Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry (v.8, #4)

Recent achievements in the understanding genetic and biochemical mechanisms of the involvement of antioxidant defense enzymes in the pathogenesis of bronchial asthma have been summarized and discussed in this review. We concluded that genetically determined abnormalities in the functioning of antioxidant defense enzymes may play a substantial role in the development of bronchial asthma. Variation in genes for antioxidant defense enzymes in combination with pro-oxidant effects of the environment are responsible for a imbalance between oxidant and antioxidant processes with the shift of the redox state towards increased free radical production and induction of oxidative stress in the respiratory system, thereby contributing to the pathogenesis of bronchial asthma.
Keywords: bronchial asthma; etiology and pathogenesis; biochemical abnormalities; oxidative stress; antioxidant defense enzymes; genetic polymorphism

Oxidative stress, impaired calcium homeostasis and mitochondrial dysfunction are the key elements of carbon tetrachloride-induced liver damage. Activation of lipid peroxidation is accompanied by changes in the activity of antioxidant enzymes, the concentration of reduced glutathione, catabolic preference of metabolic processes and amino acid imbalance. Taurine, a nonproteinogenic β-amino acid, is one of the key regulators of metabolism, antioxidant and amino acid balance corrector. The hepatoprotective properties of taurine are mainly associated with its zonal distribution within the liver lobes, significant differences in the concentrations of taurine between periportal and pericentral regions; the latter is manifested in different protective properties that depend on compartmentalization of detoxification processes in the liver lobule. Administration of taurine under conditions of carbon tetrachloride-induced liver injury prevents the increase of plasma transaminases and bilirubin, reduces the histological changes in the liver by decreasing the degree of necrosis of hepatocytes, inflammatory and fatty infiltration.
Keywords: carbon tetrachloride; taurine; liver

This review summarizes data on the main approaches used for the search of biologically active compounds modulating the level and physiological activity of incretins. Currently two groups of drugs are used in clinical practice: they either replenish the deficit of incretins (glucagon-like peptide-1 receptor agonists) or inhibit the degradation processes (dipeptidyl peptidase 4 inhibitors). In addition, new groups of substances are actively searched. These include non-peptide agonists of glucagon-like peptide-1 receptors, agonists/antagonists of glucose-dependent insulinotropic peptide, the hybrid polypeptides based on glucagon-like peptide-1 and glucagon.
Keywords: incretin; glucose-dependent insulinotropic peptide; glucagon-like peptide-1; dipeptidyl peptidase 4; type 2 diabetes mellitus

Modern methods in breast cancer diagnostics by S. N. Tamkovich; V. E. Voytsitskiy; P. P. Laktionov (302-313).
The review summarizes literature data on modern instrumental, microscopic, and molecular (metabolomics, proteomics, genetics and epigenetics) methods currently used for early breast cancer diagnostics. Special attention is paid to analytical capacities and perspectives of their application in clinical practice.
Keywords: breast cancer; tumor markers; circulating nucleic acids; early cancer diagnostics

The effect of acute hypoxia with hypercapnia on the content of monoamines in symmetrical brain structures of male BALB/c mice by I. V. Karpova; V. V. Mikheev; V. V. Marysheva; E. R. Bychkov; P. D. Shabanov (314-317).
Changes in activity of neurotransmitter monoamines and their metabolites have been investigated in the right and left brain hemispheres of male BALB/c mice after acute hypoxia with hypercapnia. This condition is characterized by a simultaneous decrease in O2 tension (hypoxia) and increased levels of CO2 (hypercapnia) in the blood and/or other tissues. The concentrations of dopamine, serotonin and their metabolites (dihydroxyphenylacetic, homovanillic and 5-hydroxyindole acetic acids) were measured in the brain cortex, hippocampus and striatum of the right and the left hemispheres by the HPLC method. In control mice (which were not exposed to hypoxia with hypercapnia) a higher concentration of serotonin was detected only in the cortex of the left hemisphere. The asymmetry in the dopamine level was not registered in all structures studied. Acute hypoxia with hypercapnia decreased the striatal dopamine level as well as serotonin levels in the hippocampus and brain cortex. Hypoxia with hypercapnia caused a decrease in dopamine metabolites in the striatum and brain cortex; however, in the right brain cortex both dopamine metabolites decreased, while in the left brain cortex only a decrease in the level of dihydroxyphenylacetic acid was found. Serotonin metabolism decreased in all brain structures of mice exposed to hypoxia with hypercapnia. It is concluded that the brain serotoninergic system is more sensitive to acute hypoxia with hypercapnia than the dopaminergic system.
Keywords: hypoxia with hypercapnia; dopamine; serotonin; striatum; hippocampus; brain cortex

The selective toxic effect of dialdehyde derivatives of pyrimidine nucleosides on human ovarian cancer cells by A. S. Efremova; S. I. Shram; M. S. Drenichev; G. A. Posypanova; N. F. Myasoedov; S. N. Mikhailov (318-322).
The effect of synthetic nucleoside derivatives on the growth and survival of cultured human ovarian cancer cells (line SKOV-3) and normal human lung fibroblasts has been investigated. The dialdehyde derivatives of uridine, 1-β-D-erythrofuranosyl uracil and 3′-O-β-D-ribofuranosyl-2′-deoxythymidine exhibited a marked toxic effect on SKOV-3 cells, while their unoxidized analogues did not exhibit such action. Cultured human fibroblasts were less susceptible to the damaging effect of the dialdehyde nucleosides. The dialdehyde derivative of 1-β-D-erythrofuranosyl uracil demonstrated the highest difference in its cytotoxic effect on these cultures: 50% or higher suppression of SKOV-3 cells growth was achieved at the concentrations of this compound ten times lower than in the case of normal fibroblasts.
Keywords: dialdehyde nucleoside derivatives; cytotoxicity; antitumor effect; human ovarian cancer cell line SKOV-3; human fibroblasts

An important role of carbonate/bicarbonate ions has been recognized in the superoxide generating reaction of adrenaline autooxidation in an alkaline buffer (a model of quinoid adrenaline oxidation in the body). It is suggested that these ions are directly involved not only in formation of superoxide anion radical (O 2 −· ) but also other radicals derived from the carbonate/bicarbonate buffer. Using various buffers it was shown that the rate of accumulation of adrenochrome, the end product of adrenaline oxidation, and the rate of O 2 −· formation depend on concentration of carbonate/bicarbonate ions in the buffer and that these ions significantly accelerate adrenaline autooxidation thus demonstrating prooxidant properties. The detectable amount of diformazan, the product of nitro blue tetrazolium (NBT) reduction, was significantly higher than the amount of adrenochrome formed; taking into consideration the literature data on O 2 −· detection by NBT it is suggested that adrenaline autooxidation is accompanied by one-electron reduction not only of oxygen dissolved in the buffer and responsible for superoxide formation but possible carbon dioxide also dissolved in the buffer as well as carbonate/bicarbonate buffer components leading to formation of corresponding radicals. The plots of the dependence of the inhibition of adrenochrome and diformazan formation on the superoxide dismutase concentration have shown that not only superoxide radicals are formed during adrenaline autooxidation. Since carbonate/bicarbonate ions are known to be universally present in the living nature, their involvement in free radical processes proceeding in the organism is discussed.
Keywords: adrenaline (epinephrine); superoxide; oxygen; nitro blue tetrazolium; adrenochrome; superoxide dismutase; carbonate/bicarbonate ions; carbon dioxide; carbonate radicals; carbon dioxide radicals

Effect of melatonin on the activities of antioxidant enzymes in blood erythrocytes of rats during acute emotional stress by S. S. Pertsov; L. S. Kalinichenko; E. V. Koplik; L. G. Nagler; E. S. Alinkina; A. I. Kozachenko (331-335).
The effect of the epiphyseal hormone melatonin on the activity of antioxidant enzymes, glutathione peroxidase (GPx), glutathione reductase (GR), and Cu/Zn-superoxide dismutase (Cu/Zn-SOD) was studied in peripheral blood erythrocytes of behaviorally passive and active Wistar rats. Acute emotional stress was modeled by immobilization of animals for1 h with simultaneous electrocutaneous stimulation. Basal activity of antioxidant glutathione enzymes in erythrocytes of behaviorally passive rats was higher than that in active animals. Administration of melatonin (2 mg/kg, intraperitoneally) was accompanied by a decrease in the activity of GPx and GR in erythrocytes from non-stressed passive animals. After experimental stress, passive rats demonstrated a significant increase in the activity of Cu/Zn-SOD and GPx in peripheral blood erythrocytes. The absence of stress-induced changes in functional activity of antioxidant defense enzymes in the blood of behaviorally active animals suggests a relatively constant oxidative status of tissues in these animals under stress conditions. Melatonin administration had little effect on stress-induced changes in functional activity of the erythrocyte antioxidant system in passive rats. Active specimens pretreated with melatonin before stress exposure were characterized by activation of study antioxidant enzymes. Quantitative parameters of the erythrocyte antioxidant defense enzymes did not differ in behaviorally active and passive rats subjected to experimental stress after melatonin injection. Thus, exogenous melatonin abolishes differences in the activity of study antioxidant enzymes in erythrocytes of animals with different behavioral parameters under basal conditions and after experimental stress. In passive rats melatonin mainly reduced the initial tension of oxidative processes. By contrast, administration of this hormone to active specimens is followed by an increase in functional activity of the antioxidant enzyme system under conditions of acute stress.
Keywords: melatonin; emotional stress; antioxidant enzymes; blood erythrocytes; rats with various behavioral characteristics

Stimulation of adenosine receptors on myeloid cells enhances leukocyte migration at the site of burn injury by K. S. Yuryeva; K. V. Nevskaya; A. N. Dzuman; O. P. Ikkert; V. V. Ivanov; I. V. Saltikova; A. E. Sazonov; L. M. Ogorodova (336-342).
Adenosine, endogenous purine nucleoside, is an ATP metabolite that also acts as an extracellular signaling molecule. The concentration of extracellular adenosine rises during hypoxia and cell damage leading to numerous pleiotropic effects. Although it has been shown that local adenosine concentrations are significantly increased during burn injury their effects at the site of the damage remain poorly investigated. Circulating myeloid cells express surface specific adenosine receptors and during burn injury they migrate to the damaged site. We have shown that during stimulation of the myeloid cells adenosine receptors for 72 h an alternative antigenic phenotype developed, which differed from that of (adenosine) unstimulated cells: the expression of the monocyte marker CD14 was preserved with already expressed dendritic cell markers (CD209, CD1a). These cells had also higher levels of mRNA expression of proinflammatory cytokines and chemoattractants (IL-6, IL-8, IL-1β). Being injected into the site of the burn injury the adenosine modified myeloid cells increased the bulk density of the mixed cellular infiltrate (granulocytes, monocytes, fibroblasts) by day 7. Thus, we have found that one of the effects of adenosine at the site of burn injury consists in increased migration of granulocytes and monocytes in response to the increased production of paracrine factors by myeloid cells.
Keywords: adenosine; monocyte; burn injury; paracrine factor

Nitric oxide and electrogenic metals (Ca, Na, K) in epidermal cells by V. I. Petukhov; L. K. Baumane; E. V. Dmitriev; A. F. Vanin (343-348).
Using atomic emission spectrometry and EPR analysis metal-ligand homeostasis (MLH) has been studied in epidermal cells of 954 liquidators of the Chernobyl accident and 947 healthy individuals. A possible association of the redox status with the quantitative changes in the MLH, which could be used as discriminators of oxidative/nitrosative stress, attracts special interest. Characteristic features of oxidative stress mainly related to electrogenic metals (Ca, K, Na), were found not only among the liquidators examined, but also in some healthy individuals (18.1%); this suggests the presence of oxidative/nitrosative stress of non-radiation origin. Correlation between intracellular production of nitric oxide (NO) with quantitative changes in the electrogenic metals may indicate the possible involvement of NO in the generation of an electric potential of the cell.
Keywords: nitric oxide; metal-ligand homeostasis; redox status; epidermis

Screening of human cytochrome P450(51) (CYP51A1) inhibitors: Structural lanosterol analogues of plant and animal origin by L. A. Kaluzhskiy; O. V. Gnedenko; A. A. Gilep; N. V. Strushkevich; T. V. Shkel; M. A. Chernovetsky; A. S. Ivanov; A. V. Lisitsa; A. S. Usanov; V. A. Stonik; A. I. Archakov (349-360).
Inhibition of cholesterol biosynthesis at post-squalene steps provide the alternative to classic statin therapy. Sterol-14α-demethylase (CYP51) is one of potential targets for such inhibition. In this study screening of potential ligands of human CYP51 (CYP51A1) among natural low-weight compounds containing steroid-like moiety has been performed by means of integration of surface plasmon resonance and spectral titration methods. Four compounds (betulafolientriol, holothurin A, theasaponin, capsicosine) exhibited high affinity to the active site of CYP51A1. These data extend the known range of compounds, which may be used as specific inhibitors of CYP51.
Keywords: surface plasmon resonance; optical biosensor; spectral titration; cytochrome P450; CYP51; triterpenes