Hormonal and Allosteric Regulation of the Luteinizing Hormone/Chorionic Gonadotropin Receptor.

Luteinizing hormone (LH) and human chorionic gonadotropin (CG), like follicle-stimulating hormone, are the most important regulators of the reproductive system. They exert their effect on the cell through the LH/CG receptor (LHCGR), which belongs to the family of G protein-coupled receptors. Binding to gonadotropin induces the interaction of LHCGR with various types of heterotrimeric G proteins (G, G, G) and β-arrestins, which leads to stimulation (G) or inhibition (G) of cyclic adenosine monophosphate-dependent cascades, activation of the phospholipase pathway (G), and also to the formation of signalosomes that mediate the stimulation of mitogen-activated protein kinases (β-arrestins).

The Autophagic and Apoptotic Death of Forebrain Neurons of Rats with Global Brain Ischemia Is Diminished by the Intranasal Administration of Insulin: Possible Mechanism of Its Action.

Insulin is a promising neuroprotector. To better understand the mechanism of insulin action, it was important to show its ability to diminish autophagic neuronal death in animals with brain ischemic and reperfusion injury. In forebrain ischemia and reperfusion, the number of live neurons in the hippocampal CA1 region and frontal cortex of rats decreased to a large extent.

Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats.

Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.

Reorganization and Suppression of Store-Operated Calcium Entry in Podocytes of Type 2 Diabetic Rats.

Type 2 diabetes mellitus (DM2) is a widespread metabolic disorder that results in podocyte damage and diabetic nephropathy. Previous studies demonstrated that TRPC6 channels play a pivotal role in podocyte function and their dysregulation is associated with development of different kidney diseases including nephropathy. Here, using single channel patch clamp technique, we demonstrated that non-selective cationic TRPC6 channels are sensitive to the Ca store depletion in human podocyte cell line Ab8/13 and in freshly isolated rat glomerular podocytes.

Prospects for the Use of Intranasally Administered Insulin and Insulin-Like Growth Factor-1 in Cerebral Ischemia.

Current approaches to the treatment of stroke have significant limitations, and neuroprotective therapy is ineffective. In view of this, searching for effective neuroprotectors and developing new neuroprotective strategies remain a pressing topic in research of cerebral ischemia. Insulin and insulin-like growth factor-1 (IGF-1) play a key role in the brain functioning by regulating the growth, differentiation, and survival of neurons, neuronal plasticity, food intake, peripheral metabolism, and endocrine functions.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.

Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers.

Dual PTP1B/TC-PTP Inhibitors: Biological Evaluation of 3-(Hydroxymethyl)cinnoline-4()-Ones.

Dual inhibitors of protein phosphotyrosine phosphatase 1B (PTP1B)/T-cell protein phosphotyrosine phosphatase (TC-PTP) based on the 3-(hydroxymethyl)-4-oxo-1,4-dihydrocinnoline scaffold have been identified. Their dual affinity to both enzymes has been thoroughly corroborated by in silico modeling experiments. The compounds have been profiled in vivo for their effects on body weight and food intake in obese rats.

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium.

A decrease in the activity of the insulin signaling system of the brain, due to both central insulin resistance and insulin deficiency, leads to neurodegeneration and impaired regulation of appetite, metabolism, endocrine functions. This is due to the neuroprotective properties of brain insulin and its leading role in maintaining glucose homeostasis in the brain, as well as in the regulation of the brain signaling network responsible for the functioning of the nervous, endocrine, and other systems. One of the approaches to restore the activity of the insulin system of the brain is the use of intranasally administered insulin (INI).

Type 1 melanocortin receptors in pro-opiomelanocortin-, vasopressin-, and oxytocin-immunopositive neurons in different areas of mouse brain.

Information on the localization of the Type 1 melanocortin receptors (MC1Rs) in different regions of the brain is very scarce. As a result, the role of MC1Rs in the functioning of brain neurons and in the central regulation of physiological functions has not been studied. This work aimed to study the expression and distribution of MС1Rs in different brain areas of female C57Bl/6J mice.

Allosteric Modulators of G Protein-Coupled Receptors.

The G protein-coupled receptors (GPCRs) are the largest group of membrane receptor proteins that are targeted by more than 30% of drugs [...

The Effects of Separate and Combined Treatment of Male Rats with Type 2 Diabetes with Metformin and Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor on Steroidogenesis and Spermatogenesis.

In men with type 2 diabetes mellitus (T2DM), steroidogenesis and spermatogenesis are impaired. Metformin and the agonists of luteinizing hormone/human chorionic gonadotropin(hCG)-receptor (LH/hCG-R) (hCG, low-molecular-weight allosteric LH/hCG-R-agonists) can be used to restore them. The aim was to study effectiveness of separate and combined administration of metformin, hCG and 5-amino--butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-]pyrimidine-6-carboxamide (TP3) on steroidogenesis and spermatogenesis in male rats with T2DM.

Effect of sleeve gastrectomy, Roux-en-Y gastric bypass, and ileal transposition on myocardial ischaemia-reperfusion injury in non-obese non-diabetic rats.

Bariatric surgery (BS) improves outcomes in patients with myocardial infarction (MI). Here we tested the hypothesis that BS-mediated reduction in fatal MI could be attributed to its infarct-limiting effect. Wistar rats were randomized into five groups: control (CON), sham (SHAM), Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and ileotransposition (IT).

Insulin and α-Tocopherol Enhance the Protective Effect of Each Other on Brain Cortical Neurons under Oxidative Stress Conditions and in Rat Two-Vessel Forebrain Ischemia/Reperfusion Injury.

Clinical trials show that insulin administered intranasally is a promising drug to treat neurodegenerative diseases, but at high doses its use may result in cerebral insulin resistance. Identifying compounds which could enhance the protective effects of insulin, may be helpful to reduce its effective dose. Our aim was thus to study the efficiency of combined use of insulin and α-tocopherol (α-T) to increase the viability of cultured cortical neurons under oxidative stress conditions and to normalize the metabolic disturbances caused by free radical reaction activation in brain cortex of rats with two-vessel forebrain ischemia/reperfusion injury.

Effects of three types of bariatric interventions on myocardial infarct size and vascular function in rats with type 2 diabetes mellitus.

Aims: The effects of three types of bariatric interventions on myocardial infarct size were tested in the rat model of type 2 diabetes mellitus (T2DM). We also evaluated the effects of bariatric surgery on no-reflow phenomenon and vascular dysfunction caused by T2DM.

Main Methods: Rats with T2DM were assigned into groups: without surgery, sham-operated, ileal transposition, Roux-en-Y gastric bypass, and sleeve gastrectomy.

Expression and localization of apelin and its receptor in the testes of diabetic mice and its possible role in steroidogenesis.

Type 1 diabetes mellitus (T1DM) is a metabolic disorder with severe hyperglycemia, one of the complications of which is testicular dysfunctions, androgen deficiency and decreased male fertility. In the diabetic testes, the expression and signaling pathways of leptin and a number of other adipokines are significantly changed. However, there is no information on the localization and expression of adipokine, apelin and its receptor (APJ) in the diabetic testes, although there is information on the involvement of apelin in the regulation of reproductive functions.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms.

Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus (GDM) and T2DM. MF treatment is demonstrated to improve the efficiency of in vitro fertilization and is considered a supplementary drug in assisted reproductive technologies. MF administration shows positive effect on steroidogenesis and spermatogenesis in men with metabolic disorders, thus MF treatment indicates prospective use for improvement of male reproductive functions and fertility.

Comparative Study of the Steroidogenic Effects of Human Chorionic Gonadotropin and Thieno[2,3-D]pyrimidine-Based Allosteric Agonist of Luteinizing Hormone Receptor in Young Adult, Aging and Diabetic Male Rats.

Low-molecular-weight agonists of luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor (LHCGR), which interact with LHCGR transmembrane allosteric site and, in comparison with gonadotropins, more selectively activate intracellular effectors, are currently being developed. Meanwhile, their effects on testicular steroidogenesis have not been studied. The purpose of this work is to perform a comparative study of the effects of 5-amino---butyl-4-(3-(1-methylpyrazole-4-carboxamido)phenyl)-2-(methylthio)thieno[2,3-] pyrimidine-6-carboxamide (TP4/2), a LHCGR allosteric agonist developed by us, and hCG on adenylyl cyclase activity in rat testicular membranes, testosterone levels, testicular steroidogenesis and spermatogenesis in young (four-month-old), aging (18-month-old) and diabetic male Wistar rats.

The effect of metformin treatment on the basal and gonadotropin-stimulated steroidogenesis in male rats with type 2 diabetes mellitus.

Type 2 diabetes mellitus impairs reproductive functions in men, and important tasks are deciphering the mechanisms of testicular dysfunctions in diabetes and the search of effective approaches to their correction. The purpose was to study the effect of four-week metformin treatment (120 mg kg  day ) of male Wistar rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes on basal and gonadotropin-stimulated steroidogenesis, intratesticular content of leptin and the leptin and luteinising hormone receptors and on spermatogenesis. Diabetic rats had hyperleptinaemia, androgen deficiency and reduced sperm count and quality, and in the testes, they had the increased leptin level and the decreased content of the leptin and luteinising hormone receptors and 17-hydroxyprogesterone.

Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice.

Diabetes mellitus impairs testicular activity and leads to infertility. Leptin is one of the endogenous regulators of the male reproductive functions, but the role of leptin and its receptor (LEPR/Ob-R) in the control of testosterone production and testicular proliferation has not been investigated so far, especially in the Type 1 diabetes mellitus (DM1). Metformin is an anti-hyperglycemic drug which is beneficial for treating the both DM2 and DM1.

The Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on the Modulation of Akt, GSK-3beta, ERK1/2, and AMPK Activities.

Insulin is a promising drug for the treatment of diseases associated with brain damage. However, the mechanism of its neuroprotective action is far from being understood. Our aim was to study the insulin-induced protection of cortical neurons in oxidative stress and its mechanism.

The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect.

In diet-induced obesity, metformin (MF) has weight-lowering effect and improves glucose homeostasis and insulin sensitivity. However, there is no information on the efficiency of MF and the mechanisms of its action in melanocortin-type obesity. We studied the effect of the 10-day treatment with MF at the doses of 200, 400 and 600 mg/kg/day on the food intake and the metabolic and hormonal parameters in female C57Bl/6J (genotype Ay/a) agouti-mice with melanocortin-type obesity, and the influence of MF on the hypothalamic signaling in obese animals at the most effective metabolic dose (600 mg/kg/day).

The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents.

The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HTR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (DR, DR), 5-HTR and 5-HTR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A /a) with the melanocortin obesity.

Brain signaling systems in the Type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases.

The changes in the brain signaling systems play an important role in etiology and pathogenesis of Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), being a possible cause of these diseases. Therefore, their restoration at the early stages of T2DM and MS can be regarded as a promising way to treat and prevent these diseases and their complications. The data on the functional state of the brain signaling systems regulated by insulin, IGF-1, leptin, dopamine, serotonin, melanocortins and glucagon-like peptide-1, in T2DM and MS, are analyzed.

The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes.

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.