[The effect of hypoxia on cholinesterase activity in rat sensorimotor cortex].

This study reports the dynamics of changes in postnatal ontogenesis of the activity of soluble and membrane-bound forms of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in sensorimotor cortex of rats as well as the pattern of their changes after prenatal hypoxia (E14, 7% O2, 3 h) or acute hypoxia in adult animals (4 months, 7% O2, 3 h). In normally developing rats the activity of the membrane-bound AChE form in the sensorimotor cortex gradually increased up to the end of the first month after birth and remained at this high level during all further postnatal ontogenesis, while the activity of the soluble form of AChE reached its maximum on the 10th day after birth and decreased significantly by the end of the first month. In animals exposed to prenatal hypoxia the activity both of the soluble and membrane bound forms of AChE during the first two weeks after birth was 20-25% lower, as compared to controls but increased by the end of the first month and even exceeded the control values remaining increased up to old age (1.

Effects of ageing and experimental diabetes on insulin-degrading enzyme expression in male rat tissues.

Due to an increasing life expectancy in developing countries, cases of type 2 diabetes and Alzheimer's disease (AD) in the elderly are growing exponentially. Despite a causative link between diabetes and AD, general molecular mechanisms underlying pathogenesis of these disorders are still far from being understood. One of the factors leading to cell death and cognitive impairment characteristic of AD is accumulation in the brain of toxic aggregates of amyloid-β peptide (Aβ).

[Attenuation of inhibitory influence of hormones on adenylyl cyclase systems in the myocardium and brain of rats with obesity and type 2 diabetes mellitus and effect of intranasal insulin on it].

The functional state of the adenylyl cyclase signaling system (ACSS) and its regulation by hormones, the inhibitors of adenylyl cyclase (AC)--somatostatin (SST) in the brain and myocardium and 5-nonyloxytryptamine (5-NOT) in the brain of rats of different ages (5- and 7-month-old) with experimental obesity and a combination of obesity and type 2 diabetes mellitus (DM2), and the effect of long-term treatment of animals with intranasally administered insulin (II) on ACSS were studied. It was shown that the basal AC activity in rats with obesity and DM2 was increased in the myocardium, and to the lesser extent in the brain, the treatment with II reducing this parameter. The AC stimulating effects of forskolin are decreased in the myocardium, but not in the brain, of rats with obesity and DM2.

[Study of hormone responsiveness of the adenylyl cyclase signaling system in erythrocyte membranes of patients with type 2 diabetes mellitus].

Peptides of the insulin superfamily (insulin, insulin-like growth factor, relaxin), epidermal.growth factor (ECF) and biogenic amines (isoproterenol, adrenalin, noradrenalin, serotonin) stimulate the adenylyl cyclase signaling system (ACSS). In erythrocyte membranes from a control group of patients, the hormone activating affect on ACSS was potentiated in the presence of guanylylimidinodiphosphate (CppNHp).

[Regulation of adenylyl cyclase signaling system by insulin, biogenic amines, and glucagon at their separate and combined action in the muscle membranes of the mollusc Anodonta cygnea].

In smooth muscles of mollusc Anodonta cygnea, hormones produce regulatory effects on the adenylyl cyclase (AC) signaling system via receptors of the serpentine (biogenic amine, isoproterenol, glucagon) and of tyrosine kinase (insulin) types. Intracellular mechanisms of their action are interconnected. Use of hormones, their antagonists, and pertussis toxin at the combined action of insulin and biogenic amines or of glucagon on the AC activity allows revealing possible intersection points in mechanisms of their action.

Effect of sodium valproate administration on brain neprilysin expression and memory in rats.

Alzheimer's disease (AD) is accompanied by memory loss due to neuronal cell death caused by toxic amyloid β-peptide (Aβ) aggregates. In the healthy brain, a group of amyloid-degrading enzymes including neprilysin (NEP) maintain Aβ levels at physiologically low concentrations but, with age and under some pathological conditions, expression and activity of these enzymes decline predisposing to late-onset AD. Hence, up-regulation of NEP might be a viable strategy for prevention of Aβ accumulation and development of the disease.

[Changes in the activity of amyloid-degrading metallopeptidases leads to disruption of memory in rats].

In old male Wistar rats (older than 12 months), or adult males (3-4 months) subjected to prenatal hypoxia (7% 02, 3 h, E14), a disruption of short-term memory was observed. The prenatal hypoxia also led to a decrease in the brain cortex expression of metallopeptidases neprilysin (NEP) and endothelin-converting enzyme (ECE-1) which regulate some neuropeptides and are the main beta-amyloid-degrading enzymes. Moreover, a significant decrease (by 2.

Variations in functional activity of the hormone-sensitive adenylate cyclase system in tissues of gastropod mollusks with streptozotocin-induced diabetes.

Treatment of gastropod mollusks of pond snail Lymnaea stagnalis and orb snail Coretus corneus with streptozotocin was followed by an increase in hexose content in the hemolymph and development of the diabetic state (day 1 after treatment). Functional activity of the hormone-sensitive adenylate cyclase system significantly decreased in the muscles and hepatopancreas of mollusks with diabetes. We revealed a decrease in the regulatory effects of biogenic amines and peptide hormones that were realized via stimulatory (octopamine, dopamine, serotonin, tryptamine, and relaxin) and inhibitory G proteins (somatostatin).

[Adenylyl cyclase signaling mechanisms of the insulin superfamily peptide action and their impairment in myometrium of pregnant women with type 2 diabetes].

For the first time we found in myometrium of the women and pregnant women that adenylyl cyclase (AC) stimulating effects of relaxin, insulin and insulin growth factor 1 are realized via six-component AC signaling mechanisms involving the following signaling chain: receptor-tyrosine kinase ==> Gi protein (beta gamma dimmer) ==> phosphatidylinositol 3-kinase ==> protein kinase C (zeta) ==> Gs protein ==> adenylyl cyclase (AC), which are similar to the discovered adenylyl cyclase signaling mechanisms of insulin and relaxin action in vertebrates (rat) and invertebrates (mollusk). The effect of relaxin is more pronounced as compared with other peptides (relaxin > insulin > insulin-like growth factor-1) in myometrium of pregnant women. It is connected with the specific role ofrelaxin as main regulator of reproductive functions.

[Structural and functional characteristics of the adenylyl cyclase signaling system regulated by biogenic amines and peptide hormones in the muscle of a worm Lumbricus terrestris].

It has been shown for the first time that biogenic amines (catecholamines and tryptophane derivatives) stimulate dose-dependently activity of adenylyl cyclase (AC) and GTP-binding of G-proteins in muscle of the cutaneous-muscle bag of the earthworm Lumbricus terrestris. By efficiency of their stimulating action on the AC activity, biogenic amines can be arranged in the following sequence: octopamine > tyramine > tryptamine = serotonin > dopamine > isoproterenol = adrenalin. The sequence of efficiency of their action on GTP-binding is somewhat different: serotonin > tryptamine > octopamine > dopamine = tyramine > adrenaline > isoproterenol.

[Structural and functional organization of the adenylyl cyclase signaling mechanism of insulin-like growth factor 1 revealed in the muscle tissue in vertabrates and invertebrates].

Based on the earlier discovered by the authors adenylyl cyclase signaling mechanisms (ACSM) of action of insulin and relaxin, the study was performed of the presence a similar action mechanism of another representative of the insulin superfamily--the insulin-like growth factor 1 (IGF-1) in the muscle tissues of vertebrates (rat) and invertebrates (mollusc). For the first time there was detected participation of ACSM in the IGF-1 action, including the six component signaling cascade: receptor tyrosine kinase --> G(i)-protein (betagamma-dimer) --> phosphatidylinositol-3-kinase (PI-3-K) --> protein kinase Czeta (PKCzeta) --> G(-)protein --> adenylyl cyclase. By this mechanism structural-functional organization at postreceptor stages, in coincides completely with the mechanism of insulin and relaxin, which we revealed in rat skeletal muscle.

Functional coupling of hormone receptors with G proteins in the adenylate cyclase system of the rat muscle tissues and brain under conditions of short-term hyperglycemia.

The sensitivity of components of the adenylate cyclase signaling system (heterotrimer G proteins and adenylate cyclase enzyme) to the regulatory effects of hormones mediated through G proteins (stimulatory effect of isoproterenol and relaxin and inhibitory effects of somatostatin) was decreased in the myocardium of hyperglycemic rats under conditions of transitory hyperglycemia caused by intravenous glucose and in hyperglycemia associated with insulin insufficiency in 24-h type 1 streptozotocin-induced diabetes mellitus. Changes in hormone sensitivity of the adenylate cyclase system were tissue-specific: clearly manifest in the myocardium, minor in skeletal muscles, and virtually absent in the brain of hyperglycemic rats. The main disorders of this system in the myocardium were observed at the stage of hormone receptor coupling with G proteins, which was seen from reduced stimulatory effect of GppNHp on adenylate cyclase activity and attenuation of the regulatory effect of hormones on adenylate cyclase enzyme and G proteins functionally coupled with it.

[Streptozocin model of diabetes mellitus in the mollusc Anodonta cygnea: functional state of the adenylyl cyclase mechanisms of action of peptides of the insulin superfamily and their effect on carbohydrate metabolism enzymes].

In terms of development of evolutionary biomedicine using invertebrate animals as models for study of molecular grounds of various human diseases, for the first time the streptozocin (ST) model of insulin-dependent diabetes in the mollusc Anodonta cygnea has been developed. This model is based on the following authors' data: (1) redetection of insulin-related peptides (IRP) in mollusk tissues: (2) discovery of the adenylyl cyclase signal mechanism (ACSM) of action of insulin and other peptides of the insulin superfamily in tissues of mammals, human, and mollusc. A.

Changed sensitivity of adenylate cyclase signaling system to biogenic amines and peptide hormones in tissues of starving rats.

In the myocardium and skeletal muscles of rats deprived of food for 2 days, basal activity of adenylate cyclase decreased, while the sensitivity of adenylate cyclase signaling system to the stimulating effects of non-hormonal agents (guanine nucleotides and NaF) and beta-agonist isoproterinol modulating adenylate cyclase through stimulating G proteins increased. In starving organism, the regulatory effects of hormones realizing their effects through inhibitory G proteins (somatostatin in the myocardium and bromocryptin in the brain) weakened. Their inhibitory effects on forskolin-stimulated adenylate cyclase activity and stimulating effects on binding of guanosine triphosphate decreased.

[The disturbance of the transduction of adenylyl cyclase inhibiting hormonal signal in myocardium and brain of rats with experimental type II diabetes].

At present, the data obtained by us and other authors give evidence that disturbances in hormonal signaling systems are the main causes of development of pathological changes and complications under the diabetes. However, the molecular mechanisms of these disturbances remain obscure, especially in the case of insulin-independent type II diabetes. Using neonatal streptozotocin model of 80- and 180-days type II diabetes the changes in functional activity of hormone-regulated adenylyl cyclase (AC) signaling systems components in the myocardium and the brain striatum of diabetic rats in comparison with the control animals were found.

Studies of the molecular mechanisms of action of relaxin on the adenylyl cyclase signaling system using synthetic peptides derived from the LGR7 relaxin receptor.

The peptide hormone relaxin produces dose-dependent stimulation of adenylyl cyclase activity in rat tissues (striatum, cardiac and skeletal muscle) and the muscle tissues of invertebrates, i.e., the bivalve mollusk Anodonta cygnea and the earthworm Lumbricus terrestris, adenylyl cyclase stimulation being more marked in the rat striatum and cardiac muscle.

[Regulatory calcium effect on adenylyl cyclase functional activity in the infusorian Dileptus anser].

Earlier we have shown that some non-hormonal activators of adenylyl cyclase (AC) and hormones of higher vertebrate animals are able to affect functional activity of the AC system in the infusorian Dileptus anser. In the present work, sensitivity of this infusorian AC to Ca2+ was studied and it was found that calcium cations at concentrations of 0.5-10 microM stimulated significantly the enzyme activity in D.

[Reactivity of the adenylyl cyclase system in rat tissues to biogenic amines and peptide hormones under starvation condition].

Under starvation condition, sensitivity of the adenylyl cyclase system to regulatory action of biogenic amines and peptide hormones in rat tissues are changed. In the myocardium and skeletal muscles, after 2 and 4 days of starvation, the regulatory effects of isoproterenol and relaxin acting via G,-proteins on the adenylyl cyclase activity and the G-protein GTP-binding are significantly increased compared with control. At the same time, regulatory effects ofsomatostatin which are realized via Gi-proteins, on adenylyl cyclase system in the myocardium are decreased.

Decrease in functional activity of G-proteins hormone-sensitive adenylate cyclase signaling system, during experimental type II diabetes mellitus.

The development of experimental type II diabetes mellitus in rats was accompanied by dysfunction of inhibitory and stimulatory heterotrimeric G-proteins, components of hormone-sensitive adenylate cyclase signal system. The function of inhibitory G-proteins decreased most significantly under these conditions, which is seen from weakened regulatory effects of somatostatin (in the myocardium) and bromocriptine (in the brain striatum) realized via inhibitory G-proteins in diabetic rats compared to controls. These hormones produce less pronounced inhibitory effect on forskolin-induced activation of adenylate cyclase.

[Involvement of adenylyn cyclase signaling mechanisms in relaxing effect of relaxin and insulin on the rat uterus, trachea and human myometrium].

Participation of adenylyl cyclase signaling mechanisms of relaxin and insulin action in their regulating influence on the process of relaxation of the rat uterine and tracheal smooth muscles and human myometrium was shown. The study was based on the discovery of novel adenylyl cyclase signaling mechanisms of relaxin and insulin action in the muscle of vertebrates which involve: receptor --> Gi protein (betagamma dimer) --> phosphatidylinositol-3-kinase --> protein kinase Csigma (zeta) --> Gs protein --> adenylyl cyclase --> cAMP. In the rat uterus, trachea and human myometrium, relaxin, insulin and isoproterenol induced relaxation of KCl-contraction.

[Comparative study of molecular mechanisms of natural and synthetic polycationic peptides action on the activity of the adenylyl cyclase signaling system].

The molecular mechanisms of action of natural and synthetic polycationic peptides, forming amphiphilic helices, on the heterotrimeric G-proteins and enzyme adenylyl cyclase (AC), components of hormone-sensitive AC system, were studied. It is shown that synthetic peptides C-epsilonAhx-WKK(C10)-KKK(C10)-KKKK(C10)-YKK(C10)-KK (peptide I) and (GRGDSGRKKRRQRRRPPQ)2-K-epsilonAhx-C(Acm)(peptide II) in dose-dependent manner stimulate the basal AC activity, inhibit forskolin-stimulated AC activity and decrease both stimulating and inhibiting AC effects of the hormones in the tissues (brain striatum, heart muscle) of rat and in smooth muscles of the mollusc Anodonta cygnea. AC effects of these peptides are decreased after membrane treatment by cholera and pertussis toxins and are inhibited in the presence of the peptides, corresponding to C-terminal regions 385-394 alphas- and 346-355 alphai2-subunits of G-proteins.

[Study of molecular mechanisms of the relaxin action on adenylyl cyclase signaling system using synthetic peptides derived from the relaxin receptor LGR7].

The peptide hormone relaxin in dose-dependent manner stimulates adenylyl cyclase activity in the rat tissues (brain striatum, heart and skeletal muscles) and the muscle tissues of invertebrates--bivalve mollusk Anodonta cygnea and earthworm Lumbricus terrestris. Adenylyl cyclase stimulating effect of the hormone is most expressed in striatum and heart muscles of rats. For identification of the type ofrelaxin receptors, participating in the realization of this effect of the hormone, the peptides 619-629, 619-629-Lys(Palm) and 615-629 derived from the primary structure of C-terminal region of the third intracellular loop of the relaxin receptor of type 1 (LGR7), were synthesized by us for the first time.

[Molecular causes of changes in sensitivity of adenylyl cyclase signaling system to biogenic amines in the heart muscle during experimental streptozotocin diabetes].

Changes in hormonal sensitivity of the adenylyl cyclase signaling system (ACS) and their possible molecular causes in the heart muscle of rats with experimental streptozotocin diabetes (type I diabetes) are investigated. An increase in stimulating effects of noradrenaline and isoproterenol on adenylyl cyclase (AC) activity have been shown. In the case of noradrenaline, this increase is due to suppression of Gi-protein function and Gi-coupled inhibitory AC signaling pathway.