findings are discussed from the standpoint that considers heterogeneity of the culture of Escherichia coli K12 as a mechanism of its adaptation to the presence of xenobiotics.

The effect of xymedon on Ca2+ currents in entorhinal cortex LIII pyramidal neurons was studied using brain slices from 10-17-day old rats, which were analyzed by means of the infrared video assisted whole cell patch clamp recording. The sample slices were superfused with artificial cerebrospinal fluid containing tetrodotoxin, 4-aminopyridine, and tetraethylammonium for the blocking of Na+ and K+ channels, respectively. Xymedone was added to artificial cerebrospinal fluid and to all extracellular solutions. The slices were exposed to different concentrations of xymedone for 3 hours followed by patch-clamp recordings. Control recordings were run with the vehicle. Xymedone in a concentration of 0.01 mM decreased the maximum voltage-dependent Ca2+ current amplitude by 39.8 %, while 1 mM of xymedone inhibited the Ca2+ currents almost completely. The obtained data showed for the first time that xymedone exhibits a calcium channel blocker activity in neurons. Possible neuroprotective mechanisms of xymedone are discussed.

An induction of apoptosis by RNase from Bacillus intermedius (binase) and its mutants characterized with low catalytic activity (Lys26Ala and His101Glu) in human myelogenic erythroleukemia K562 cells, human lung carcinoma A549 cells and human peripheral blood mononuclear cells was studied. For the first time selective apoptogenic effects of binase toward leukemic blood cells was determined. Neither antiproliferative nor apoptotic effects of binase were detected in normal human peripheral blood mononuclear cells. Formation of low molecular weight oligonucleosomal DNA fragments (less than 50 Kb) which are an early marks of apoptosis was registered in solid tumor cells treated by binase. Using mutant RNases it was shown that decrease of catalytic activity to 2.5% of wild type enzyme activity leads to the loss of apoptogenic properties of enzyme. Selective apoptogenicity of binase found towards malignant cells confirmed that antitumor agents based on bacterial RNases could be considered as an alternative to standard chemotherapeutic drugs.

The effect of xymedone, a non-glucoside analog of pyridine nucleosides, on the apoptosis of human CD4+ T cells of the Jurkat line was studied by laser flow cytometry method. Xymedone decreased the membrane expression of phosphatidylserine and suppressed the increase in permeability of the cytoplasmic membrane, thus inhibiting the onset of a degradation stage of the apoptotic cascade. Possible mechanisms of the antiapoptogenic effect of xymedone within the framework of a (cytochrome C/caspase 3)-dependent signal pathway of the apoptosis are discussed.

Apoptosis (from Greek apoptosis, i.e., falling of leaves) is the phenomenon of programmed cell death, which plays an important role in the normal embryonic development and maintenance of homeostasis of the differentiated tissues of adult organisms. Completion of the apoptosis process is accompanied by specific morphological and biochemical changes in the involved cells. Various disturbances in the control of apoptosis underlie various neurodegenerative diseases, the formation of malignant tumors, autoimmune disturbances, and developmental abnormalities. A deficit of neurotrophic factors leads to apoptosis of neurons. Survival of specific cell populations of neurons is controlled by neurotrophic factors and their combinations. Oncogene bcl-2, a repressor of cell death, belongs to the better studied factors controlling apoptosis. The terminal stages of cell death, including death of neurons, depend on the activation of caspases, specifically caspase-1 (interleukin-1 beta-converting enzyme). Ca2+ and reactive forms of oxygen play an important role in the initiation of apoptosis by changing mitochondrial permeability. Neuregulin, a factor of neuronal origin, is the main controlling factor in apoptosis of Schwann cells, and this process determines the size of their definitive population. Fibroblast growth factor b diminishes apoptosis of Schwann cells in regenerating nerve fibers.

Effects of the pyrimidine derivatives of xymedone and methyluracil upon the induction of point mutations of the base pair substitution type in the Salmonella/microsome test and the frequency of chromosome aberrations in the lymphocytes of patients with the chronic osteomyelitis diagnosis. Xymedone more effectively than methyluracil inhibited the induction of point mutations by nitrosomethylurea. In the case of the cyclophosphane induced mutagenesis, the two preparations exhibited comparable antimutagen effects. Both xymedone and methyluracil (1.5 g/day, 10 days) reduced the (increased) frequency of chromosomal aberrations in the lymphocytes of patients with the chronic osteomyelitis diagnosis. The anticlastogenic effect of methyluracil vanished 5 days after termination of the 10-day administration course, while xymedone exhibited an afteraction anticlastogenic effect over this period. Interrelation of the antimutagen effect and immunomodulating activity of xymedone is discussed.

The study was undertaken to examine 59 patients with destructive pulmonary tuberculosis who had T-cell dysfunction (loss of CD3+, CD4+, lymphocytes, slightly positive tuberculin test) and augmented IgA and IgG production. Oral Xymedone given in a dose 2.0 g daily for two 2 months in combination with antibacterial therapy abolished lymphopenia, restored CD4+ counts, CD4+/CD3+ ratio, upregulated IgG levels, but did not affect IgA levels. The Xymedone-treated patients developed fewer side effects due to basic antibacterial chemotherapy and showed more rapid culture conversion, resolution of pulmonary infiltration and closure of destructive cavities.

It was established in experiments on albino unbred mice and during treatment of patients with osteomyelitis that 30 mg/kg of ximidon suppresses the formation of micronuclear polychromatophilic erythrocytes found in the bone marrow of mice and peripheral blood of patients with chronic osteomyelitis. The interrelationship of the results obtained with the modulating effect of ximidon on the mitochondrial, thiol, and adenylate cyclase-dependent mechanisms of cell regulation is discussed.

It was demonstrated in experiments on guinea pigs that a 30 mg/kg dose of ximedon changes the content of SH-groups in immunocompetent cells depending on the duration of drug administration and the organ to which the cells under test belong. Maximum increase of the SH-groups was recorded in the thymocytes. The dynamics of changes in Ca(2+)-ATPase activity repeated the fluctuations in the SH-group content in the splenic and bone marrow cells. In the bone marrow cells of CBA x C57B1 mice 3 mg/kg ximedon suppressed the induction of chromosome aberrations caused by cyclophosphane. The interrelationship of changes in the cell sulfhydryl status with Ca(2+)-ATPase activity and the antimutagenic effect of ximedon is discussed.

Experiments with guinea pig immunocompetent cells and nonadherent and adherent mononuclear fractions of the peripheral blood of healthy donors, and patients with rheumatoid arthritis and purulent surgical infection disclosed different levels of Ca(2+)-ATPase activity. Thymectomy in adult guinea pigs led to diminution of activity of the enzyme in all lymphoid organs. The effect of ximedon (30 mg/kg) on Ca(2+)-ATPase activity depended on the thymus and duration of treatment with the drug, and was of a two-phase character.

Experiments on guinea pigs showed that xymedon in a dose of 30 mg/kg stimulates nucleic acid synthesis in thymocytes and increases the blood serum nucleic acid content. Xymedon increased secretion of endogenous DNA by human lymphocytes stimulated with PNA in vitro. The systemic immunotropic mechanisms of pyrimidine derivatives are discussed.