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Background. Metabolic syndrome (MS) is characterized by a number of pathogenetic factors that adversely affect the function of the central nervous system (CNS). The study of early stages of ultrastructural damages in the CNS in the conditions of MS is important for compensation and prevention of pathological states leading to the brain hypoxia and cognitive disorders. Objective. The aim was to investigate the morphological characteristics of the brain tissue and the cerebral capillaries in neocortex (the I-VI layers) sensorimotor region of rats with MS induced by a long-term (15 weeks) high-carbohydrate/high-fat (HC/HF) diet. Design and methods. The neocortex ultrastructure was investigated using an electron microscopy. Results. The moderate destructive changes in the components of the neurovascular units of the sensorimotor region of the cerebral cortex were detected in MS rats. Regardless of the functional response of brain capillaries (vasodilatation / vasoconstriction) to systemic insulin resistance and hyperglycemia, the signs of blood-brain barrier (BBB) dysfunctions were detected in MS-rats, such as an increase in the thickness and the impaired integrity of the basement membrane, endothelial microclasmosis, edema, and the estruction of perivascular glia. The destructive changes in cerebral capillaries were combined with neuro-vasal contacts increased 2,3 times, the proportion of apoptotic neurons increased 5 times and the proportion of normochromic neurons accurately reduced by 13 %. Conclusion. In neocortex sensorimotor region of rats with MS induced by the HC/HF diet, the moderate dysfunction of the BBB and the reactive changes in neurons and neuro-vasal contacts were shown, and the cause of which may be hyperglycemia, dyslipidemia, and systemic insulin resistance typical for MS.

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

Diabetic peripheral neuropathy (DPN) is one of the commonest complications of type 1 diabetes mellitus (DM1). The aims of the present work were to study the dynamics of the development of pain-type DPN and the functional status of the hormone-sensitive adenylyl cyclase signal system (ACSS) in the skeletal muscle of rats with models of acute and mild DM1 and to investigate the influences on these of insulin therapy using different routes of hormone administration – intranasal and peripheral. The nociceptive threshold in rats decreased in both models of DM1; the stimulatory effects of guanine nucleotides (GIDP) and adrenergic agonists (isoproterenol, BRL-37344) on adenylyl cyclase (AC) also decreased. The AC-stimulating effect of relaxin decreased in animals with acute DM1, while the change in mild DM1 was minor. Peripheral administration of insulin to rats with acute DM1 increased the nociceptive threshold and partially restored the AC effect of the β3 agonist BRL-37344. Intranasal administration of insulin to rats with mild DM1 also led to an increase in the nociceptive threshold and partially restored basal and BRL-37344-stimulated AC activity in the skeletal muscle of diabetic animals. Thus, skeletal muscle in rats with acute and mild DM1 showed impaired nociceptive sensitivity and ACSS function, which was partially restored by treatment of animals with insulin given peripherally (acute DM1) or intranasally (mild DM1).

To develop the approaches for the prevention and treatment of metabolic syndrome (MS), a pathological state widespread in modern population, that involves a complex of metabolic and functional disorders, appropriate animal models of MS are required. One of these models is induced by the consumption of combined high-carbohydrate and high-fat (HC/HF) diet consisting of excess amount of easily digestible carbohydrates and saturated fats. At the same time, the character, temporal dynamics and severity of metabolic abnormalities in MS induced by HC/HF diet are still poorly understood. The aim of work was the characterization of metabolic changes in Wistar rats with MS induced by 10- and 15-week HC/HF diet that includes the consumption of 30% sucrose solution (instead of drinking water) and food rich in saturated fats. Rats that received HC/HF diet for 15 weeks had a number of features characteristic of MS, such as increased body weight and content of abdominal fat, hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, insulin resistance, dyslipidemia, as well as the markers of impaired function of the cardiovascular system (hyperhomocysteinemia, the reduced level of vasodilator nitric oxide, the increased concentration of vasoconstrictor endothelin 1). In rats, which were on the diet for 10 weeks, the metabolic abnormalities were less pronounced, indicating an insufficiency of 10-week duration of HC/HF diet for MS induction. Thus, the model of MS induced by 15-week HC/HF diet has the characteristic features that allow for extrapolation of the obtained data to similar pathologic changes in human, and can be used to study the etiology and pathogenesis of MS and the search of effective ways of MS prevention and treatment.

In the last years intranasally administered insulin (II) is widely used to treat Alzheimer's disease and other cognitive disorders. Meanwhile, it is little used to treat the type 2 diabetes mellitus (DM2); which is due to insufficient knowledge of molecular mechanisms of its action on hormonal and metabolic status of an organism. The effect of II on the activity of hypothalamic signaling systems, which plays a key role in the central regulation of energy metabolism, is still poorly understood. The aim of the present work was to study the effect of five-week treatment of male rats with neonatal model of DM2 using 11 (0.48 IU/rat) on metabolic parameters and on functional activity of the hypothalamic signaling systems. It was shown that treatment of diabetic rats with II'(Group DI) normalized plasma glucose level, restored glucose tolerance and its utilization. In the hypothalamus of rats of the Group DI the-regulatory effects of agonists of type 4 melanocortin receptors (MC4R), type 2 dopamine receptor (D2-DAR) and subtype 1B serotonin receptor (5-HTIBR) on adenylyl cyclase (AC) activity, which were reduced in DM2, restored. Moreover, the inhibitory effect of 5-HTIR agonists even was increased as compared to control. In the Group DI, the res- toration of AC regulation by hormones was accompanied by a significant increase in the expression of genes encoding 5-HTIBR and MC4R. Along with this, the attenuation of the AC stimulating effect of D1-DAR agonists and the decreased expression of Drdl gene were found, promoting the enhancement of the negative dopamine effect on AC activity. The II treatment did not significantly affect the expression of genes encoding insulin receptor and insulin receptor substrate 2, which was reduced, though to a small extent, in the hypothalamus of diabetic rats. Thus, the II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortins, serotonin and do- pamine, which is one of the mechanisms of positive influence of II on energy metabolism and insulin sensitivity in the peripheral tissues.

The article focuses on the main features of the secular world in its interaction with postmodernization processes of Western and Russian social and cultural spheres. The author provides the new «American theology» construct dealing with a number of different typologies of God, responding in a way to the objective postmodern changes. Western philosophers’ and theologists’ concepts confined to postmodernization of religion, including G. Richardson’s concept of «technological God» and H. Cox’s concept of «political God», are outlined. The author follows modern contradictory tendencies and processes that simultaneously impose social and cultural secularization while actualizing religion by raising its spiritual and existential significance for individuals and society as a whole. Ch. Taylor’s views on the secular age are also analyzed in this very item.

The functioning of the serotonergic system of the brain is impaired in type II diabetes (T2D), and this leads to metabolic and hormonal dysfunction. The elevation of serotonin level in the CNS is one of the approaches for correcting of the serotonergic system of the brain. The aim of the present work was to investigate the effect of intranasal serotonin (InS) administration for 5 weeks at a daily dose of 20 μg on the metabolic parameters and functional activity of adenylate cyclase signaling system (ACSS) sensitive to peptide hormones and biogenic amines in the hypothalamus of male rats with neonatal T2D. Neonatal model of T2D was induced by injecting streptozotocin (70 mg/kg) into 5-day-old rat pups. Four-month-old animals with apparent T2D manifestations were divided into two groups: an untreated group (D0, n = 6) and a group that received InS treatment (DIS, n = 6). InS administration to diabetic rats restored ACSS regulation by the agonists of type 2 dopamine receptors (DA2R) and type 4 melanocortin receptors (MC4R) and enhanced the inhibitory effect of serotonin on adenylate cyclase activity. Elevated expression of genes encoding DA2R, MC4R, and serotonin receptor of the 1B subtype (5-HT1BR) was among the main causes of this change. The relative activity of signaling cascades involving various types of serotonin (Gs-coupled 5-HT4,6,7R/Gi-coupled 5-HT1R), dopamine (DA1R/ DA2R), and melanocortin (MC3R/MC4R) receptors involved in ACSS regulation was also altered in the animals of the DIS group. InS administration restored hormonal regulation in the hypothalamus, improved glucose tolerance, and increased the sensitivity of tissues to insulin. The data obtained show that the elevation of serotonin level in the CNS is a promising approach for the recovery of hypothalamic signaling pathways in T2D and correction of the metabolic disturbances dependent on these pathways.

In the last years intranasally administered insulin (II) is widely used to treat Alzheimer's disease and other cognitive disorders. Meanwhile, it is little used to treat the type 2 diabetes mellitus (DM2); which is due to insufficient knowledge of molecular mechanisms of its action on hormonal and metabolic status of an organism. The effect of II on the activity of hypothalamic signaling systems, which plays a key role in the central regulation of energy metabolism, is still poorly understood. The aim of the present work was to study the effect of five-week treatment of male rats with neonatal model of DM2 using 11 (0.48 IU/rat) on metabolic parameters and on functional activity of the hypothalamic signaling systems. It was shown that treatment of diabetic rats with II'(Group DI) normalized plasma glucose level, restored glucose tolerance and its utilization. In the hypothalamus of rats of the Group DI the-regulatory effects of agonists of type 4 melanocortin receptors (MC4R), type 2 dopamine receptor (D2-DAR) and subtype 1B serotonin receptor (5-HTIBR) on adenylyl cyclase (AC) activity, which were reduced in DM2, restored. Moreover, the inhibitory effect of 5-HTIR agonists even was increased as compared to control. In the Group DI, the res- toration of AC regulation by hormones was accompanied by a significant increase in the expression of genes encoding 5-HTIBR and MC4R. Along with this, the attenuation of the AC stimulating effect of D1-DAR agonists and the decreased expression of Drdl gene were found, promoting the enhancement of the negative dopamine effect on AC activity. The II treatment did not significantly affect the expression of genes encoding insulin receptor and insulin receptor substrate 2, which was reduced, though to a small extent, in the hypothalamus of diabetic rats. Thus, the II treatment of rats with the neonatal model of DM2 partially restores the hypothalamic AC signaling pathways regulated by melanocortins, serotonin and do- pamine, which is one of the mechanisms of positive influence of II on energy metabolism and insulin sensitivity in the peripheral tissues.

Diabetic peripheral neuropathy (DPN) is one of the most common complications of the type 1 diabetes mellitus (DM1). The aim of the work was to study the dynamics of a painful DPN and functional state of the hormone-sensitive ACSS in the skeletal muscles of rats with the models of acute and mild DM1, as well as the study of impact on them of insulin therapy with different ways of hormone delivery - intranasal and peripheral. In both models of DM1, the level of nociceptive threshold in rats decreased and the stimulatory effects of guanine nucleotides (GppNHp) and adrenergic agonists (isoproterenol, BRL-37344) on adenylyl cyclase (AC) activity were attenuated. The AC stimulating effect of relaxin decreased in animals with acute DM1, but in mild DM1, the decrease was insignificant. Peripheral administration of insulin in rats with acute DM1 increased the nociceptive threshold and partially restored the AC effect of ß 3-agonist BRL-37344. Intranasal administration of insulin in rats with DM1 also increased the nociceptive threshold and partially restored the basal and BRL-37344-stimulated AC activity in the skeletal muscles of diabetic animals. Thus, in the skeletal muscles of rats with acute and mild DM1 the nociceptive sensitivity and the functions of ACSS were disturbed, and they were partially restored by the treatment with peripheral (acute DM1) or intranasal (mild DM1) insulin.

The decrease in the function of thyroid gland (TG), which is often observed in obesity and metabolic syndrome, results in the hypothyroid state and is one of the causes of metabolic and functional disorders. It is assumed that thyroid hormone treatment normalizing hormone levels in an organism is able to prevent these disorders. However, studies of the effect of this therapy on metabolic parameters in animals with experimental obesity are very scarce, and data concerning its influence on the activity of the adenylyl cyclase signaling system (ACSS) are absent. At the same time, it is known that disturbances in the hormonal regulation of ACSS play a key role in etiology and pathogenesis of diseases associated with metabolic disorders. This work was aimed at studying the effect of long-term levothyroxine treatment of obese male rats on their carbohydrate and lipid metabolism, thyroid status, and the activity of ACSS and its hormonal regulation in the brain, myocardium, epididymal fat, and TG. The rats with obesity caused by a three-month high-fat diet received levothyroxine for four weeks (orally, with a daily dose of 20 μg/kg) (group OB + LT), whereas the control animals and untreated obese rats received placebo instead of the hormone. As a result of the treatment, the levels of thyroid hormones increased, the body and adipose tissue weight decreased, the levels of triglycerides, total and atherogenic cholesterol decreased, and glucose utilization increased. In addition, the ACSS activity impaired in obesity was restored in the brain, myocardium, and epididymal fat tissue. In the brain, the levothyroxine treatment restored the stimulatory effects of serotonin and dopamine, as well as the inhibitory effects of the agonists of the subtype 1B 5-hydroxytryptamine receptor and type-2 dopamine receptor on the adenylyl cyclase (AC) activity. In the myocardium, the stimulatory effects of β1/β2-agonists and relaxin reduced in obesity were also restored. It should be noted, however, that the effects of β3-agonists augmented in obesity did not change in group OB + LT, resulting in the enhanced activating influence of β-agonists on AC and creating certain risks of the development of cardiovascular diseases. The increase in the lipolytic effect of β-agonists and the weakening of the antilipolytic effect of N6-cyclopentyladenosine, an agonist of type 1 adenosine receptor, was found in the epididymal fat, indicating the increased lipolysis in adipose tissue. The sensitivity of AC to the thyroid-stimulating hormone in TG decreased in group OB + LT with an excess of thyroid hormones. Thus, the treatment with levothyroxine not only improves the energy metabolism and prevents the deficiency of thyroid hormones in experimental obesity but also restores the hormonal regulation of ACSS, which can be one of the mechanisms of action of thyroid hormones on the brain and peripheral tissue functions in obesity and other metabolic disorders associated with the hypothyroid state.

To develop the approaches for the prevention and treatment of metabolic syndrome (MS), a pathological state widespread in modern population, that involves a complex of metabolic and functional disorders, appropriate animal models of MS are required. One of these models is induced by the consumption of combined high-carbohydrate and high-fat (HC/HF) diet consisting of excess amount of easily digestible carbohydrates and saturated fats. At the same time, the character, temporal dynamics and severity of metabolic abnormalities in MS induced by HC/HF diet are still poorly understood. The aim of work was the characterization of metabolic changes in Wistar rats with MS induced by 10- and 15-week HC/HF diet that includes the consumption of 30% sucrose solution (instead of drinking water) and food rich in saturated fats. Rats that received HC/HF diet for 15 weeks had a number of features characteristic of MS, such as increased body weight and content of abdominal fat, hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, insulin resistance, dyslipidemia, as well as the markers of impaired function of the cardiovascular system (hyperhomocysteinemia, the reduced level of vasodilator nitric oxide, the increased concentration of vasoconstrictor endothelin 1). In rats, which were on the diet for 10 weeks, the metabolic abnormalities were less pronounced, indicating an insufficiency of 10-week duration of HC/HF diet for MS induction. Thus, the model of MS induced by 15-week HC/HF diet has the characteristic features that allow for extrapolation of the obtained data to similar pathologic changes in human, and can be used to study the etiology and pathogenesis of MS and the search of effective ways of MS prevention and treatment.Для разработки методов профилактики и лечения метаболического синдрома (МС), необходимы адекватные его модели на животных. Одна из таких моделей индуцируется потреблением комбинированного высокоуглеводного и высокожирового (ВУ/ВЖ) рациона. Однако характер, динамика во времени и степень тяжести метаболических нарушений при индукции МС с помощью ВУ/ВЖ диеты остаются мало изученными. Цель работы состояла в характеристике метаболических изменений в организме крыс линии Wistar с МС, вызванным 10- и 15-недельной ВУ/ВЖ диетой, которая включала потребление 30 % раствора сахарозы (вместо питьевой воды) и пищи, обогащенной насыщенными жирами. У крыс, получавших ВУ/ВЖ диету в течение 15 нед, отмечали признаки, характерные для МС, — повышение массы тела и удельного содержания абдоминального жира, гипергликемию, гиперинсулинемию, нарушенную толерантность к глюкозе, инсулиновую резистентность, дислипидемию, а также — маркеры нарушений функции сердечно-сосудистой системы — гипергомоцистеинемию, снижение уровня оксида азота и повышение концентрации эндотелина-1. У крыс, находящихся на диете в течение 10 нед, метаболические нарушения были выражены намного слабее, что указывает на недостаточность данной продолжительности ВУ/ВЖ диеты для индукции МС. Таким образом, модель МС, вызываемая 15-недельной ВУ/ВЖ диетой, имеет характерные признаки, позволяющие проводить экстраполяцию полученных данных на сходные патологические изменения у человека, и может быть использована для изучения этиологии и патогенеза МС и поиска эффективных путей его профилактики и лечения.

One of the key causes of diabetes mellitus (DM) and its complications are hormonal disturbances in functioning of hormonal signaling systems, including the adenylyl cyclase signaling system (ACSS). The goal of this work was to study the functional state and hormonal sensitivity of ACSS in the epididymal adipose tissue of male rats in the 7-month model of mild type 1 DM (DM1), in the 18-month neonatal model of type 2 DM (DM2), and in the taken for comparison model of the 30 day-longs acute DM1. It is shown for the first time that in adipocytes from the epididymal fat of rats with the studied DM models the basal AC activity and its stimulation by forskolin were decreased, which indicates a weakening of the catalytic functions of the enzyme adenylyl cyclase (AC). Stimulation of AC by guanine nucleotides in DM changed to the lesser extent, which argues in favor of preservation of functions of heterotrimeric Gs-proteins in the epididymal fat. In rats with DM1 the sensitivity of AC of adipocytes to agonists of β-adrenergic receptors (β-AR), activators of lipolysis, remained practically unchanged, while in animals with DM2 the AC stimulating effects of β-AR-agonists were reduced or completely blocked, like in the case of β3-AR-agonists BRL-37344 and CL-316243. In adipocytes of rats with DM1 the AC inhibitory effect of N6-cyclopentyladenosine, agonist of type 1 adenosine receptors (Aden1R), an inhibitor of lipolysis, was attenuated, whereas in DM2 this effect was completely preserved. Thus, in the epididymal adipose tissue of rats with DM1 the antilipolytic AC cascades including Aden1R were decreased and the stimulation of AC by β-AR-agonists was preserved, whereas in rats with DM2 the β-AR-mediated AC cascades activating lipolysis were reduced, but Aden1R-mediated AC cascades inhibiting lipolysis did not change. The changes of hormonal regulation of ACSS in adipocytes from the epididymal fat lead to disturbances of the metabolic status of animals with DM1 and DM2 and should be considered in the diagnostics and treatment of DM and its complications.

In type 1 diabetes mellitus (DM), changes occurring in the adenylyl cyclase signaling system (ACSS) are one of the key causes of complications of the disease. Since type 1 DM has been most often diagnosed in childhood and adolescence, the study of changes in ACSS in the early development of the disease is a genuine problem. For this, we developed a prolonged model of type 1 DM, which was induced by treatment of 6-week-old rats with moderate doses of streptozotocin (1.5M-DM), and studied the functional state of ACSS in the brain, myocardium, and testes of rats with this model of the disease 7 months after its start. The 1.5M-DM model was compared with the model that was induced by streptozotocin treatment of adult, 5-month-old animals (5M-DM). It was shown that, in 1.5M-DM, in the tissues of diabetic rats, the functional activity of ACSS sensitive to biogenic amines and polypeptide hormones was significantly changed. In rats with 1.5M-DM, the adenylate cyclase (AC) inhibitory effects of somatostatin (in all studied tissues), noradrenaline (in the myocardium and the brain), and agonists of type 1 serotonin receptor (in the brain) were weakened to the greatest degree. In the brain, the AC-stimulating effects of relaxin, isoproterenol, and agonists of Gs-protein-coupled serotonin receptors also decreased; in the myocardium, the corresponding effects of GppNHp, relaxin, and β-adrenergic agonists declined; and, in the testes, the AC effects of GppNHp and chorionic gonadotropin declined. When comparing the 1.5M-DM and 5M-DM models, the most pronounced differences between them were found in the effect of DM on hormonal regulation of ACSS in the brain, this being true both for AC-stimulating effects of dopamine and PACAP-38 and for AC-inhibiting effects of bromocriptine and somatostatin. These results indicate significant changes in hormonal regulation of the nervous, cardiovascular, and reproductive systems in rats with early induction of type 1 DM, in some cases more severe changes as compared with late model of 5M-DM. These changes may be the basis for development of diabetic cardiomyopathy, cognitive deficiency, and hypogonadotropic states, which are often detected in children and adolescents with type 1 DM.

The alterations and abnormalities in hormone -sensitive adenylyl cyclase (AC) system occur at early stages of the type 2 diabetes mellitus (T2DM) and at later stages of the disease they are, according to our vi ew, one of the factors causing T2DM complications. To study the changes in AC system likely to be involved in the development of these complications one needs a very long model of T2DM. Purpose: The aim of this work was the study of AC system in the myocardium, brain and testes of three-, eight-and 18-month-old male rats with experimental T2DM compared with control animals of the same age.

Liver resection is the essential method of cholangiocellular carcinoma treatment. However due to low resectability and high incidence of recurrences search for additional curative methods is necessary.To improve the results of surgical treatment of patients with cholangiocellular carcinoma especially with complications and poor prognosis.A total of 95 surgical procedures for intrahepatic cholangiocarcinoma have been performed in the department of liver andpancreatic tumors at N.N. Blokhin Russian Cancer Research Center since 1998 to 2014. 11 patients had obstructive jaundice as the first symptom of the disease. Extended liver resections were done in most cases (84.2%). Preoperative treatment was performed in 3 patients. Adjuvant chemotherapy after R0-resection was applied in 15 patients.The postoperative mortality rate was 4.2%. Postoperative complications were observed in 51 (53.7%) patients. Complication grade III after adjuvant chemotherapy was observed in one (6.7%) patient. Median survival after liver resection was 25 months, 5-year survival rate - 25.3%. In stage I-II five-year survival reached 66.7%. In patients with obstructive jaundice 5-year survival rate was 26.7%, median survival - 37 months. There was no improvement of survival in case of adjuvant therapy.Liver resection remains essential treatment of cholangiocellular carcinoma including patients with obstructive jaundice. Additional curative methods are necessary to increase resectability and decrease the risk of recurrence.Резекция печени - основной вид лечения больных холангиоцеллюлярным раком, но в связи с низкой резектабельностью и высоким уровнем рецидива необходим поиск дополнительных методов лечения. Цель - улучшить результаты хирургического лечения больных холангиоцеллюлярным раком, особенно при наличии осложнений опухоли и плохого прогноза. Материал и методы. С 1998 по 2014 г. в хирургическом отделении опухолей печени и поджелудочной железы РОНЦ им. Н.Н. Блохина выполнено 95 операций по поводу внутрипеченочной холангиокарциномы, у 11 из них заболевание манифестировало механической желтухой. Обширные резекции печени преобладали (выполнены у 84,2% больных). Предоперационное лечение осуществлено 3 больным. Адъювантная химиотерапия после R0 резекции проведена 15 больным. Результаты. Послеоперационная летальность составила 4,2%. Послеоперационные осложнения отмечены у 51 (53,7%) больного. Осложнение адъювантной химиотерапии III степени отмечено у 1 (6,7%) больного. Медиана продолжительности жизни больных после резекции печени составила 25 мес, пятилетняя выживаемость 25,3%. При I-II стадии пятилетняя выживаемость достигла 66,7%. В группе больных с механической желтухой пятилетняя выживаемость составила 26,7%, медиана продолжительности жизни - 37 мес. Не отмечено улучшения выживаемости после проведения адъювантной терапии. Заключение. Резекция печени остается основным методом лечения холангиоцеллюлярного рака, в том числе у больных с механической желтухой. С целью увеличения резектабельности и снижения риска рецидива заболевания необходим поиск дополнительных методов лечения.

We studied reactivity of insulin signal pathway elements, insulin receptor and insulin receptor substrate protein-2 (IRS2 protein), in rat brain in response to insulin insufficiency and insulin resistance during the development of experimental type 1 or type 2 diabetes mellitus. In type 1 diabetes mellitus characterized by acute insulin insufficiency, specific binding of insulin in rat brain increased 2-fold in comparison with the control and IRS2-gene expression in rat hypothalamus and cortex 2-4 fold surpassed the normal values. In type 2 diabetes mellitus (110 and 190 days of development), changes in the test parameters in rat brain were less pronounced. These findings attest to involvement of the brain insulin signal pathway into the response to systemic insulin deficiency in type 1 diabetes mellitus.

A leading role in the interactions of most serotonin-type hormone receptors with heterotrimeric G proteins is played by their third cytoplasmic loops. Studies in recent years have shown that synthetic peptides corresponding to the membrane-proximal parts of these loops may have selective influences on the transmission of hormone signals via their homologous receptors and trigger the signal cascade in the absence of hormone. We report the first synthesis of peptides derived from the C-terminal region of the third cytoplasmic loop of type 1B serotonin receptors, along with studies of their influences on the serotonin sensitivity of the adenylate cyclase system in the rat brain. Peptides 300–316 and 306–316 (numbered from amino acid positions in the rat serotonin subtype 1B receptor molecule) at micromolar concentrations, in the absence of hormone, stimulated GTP-binding Gi-proteins coupled with subtype 1B serotonin receptors and inhibited forskolin-stimulated adenylate cyclase activity. Studies using selective serotonin receptor agonists and antagonists showed that peptides 300–316 and 306–316 inhibit the transmission of the serotonin signal via the homologous receptor but have weak effects on other types of serotonin receptor. Peptide 300–316 were markedly more active than its shortened analog 306–316 in terms of the selectivity and efficacy of actions on the adenylate cyclase signaling system, which is regulated via subtype 1B serotonin receptors. These data provide evidence that region 300–316 of subtype 1B serotonin receptors is involved in the interaction with Gi proteins and includes the main molecular determinants responsible for transmission of the serotonin signal to adenylate cyclase.

The regulatory effect of peptides of the insulin hyperfamily--insulin, insulin-like growth factor (IGF-1), and relaxin, as well as of epidermal growth factor (EGF) on activity of glycogen synthase (GS) in rat skeletal muscles was studied in norm and in experimental diabetes mellitus of the 1st and 2nd types (DM1, DM2). In norm, peptides in vitro stimulated maximally the GS activity at a concentration of 10-8 M. The row of efficiency of the peptide action was as follows: insulin > IGF-1 > relaxin. In DM1 the basal GS activity did not change, while effect of insulin in vitro was decreased more sharply as compared with action of IGF-1 and relaxin at the 30th day of development of diabetes, i. e., the efficiency row was as follows: IGF-1 = relaxin > insulin. Administration of insulin in vivo did not restore sensitivity of the enzyme to the action of hormone in DM1. In DM2, the GS activity (both the total and active form) decreased. while the stimulatory effect ofpeptides and EGF on the enzyme was absent. Insulin introduced in vitro did not lead to restoration of the enzyme reaction. The conclusion has been made that the insulin resistance affects the basal GS activity in rat skeletal muscles as well as the regulation of the enzyme by peptides of the insulin nature and by EGF, which is more obvious in DM2, than in DM1.

In diabetes mellitus (DM) and its complications the functional activity of hormonal signaling systems and their sensitivity to the regulatory action of hormones are changed. We studied the activity of receptor forms of guanylyl cyclase (rGC) sensitive to natriuretic peptides ANP and CNP in the tissues of female rats with 240 day neonatal streptozotocin DM and the effects of intranasal administration of insulin and serotonin (6 weeks, daily dose for rat is 0.48 IU insulin or 20 μg serotonin). In diabetic rats, the increase of the basal rGC activity in the myocardium and its decrease in the uterus and ovaries were found, while in the brain, there were no differences from the control. The treatment of diabetic rats with insulin led to a decrease of the basal rGC activity in the myocardium and its restoration to a normal level in the ovaries. The administration of serotonin produced a less pronounced decrease in the basal enzyme activity in the myocardium compared to insulin and an insignificant increase in the brain. In the myocardium of diabetic rats, the guanylyl cyclase (GC)-stimulating effect of ANP was attenuated, whereas the CNP effect was enhanced; in the ovaries, the GC-stimulating effect of CNP and, to a lesser degree, the effect of ANP were decreased. In the uterus and brain of a diabetic rats, the rGC sensitivity to hormones was practically did not change. The administration of insulin to diabetic rats induces an increase of GC effect of ANP in the myocardium to its values in control and a decrease of CNP effect, as well as partially restored GC effect of CNP in the ovaries under the influence of CNP. The administration of serotonin somewhat enhanced effect of natriuretic peptides in the brain of both control and diabetic animals. Thus, in the neonatal model of type-2 DM in the myocardium and the tissues of the reproductive systems of rats, the functioning of natriuretic peptide-sensitive rGC is changed. The treatment of animals by insulin substantially restores rGC activity, while the intranasal serotonin administration has a little effect.

Sensitivity of the adenylyl cyclase signaling system (ACSS) to polypeptide hormones and biogenic amines is studied in testes and ovaries of rats after the 2- and 4-day fasting as compared with control animals. In tissues of the fasted rats there is shown a decrease in the basal activity of adenylyl cyclase (AC) and of the basal level of the GTP binding of heterotrimeric G proteins. An increase in duration of fasting from 2 to 4 days led to intensification of these changes. In the fasted rats, the AC-stimulating effects of chorionic gonadotropin, PACAP-38, and isoproterenol, realized via G protein of stimulatory type are enhanced, whereas the inhibitory effects of somatostatin on the AC activity realized via G protein of the inhibitory type are reduced. In testes of the fasted rats the stimulating effect of serotonin on AC via both types of G proteins increased, whereas the inhibitory effects of the hormone decreased. Thus, under conditions of fasting, in rat testes and ovaries the ACSS sensitivity to regulatory effects of hormones is changing: their stimulatory effects are increased, while its inhibitory effects, on the contrary, are decreased. We suggest that these changes are one of the key mechanisms of adaptation of organism to deficiency of nutritional resources to be aimed at intensifying the tissues catabolic processes, preferably lypolysis.

Type-1 diabetes mellitus (DM) leads to numerous disturbances in the male and female reproductive systems. As was shown previously, one of the main causes of the development of complications in DM is a change in the sensitivity of the adenylyl cyclase signaling system (ACSS) to hormones. The aim of this work consisted in detection of disturbances in the hormone-regulated ACSS in reproductive system of rats with experimental type-1 DM (EDM1) caused by administration of streptozotocin. It has been shown that, in the testes of male rats with 5-day-long EDM1 the stimulating effects of human chorionic gonadotropin (HCG) and PACAP-38 on adenylyl cyclase (AC) and the GTP binding of G proteins are decreased considerably. In the uteri of female rats with EDM1 the effects of relaxin, PACAP-38, and biogenic amines are markedly decreased, whereas in ovaries only the effects of HCG are decreased. In all studied tissues of rats with EDM1 the attenuation of somatostatin inhibitory effects was observed, while in the uterus the inhibitory effects of serotonin and adrenalin were also decreased. Thus, in the reproductive tissues of rats with EDM1, the hormone regulatory effects on ACSS are decreased, especially the effect of HCG and the hormones, AC-inhibitors. We believe that the sensitivity of ACSS to hormones in EDM1 underlies the development of pathological changes in the reproductive system of diabetic rats under the conditions of hyperglycemia and insulin deficiency characteristic of type-1 DM.

The regulatory effects of insulin, insulin-like growth factor 1 (IGF-1), and relaxin on glucose-6-phosphate dehydrogenase (G6PDH) and glycogen synthase (GS) activities have been studied in myometrium of pregnant women of control group and with diabetes mellitus of different etiology. In patients with type 1 diabetes G6PDH activity did not differ from the control group, but the enzyme activity was sharply decreased in pregnant women with type 2 diabetes and gestational diabetes. In the control group maximal stimulation of G6PDH activity was observed at 10−9 M of peptides and their stimulating effect decreased in the following order: insulin > relaxin > IGF-1. In pregnant women with types 1 diabetes insulin effect on the enzyme activity was lower than in the control, and the effects of IGF-1 and relaxin were absent. In the group of pregnant women with type 2 diabetes and gestational diabetes the effects of insulin and IGF-1 were decreased, but the effect of relaxin was somewhat higher thus giving the following order in their efficiency relaxin > IGF-1 = insulin. At 10−9 M peptides exhibited similar stimulating effects on the active form of GS-I, but had no influence on the total enzyme activity in the control group of pregnant women. In patients with type 1 diabetes GS activity remained unchanged (versus control), and peptides did not stimulate the enzyme activity. In patients with type 2 diabetes a significant decrease in GS activity was accompanied by the decrease in the effect of peptides, giving the following order of their efficiency: insulin = IGF-1 > relaxin. In myometrium of pregnant women with gestational (treated and untreated) diabetes GS activity decreased, the effect of insulin was weaker, whereas the effects of relaxin and IGF-1 increased thus giving the following order of their efficiency: relaxin > IGF-1 > insulin. Insulin therapy of type 1 diabetes incompletely restored sensitivity of the enzymes to the peptide actions. At the same time, in women with gestational diabetes and subjected to insulin therapy the stimulating effect of relaxin on the enzyme activities increased. This fact suggests that relaxin exhibits replacement functions under conditions of attenuated insulin action.

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 streptozotocin (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 mollusc 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. cygnea; (3) concept of molecular defects in hormonal signal systems as causes of endocrine diseases. Studies on the ST model have revealed in mollusc smooth muscle on the background of hyperglycemia at the 2nd, 4th, and 8th day after the ST administration a decrease of the ACSM response to activating action of insulin, IGF-1, and relaxin. These functional disturbances were the most pronounced at the 2nd day of development and rather less marked at the 4th and 8th day. Analysis of data on effect of hormonal and non-hormonal (NaF, GIDP, and forskolin) ACSM activators has shown that the causes of impair of signal-transducing function of this mechanism are (1) a hyperglycemia-induced increase of the basal AC activity and as a consequence—a decrease of the enzyme catalytic potentials in response to hormone; (2) a decrease of functions of Gs-protein and of its coupling with AC. Besides, administration of ST produced in the mollusc muscle an attenuation of regulation by insulin of carbohydrate metabolism enzyme (glucose-6-phosphate dehydrogenase, glycogensynthase). The pattern of disturbances in the studied parameters in the mollusc is very similar to that revealed by the authors in rat and human muscle tissues in type 1 diabetes.

Modern data on the specific regulatory functions of insulin-receptor signaling in the brain is reviewed. Insulin, indistinguishable from its pancreatic form, and typical insulin receptors are widely expressed in various compartments of the brain. Insulin penetrates into the brain by means of receptor-dependent transport across the blood-brain barrier and participates in the regulation of energy homeostasis and the reproductive and cognitive functions of an organism. In the last decade convincing evidence has been provided that brain insulin and insulin-receptor signaling are necessary for the normal functioning of neurons, although the neuronal effects of insulin remain rather disputable. Any disorganization of this system provokes neurodegenerative diseases.

In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 μg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation byβ-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.

To identify insulin-like receptors in the mollusc Anodonta cygnea, specific binding of 125I-insulin and 125I-IGF-1 by WGA-purified glycoprotein fractions of foot muscles and neural ganglia is studied. The binding sites for IGF-1 are detected for the first time in invertebrates, both in the muscles, and in the neural tissue of the mollusc. The level of 125I-IGF-1 binding in the muscle tissue was equal to 2.8 ± 0.1, in the neural tissue, to 4.0 ± 0.2% per 5 µg of protein. The equilibrium dissociation constant (Kd) was equal to 4.8 ± 0.3 and 4.3 ± 0.2 nM, respectively. The relative affinity of the binding sites to insulin did not exceed 1% of their affinity to IGF-1. Binding of 125I-insulin in the muscle tissue was not detected; the level of labeled insulin binding in the neural tissue was equal to 0.5% per 5 µg of protein. In the sarcolemmal fraction of the mollusc foot, IGF-1 and, to a lesser degree, insulin at a dose of 100 nM initiated phosphorylation of tyrosine in a protein with mol. mass of 70 kDa. The minor band of the phosphorylation was also detected in the zone of protein of 80 kDa. The conclusion is made about the existence in molluscan tissues of high-conserved receptors-tyrosine kinases identical by functional parameters to the mammalian receptor of IGF-1. From this, it is suggested that the peptides close by structure to vertebrate IGF-1 may be involved in physiological processes in A. cygnea. The problem of the nature of the insulin-binding sites in the molluscan neural tissue is discussed.

Activity of glycogen synthase (GS) in the muscle tissue of the lamprey Lampetra fluviatilis is studied in dynamics of the pre-spawning period as well as under effects of insulin and IGF-1. It is shown that GS exists in the muscles in two forms, the active (I-form) and inactive (D-form), the I-form prevailing during all studied time periods. With approaching the spawning, the GS activity fell 1.5–2 times due to a decrease of the I-form activity. From October to January, both insulin and IGF-1 stimulated GS at concentrations of 10−10–10−8 M and 10−9–10−8 M, respectively. The maximally effective concentrations (10−9 M insulin, 10−8 M IGF-1) produced a 2.5–3-fold rise of the I-form activity of GS at the period from October to December. In January the stimulating effect of these peptides decreased. In March the GS was insensitive both to insulin and to IGF-1. The obtained data indicate participation of insulin and IGF-1 in regulation of glycogen synthesis in lamprey skeletal muscles, the ability of IGF-1 to stimulate the enzyme activity being shown in the lower vertebrates for the first time. It is concluded that IGF-1 takes part in regulation of the carbohydrate metabolism already at early stages of evolution of vertebrates.

The possibility of using liquid-crystal microlenses for solving the problems of optical limiting is demonstrated. A compact optical system based on these microlenses is suggested and studied; in this system, two-photon absorption in extrinsic nematic liquid crystals is used as a limiting mechanism.

Histological analysis and electron microscopy of 12 benign pheochromocytomas and 9 malignant pheochromoblastomas showed that there are no reliable histological differences between cells of benign and malignant tumor of the adrenal medulla. The ratio of ultrastructurally differentiated and undifferentiated cells in the tumor can reflect their maturity; the more ultrastructurally undifferentiated and less differentiated cells in the tumor, the higher is the malignant potential of this tumor.

One of the key causes of diabetes mellitus (DM) and its complications are hormonal disturbances in functioning of hormonal signaling systems, including the adenylyl cyclase signaling system (ACSS). The goal of this work was to study the functional state and hormonal sensitivity of ACSS in the epididymal adipose tissue of male rats in the 7-month model of mild type 1 DM (DM1), in the 18-month neonatal model of type 2 DM (DM2), and in the taken for comparison model of the 30-day acute DM1. It is shown for the first time that in adipocytes from the epididymal fat of rats with the studied DM models the basal AC activity and its stimulation by forskolin were decreased, which indicates a weakening of the catalytic function of the enzyme adenylyl cyclase (AC). Stimulation of AC by guanine nucleotides in DM changed to the lesser extent, which speaks in favor of preservation of functions of heterotrimeric G(s)-proteins in the epididymal fat. In rats with DM1 the sensitivity of AC of adipocytes to agonists of β-adrenergic receptors (β-AR), activators of lipolysis, remained practically unchanged, while in animals with DM2 the AC stimulating effects of β-AR-agonists were reduced or completely blocked, like in the case of β3-AR-agonist BRL-37344 and CL-316243. In adipocytes of rats with DM1 the AC inhibitory effect of N6-cyclopentyladenosine, agonist of type 1 adenosine receptors (Aden1R), an inhibitor of lipolysis, was attenuated, whe- reas in DM2 this effect was completely preserved. Thus, in the epididymal adipose tissue of rats with DM1 the antilipolytic AC cascades including Aden1R were decreased and the stimulation of AC by β-AR-agonists was preserved, whereas in rats with DM2 the β-AR-mediated AC cascades activating lipolysis were reduced, but Aden1R-mediated AC cascades inhibiting lipolysis did not change. The changes of hormonal regulation of ACSS in adipocytes from the epididymal fat lead to disturbances of the metabolic status of animal with DM1 and DM2 and should be considered in the diagnostics and treatment of DM and its complications.

We analyzed the dynamics of neuropathic pain development and changes in catalase and superoxide dismutase (SOD) activities in the brain, liver, and skeletal muscles of male Wistar rats with 1-month streptozotocin-induced diabetes mellitus. A decrease in mechanical nociceptive threshold was revealed that progressed during the disease progress. Insulin treatment restored nociceptive threshold in diabetic animals to the control values. Catalase activity in the liver and skeletal muscles of diabetic rats increased by 1.5 and 2 times, respectively, in comparison with the control, while insulin treatment reduced enzyme activity to the control level. In the brain, catalase activity was reduced by 1.5 times and insulin therapy did affect this parameter. SOD activity in the studied tissues remained unchanged during diabetes and was not affected by insulin therapy. A strong negative correlation between nociceptive threshold in rats and catalase activity in their liver and skeletal muscles was found.

An analysis is made of the advantages of impurity liquid-crystal systems that are associated with the existence of the excitonic mechanism of electronic excitation energy transfer in them. Using the two-photon absorption in such systems, one can substantially expand the dynamic range of optical limitation.

Binding of 125I-insulin and 125I-IGF-I to partially purified receptors of lamprey skeletal muscles was studied during pre-pawning migration. It has been shown that throughout this whole period the IGF-I binding to skeletal muscle predominates over the insulin binding. Besides, a certain time dynamics was observed: the insulin binding rose since October to reach maximum in February–March, then it decreased to a minimum level in May; the IGF-I binding also increased: it rose statistically significantly in March compared to October, became maximal in April, and then decreased to a minimum. The dynamics of the receptor IGF-I binding has been shown to depend on changes of receptor affinity, whereas the change of the insulin binding was determined by binding capacity (the number of binding sites). Highly specific IGF-I receptors of the lamprey skeletal muscle bound insulin with an affinity about 1% from that of IGF-I, while insulin receptors had identical affinity for the insulin and IGF-I binding. Both peptides, insulin and IGF-I, activated autophosphorylation of beta-subunits in their receptors. The increase of the IGF-I binding from October to April could be a factor that maintains a high functional activity of lamprey skeletal muscles in the course of the pre-pawning migration. It is suggested that IGF-I promotes maintaining this activity due to its property of inhibiting apoptosis.

We studied the diurnal dynamics of testosterone concentration in male rats with 240-day neonatal streptozotocin-induced diabetes mellitus, which is similar to human type 2 diabetes mellitus. We also studied the effects of intranasal administration of luliberin on testosterone level and the regulation of activities of adenylate cyclase and stimulatory G-proteins in the testicles of diabetic and intact animals by human chorionic gonadotropin. In rats with neonatal diabetes, a decrease in the mean diurnal level of testosterone and its morning rise were observed. The increase in testosterone level 30 min after luliberin administration was significantly reduced in diabetic animals, but no differences in the response to luliberin were observed in intact and diabetic rats 2-6 h after the treatment. The stimulatory effects of human chorionic gonadotropin on adenylate cyclase activity and binding of guanosine triphosphate by stimulatory G-proteins were reduced in the plasma membranes from the testicles of rats with neonatal diabetes in comparison with control specimens. Therefore, rats with neonatal diabetes were characterized by androgen deficiency, which can be related to the impairment of hypothalamic–pituitary–gonadal axis and reduced sensitivity of the adenylate cyclase system in the testicles of diabetic rats to human chorionic gonadotropin.