[Influence of alpha-lipoic acid on liver glutathione system of healthy and Ehrlich ascites carcinoma transplanted mice].

Influence of alpha-lipoic acid (LA) on liver glutathione system of Ehrlich ascites carcinoma (EAC) transplanted mice was studied. LA causes multidirectional influence on glutathione system of healthy mice. EAC transforms LA influence, strengthening prooxidative effects more expressed at introduction in early terms after inoculation of the tumor. The mechanism explaining realization of LA prooxidative effects as a result of interaction with glutathione system is suggested.

[Catecholamines and their metabolites in children with Asperger and Kanner syndromes].

Children with Asperger and Kanner syndromes in the stable state demonstrate similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine and by an increase in dopamine and homovanylic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanylic acid, epinephrine and MHPG. Only in children with Kanner syndrome in the aggravated state plasma MHPG increases, excretion of tyrosine decreases and excretion of normetanephrine increases. The observed imbalance in dopamine and epinephrine/norepinephrine systems justifies combined analysis of changes in catecholamines and their metabolites levels as the most informative approach in the study of the effect of autistic disorders.

[Nuclear glutathione and its functions].

During recent years the nuclear localization of glutathione has been confirmed and this fraction has been quantitatively determined. The nuclear GSH and the enzymes of its metabolism realize independent and important functions. They considerably differ from functions of hyaloplasmic and mitochondrial GSH. Glutathione interacts with regulatory pathways, involved into signal transmission into the nucleus.

[Glutathione system. II. Other enzymes, thiol-disulphide metabolism, inflammation and immunity, functions].

The great significance of glutathione as a redox regulator and the reducing carrier has been established. There is a clear necessity for subdivision of an independent mitochondrial glutathione subsystem. The data on a specificity of glutathione metabolism in different organs are accumulated. The significance of glutathione system for inflammation and immunity has been proved. The investigations of glutathione system for elucidation of pathogenesis of diseases and its diagnostics are used in medicine.

[Glutathione system. I. Synthesis, transport, glutathione transferases, glutathione peroxidases].

Studies of glutathione system in all basic trends have been extended considerably during recent 10-15 years. A series of new metabolic enzymes has been discovered. Many of them are polyfunctional and their new activities have been recognized. The enzymes interact with hormones and signal transduction systems. The studies of intracellular, intercellular and inter organs transports have been considerably advanced. The important achievement consist in unmasking new functions not only by selective substances-analytics but also by gene engineering methods as well.

[The blood glutathione system in cerebral vascular diseases and its treatment with alpha-lipoic acid].

The changes of glutathione metabolism are rare in dyscirculatory encephalopathy and ischemic stroke (IS) of mild severity. The frequent and considerable changes have been revealed in IS of moderate and high severity as well as in hemorrhagic stroke. An increase of activities of glutathione peroxidase and glutathione transferase is the most typical. The increase of enzyme activity was not observed at the beginning of treatment after 3 days and in patients with severe degree of disease who died later. A standard therapy decreased the quantity and/or expression of changes of the glutathione metabolism in patients with IS of moderate and high severity while the addition of alpha-lipoic acid (alpha-LA) led to the complete normalization in IS of moderate severity and normalization of most parameters in IS of high severity. The increase of functional activity of the glutathione system at the early stage of treatment of IS and the favorable changes during the treatment, in particular after the addition of alpha-LA, were correlated with the improvement of neurological status assessed with the NIHSS. It has been confirmed that the glutathione system plays an important role in the tolerance to brain ischemia.

[Glutathione system in erythrocytes and blood plasma in strokes and dyscirculatory encephalopathy].

In dyscirculatory encephalopathy and moderate ischemic stroke there are single changes of components of glutathione metabolism. In moderate and severe ischemic stroke frequent and considerable changes have been revealed. Changes in hemorrhagic stroke are also expressed. An increase of activities of glutathione peroxidase and glutathione transferase is the most typical, rarely the increase of glutathione reductase and GSH is observed. The increase of enzymes activity was absent at the delayed oneset of treatment (more than 3 days) and in severe cases patients who died later. Glutathione system is important in the tolerance to cerebral ischemia.

Mitochondrial glutathione.

Many functions of mitochondrial GSH are significantly different from those of cytosolic GSH. This review considers the peculiarity of functions of mitochondrial GSH and enzymes of its metabolism, especially glutathione peroxidase 4, glutaredoxin 2, and kappa-glutathione transferase.

[Glutathione system in erythrocytes and plasma in viral hepatitis].

In all 5 acute (AVHs) and chronic viral hepatites (CVHs) there was the increase of erythrocyte activities of glutathione peroxidase (GPx) and glutathione reductase (GR), and the decrerase in GSH concentration. In blood plasma there was accumulation of GPx, glutathione S-transferase (GST) and y-glutamyl transferase (gammaGT). GSH and GR increased in plasma only in AVHs. In CVH C erythrocyte GST increased. Evidently changes in the erythrocyte glutathione system are reactions to oxidative stress and in blood plasma they are consequences of inflammation and hepatocyte cytolysis. Changes were more pronounced in middle-heavy course than in the heavy one. These changes have pathogenic importance and can be used in addition to complex diagnostics. They are significantly differed from changes in chronic gall-bladder diseases. Necessity of separate investigation of glutathione system in erythrocytes and blood plasma but not in whole blood is argued.

[Regulation of metabolic and energetic mitochondrial functions by hormones and signal transduction systems].

The discovery of the complex regulation of mitochondria functions by hormones and signal transduction systems is one of the new and important achivements of mitochondriology. A number of hormones of all the chemical classes and with different action mechanisms stimulate many mitochondrial processes, including Krebs cycle, respiratory chain, oxidative phosphorylation, energy dependent syntheses. These effects are realized and/or reproduced by receptors, the second messengers (cAMP, Ca2+, diacylglycerol), protein and tyrosine kinases, anchor proteins, transcription factors. All the main kinases are found in mitochondria; protein kinases and/or tyrosine kinases phosphorylate the protein 18 kDa from complex I, cytochrome c-oxidase, ATP-synthase, protein binding to cAMP/Ca2+ response element, voltage dependent anione channel, steroidogenic acute protein, proapoptotic protein BAD and also other proteins of mitochondrial membranes. Pleiotropy of calcium regulation of mitochondrial functions is proved. The receptors of lipophilic hormone, growth hormone, epidermal growth factor and neurotrophins are discovered in mitochondria. In cellular signaling mitochondria play the integrative role.

Molecular mechanisms of hormonal activity. II. Kinase systems. Systems with intracellular receptors. Transactivation of STS.

Hormone receptors and other components, functional mechanisms, and biological role of analyzed signal transduction systems (STS) are described. The recently revealed module principle of the structure and STS transactivation providing diversity and plasticity of regulation are highlighted. STS activities are significantly changed in many diseases. Novel promising pharmaceuticals targeted to certain components of STS increase in number from year to year. The data published by the beginning of January 2004 are summarized in this review.

Molecular mechanisms of hormonal activity. I. Receptors. Neuromediators. Systems with second messengers.

Hormone signal transfer along all of the cell compartments including nucleus is powered by signal transduction systems. Characteristics and importance of hormone receptors, principal components, functional mechanisms, and biological role of different systems with second messengers are described. Considerable examples of the importance of these systems for medicine are adduced. The drugs modifying these systems comprise more than 65% of contemporary medicines.

[General hormonology]. / Obshchaia gormonologii.

Research of hormones and mechanisms of their action is one of the most rapidly developing branches of modern biology. During the last 15 years it has been shown that hormones regulate all vital processes: metabolism and functions as well as template syntheses and other cellular processes (proliferation etc.), determined by genome. The majority of hormones showed new effects, their action proved to be pleiotropic. The comparative analysis has shown the fundamental uniformity of biological functions and signification, the basic features and properties, molecular mechanisms of action for all types of intercellular receptor regulators' activity. Therefore they are appropriate to be combined into a complete community, so-called "hormones". The science of all hormones is to be defined as hormonology. The activity of hormones considerably changes upon many diseases. Substances, which influence hormonal systems, make 2/3 of modern medications.

Influence of changes in glutathione concentration on body temperature and tolerance to cerebral ischemia.

Two compounds that deplete glutathione (buthionine sulfoximine and diethyl maleate) with different mechanisms of action decrease body temperature and increase tolerance to complete global cerebral ischemia, both correlating closely with the glutathione concentration decrease. Glutathione apparently participates in the regulations of these functional parameters. GSH diethyl ester does not influence the latter, though it increases moderately the GSH concentration. Injection of GSH ester into the cerebral ventricles or subcutaneously selectively increases the GSH level in the brain and liver. An influence of the brain on the glutathione system in the liver was revealed. Diethyl maleate and GSH ester increase the activity of glutathione metabolizing enzymes under certain conditions.

[The correlation of tolerance to cerebral ischemia and body temperature with glutathione concentration]. / Vzaimosviaz' tolerantnosti k ishemii golovnogo mozga i temperatury tela s kontsentratsiei glutationa.

Methodic approaches for the purposeful changes of glutathione concentration in the brain and liver by administration of glutathione depletors and prodrugs have been modified. Two different depletors (diethylmaleate and buthionine sulfoximine) cause considerable increase of tolerance to the complete global cerebral ischemia and hypothermia development which correlate closely with the decrease of GSH concentration. Five GSH prodrugs (GSH esters and oxothiazolidine carboxilate) and GSH itself usually decrease slightly body temperature but do not influence tolerance to ischemia in the most of series. The increase of tolerance to the complete global cerebral ischemia is connected not with GSH accumulation, but with its decrease. Evidently one of the two opposite GSH effects, sensitizing or protecting one, can predominate in different forms of cerebral ischemia.

[Catecholamines: biochemistry, pharmacology, physiology, clinical aspects]. / Katekholaminy: biokhimiia, farmakologiia, fiziologiia, klinika.

Catecholamines (CAs) realise activity of certain cerebral neurons, sympathoadrenal system and peripheral cells producing dopamine. CAs control metabolism, template biosynthesis, cytological, physiological and psychological processes. During recent 10-15 years complex employment of various interdisciplinary approaches (including molecular biology techniques) resulted in some important achievements. Cellular transporters and 10 individual receptors were discovered and studied. Basic mechanisms of CA signal transduction into nucleus and mitochondria, regulation of gene expression, hyperplasia, hypertrophy and biological oxidation have been recognised. It was found that besides central neurotransmitter action DA also acts as peripheral auto- and paracrinic hormone. CA participate in pathogenesis of many illnesses and in the defence mechanisms of a body. CA and related substances are effective and widely used drugs.

[Amino acids and their metabolites in blood and urine of children with minimal cerebral dysfunction]. / Aminokisloty i ikh metabolity v krovi i moche pri minimal'noi tserebral'noi disfunktsii u detei.

The following changes were found in children in the minimal cerebral dysfunction: the hypoaminoacidemia and hypoaminoaciduria with decrease of glutamate and aspartate, their amides, methionine and serine in the blood and urine; decrease of lysine, taurine, tyrosine, catecholamines and serotonin in the blood; increase of GABA and glycine in the blood; increase of xanthurenate, proline and cysteine in the urine. The ratio excitatory/inhibitory mediatory amino acids decreased significantly. The ratio essential/nonessential amino acids and concentrations of amino acids, transporting by x-AG, beta and A/ASC systems, decrease in the blood; majority of transporting systems in the kidney functions augmently. Disturbances of amino acids metabolism disappear or decrease in successful treatment.

[Classification of drugs by biochemical mechanism of action]. / Klassifikatsiia lekarstv po biokhimicheskim mekhanizmam deistviia.

Biochemical drugs classification is proposed. Drugs are divided into 6 classes, according to their action on: 1) signal-transduction systems, 2) other components of plasmatic membranes, 3) intracellularly, 4) gene therapy, 5) extracellularly, 6) invasive agents. Concrete biochemical mechanisms of action of every class drugs are considered and described.