Laboratory of Molecular Endocrinology and Neurochemistry

The main directions of scientific activity:

1. Research of the molecular mechanisms underlying the development of type 1 and type 2 diabetes mellitus (DM) and metabolic syndrome and their complications from the nervous and endocrine systems, as well as the development of new approaches for their timely diagnosis and treatment. Using a wide range of experimental, including genetically determined, models of obesity, type 1 and type 2 diabetes and metabolic syndrome in rodents, functional disorders occurring in hormonal signaling systems in various parts of the brain, as well as in components of the hypothalamic-pituitary-gonadal and thyroid axes, were established and investigated their role in the etiology and pathogenesis of these metabolic disorders and their complications. New approaches for the treatment of type 1 and type 2 diabetes have been proposed based on the use of regulators of neurotransmitter and hormonal systems of the brain, including intranasally administered insulin and C-peptide, as well as peptide analogues of leptin, D2-agonist bromocriptine. The antidiabetic properties and anorexigenic effect of new inhibitors of the enzyme phosphotyrosine phosphatase 1B, which is a negative regulator of insulin and leptin signaling, have been studied. All this made it possible to form a theoretical and experimental platform for the further development of innovative strategies for the treatment and timely diagnosis of both obvious forms of diabetes and the pathological conditions preceding it.

2. Development of low-molecular allosteric ligands of luteinizing and thyroid-stimulating hormone receptors, study of the molecular mechanisms of their action and biological activity in vivo.. The concept of allosteric regulation of luteinizing hormone (LHR) and thyroid-stimulating hormone (TSH) receptors belonging to the GPCR receptor superfamily is being developed. Within the framework of this concept, new low molecular weight ligands with the activity of allosteric agonists, reverse agonists and antagonists that interact with transmembrane allosteric sites of these receptors have been created based on the thienopyrimidine structure. As a result, a series of thienopyrimidine derivatives (TP1, TP3, TP4/2) have been identified, which, with prolonged use, stimulate testicular steroidogenesis and spermatogenesis when administered to male rats, and at the same time do not cause (unlike gonadotropins) desensitization of LGR and their signaling systems. These derivatives are effective in diabetes mellitus and aging, improving the androgenic status and restoring spermatogenesis indicators. A line of thienopyrimidine derivatives, allosteric TSH agonists capable of inhibiting TSH-stimulated thyroidogenesis (in vitro) and tyroliberin (in vivo), which may be useful in the correction of thyroid dysfunction, has been developed.

3. To study the role of adipokines in the regulation of endocrine functions, to decipher the molecular mechanisms of their influence on the reproductive and thyroid systems and to study violations of these mechanisms in diabetic pathology. New relationships have been established between the level of leptin and a number of other adipokines in the blood and the activity of their signaling systems and the functional state of various components of the hypothalamic-pituitary-gonadal and thyroid axes in normal and experimental type 1 and type 2 diabetes mellitus. It has been shown that in conditions of hyperleptinemia in type 2 diabetes mellitus, steroidogenesis and spermatogenesis are disrupted in connection with the development of leptin resistance in the testes, while a lack of leptin in the hypothalamus, as a result of impaired leptin transport through the BBB, leads to a weakening of the hypothalamic regulation of the gonadal system. These data allow us to consider the adipokine system as one of the targets for the correction of endocrine disorders.

4. Comparative study of the central and peripheral mechanisms of action of metformin in diabetes mellitus and metabolic syndrome, and their effect on the functions of the reproductive and thyroid systems. Metformin is traditionally considered as an andidiabetic drug, the targets of which are peripheral tissues, and the main mechanism of action is the normalization of energy metabolism in these tissues and an increase in their sensitivity to insulin in conditions of insulin resistance, typical for type 2 diabetes mellitus and metabolic syndrome. We have received numerous evidence in favor of the effect of metformin on hypothalamic signaling systems and, as a result, on the central regulation of energy metabolism and endocrine functions. Data were obtained on the ability of metformin to improve testicular steroidogenesis and spermatogenesis, weakened in diabetic pathology, and on the synergism between its effects and LHR agonists on the gonadal axis. Thus, new opportunities are opening up for the therapeutic use of metformin, including for the control of the functions of the endocrine system in metabolic disorders. 5. Investigation of the regulatory and modulating effect of alpha-tocopherol, gangliosides and insulin and their combinations on the functional activity of signaling systems and redox balance in brain neurons as a key mechanism of their neuroprotective and antioxidant effects. The neuroprotective and antioxidant effects of alpha-tocopherol have been established for the first time when it is exposed to cortical cells and PC12 cell culture subjected to oxidative stress. The molecular mechanisms of the regenerative effect of ganglioside GM1 on intracellular respiration of PC12 cells and isolated mitochondria of rat brain neurons, which include components of the 3-phosphoinositide pathway, a cascade of mitogen-activated protein kinases and Trk-family tyrosine kinase receptors, have been deciphered. It has been shown that with the combined action of alpha-tocopherol, gangliosides and insulin on nerve cells, their neuroprotective and antioxidant effects are not only preserved, but also enhanced. Thus, an increase in the effectiveness of restoring cognitive functions in diabetic rats was found when they were treated together with gangliosides and intranasally administered insulin. An increase in the neuroprotective effect of insulin on cortical neurons subjected to oxidative stress has been shown when it is combined with alpha-tocopherol. For the first time, the neuroprotective and antioxidant effect of a combination of alpha-tocopherol and intranasally administered insulin on neurons in the brain of rats with bicascular ischemia and subsequent reperfusion was established. These data can serve as a theoretical and experimental foundation for the creation of new effective combinations of neuroprotectors as drugs for the treatment of neurodegenerative and ischemic brain lesions. 6. The study of canonical and non-canonical autophagy in the reproductive system of humans and animals in normal and pathological conditions of various etiologies. The main components of canonical autophagy in somatic Sertoli cells in rat testicles were characterized for the first time. The role of non-canonical autophagy in the process of removing apoptotic substrates in testicular Sertoli cells and in human granulosa cells was revealed due to the activation of the hybrid process of phagocytosis associated with autophagy proteins (LC3-associated phagocytosis, LAP). Activation of canonical autophagy, in particular, mitophagy in testicular cells of patients suffering from cryptorchidism, was revealed. This work was awarded as the best publication of 2021 in the international journal Asian Journal of Andrology.