Vol 21, No 3 (2023)

Ferroptosis as the type nonapoptosis adjustable destruction of cells arises and develops by means of difficult signals and regulatory mechanisms. The reactive oxygen species (ROS) used to initiate ferroptosis come from a variety of sources, including iron-mediated Fenton reactions, mitochondrial ROS, and membrane-associated ROS driven by the NOX protein family. Polyunsaturated fatty acid-containing phospholipids are the main substrates of lipid peroxidation in ferroptosis, which is positively regulated by enzymes, such as ACSL4, LPCAT3, ALOXs, or POR. Selective activation of autophagic degradation pathways promotes ferroptosis by increasing iron accumulation to cause lipid peroxidation. In contrast, system Xc^–-glutathione–GPX4 axis plays a central role in limiting lipid peroxidation, although other antioxidants (such as coenzyme Q10 and tetrahydrobiopterin) can also inhibit ferroptosis. A main nuclear mechanism of cell defense against ferroptosis is the activation of the NFE2L2-dependent antioxidant response by transcriptionally upregulating the expression of antioxidants or cytoprotective genes. Additionally, the membrane damage caused by ferroptotic stimulus can be repaired by ESCRT-III-dependent membrane scission machinery. In this review, we summarize recent progress in understanding the signaling pathways and defense mechanisms of ferroptosis.

It is reported that the traditional scheme of finding and developing a new drug and conducting the whole complex of preclinical studies requires several thousand chemical compounds, hundreds of millions of US dollars and more than 12 years of work. It is shown that physicochemical pharmacology was born in Russia at the end of the 20^th century, which in our days has been transformed into “physicochemical repurposing of known medicines”. The first successfully repurposed known drug was a solution of 4% potassium chloride, which had previously traditionally belonged to the group of macro- and microelements, used by intravenous injections to regulate acid-base balance and rhythmic activity of the heart. In 1983, it was stated that this medicinal solution, when heated to 39–42°C and applied topically by irrigation of the bleeding surface, could be classified as a vasoconstrictor and hemostatic drug. Hyperthermia was used as a physico-chemical reprofiling factor, which, according to the Arrhenius law, accelerated and intensified, on the one hand, the spastic action of K⁺ cations on the gaping blood vessels (formation of hyperkalium contracture in the smooth muscles of the vascular wall) and, on the other hand, the blood clotting process in the wound. In subsequent years, the promise of physicochemical repurposing of known drugs was shown on the example of water, hydrogen peroxide, sodium chloride and sodium bicarbonate by purposefully changing their temperature, acid, osmotic activity, as well as the amount and quality of gas content (passing). A chronology of the physicochemical repurposing of known drug solutions and tablets is described and the essence of such new groups of drugs as bleachers of bruises and pyolytics is given. It is shown that both groups of drugs were discovered in Russia and are intended for local use to bleach bruises (blood stains) and dissolve thick mucus, sputum, pus, blood clots, meconium and other dense biological tissues containing the enzyme catalase. It is pointed out that the advantage and at the same time the limitation of the known drugs repurposed according to this scheme is their local application, since their new pharmacological activity is caused mainly by the physical and chemical principle of action, which is manifested by local interaction with the selected area of the patient’s organism.

BACKGROUND: Factors that may trigger episodes of binge eating include mental and physical stress, dietary restrictions of high-calorie foods. In a rodent model it has been shown that intermittent consumption of high-calorie foods causes binge eating regardless of body weight gain.

AIM: To investigate the effect of a novel ghrelin receptor antagonist Agrelax on binge eating in in adult rats after maternal deprivation in early ontogeny.

MATERIALS AND METHODS: Animals were weaned for 180 min from day 2 to day 12 after birth; males 90–100 days of age were used in the experiments. In the development of binge eating, animals received a high-carbohydrate diet (Nutella paste — based chocolate mixture) for 1 h every day or every third day for 1.5 months. Fifteen minutes before feeding, the chocolate paste was placed within 5 cm of reach with visual contact. Agrelax, a novel ghrelin receptor antagonist, was administered intranasally 1µg/1µl, 20µl for 7 days.

RESULTS: Maternal deprivation induced bindge eating of high-calorie foods in adult rats. When chocolate was given 3 times a week, its consumption increased (p < 0.001) in the maternal deprivation group relative to the control group. After a course of administration of agrelax, chocolate consumption did not differ significantly from that in the control group. The daily consumption of standard food did not differ relative to the control group both before and after the course of agrelax administration. When chocolate was given daily, the maternal deprivation rats did not develop food addiction. At the same time agrelax did not induce a change in chocolate consumption relative to the control group.

CONCLUSIONS: The findings suggest new ways to synthesize pharmacological agents of peptide nature based on ghrelin and its antagonists for correction of food addiction caused by psychogenic stresses in ontogenesis.

Background. Osteoporosis is a problem all over the world with important clinical and economic consequences. A significant contribution to solving the problem of the spread of osteoporosis can be the creation of drugs based on unique biologically active compounds.

The aim was to evaluate the processes of osteogenesis, according to the formation of an organic matrix of bone tissue, as well as to evaluate markers of bone remodeling in blood serum at the stages of anti-osteoporosis therapy.

Materials and methods. The study was performed on an experimental model of osteoporosis using biochemical methods for analyzing markers of osteoporosis in blood serum, as well as atomic absorption spectroscopy and X-ray densitometry.

Results. According to the results of the study, the specific anti-osteoporotic activity of the new drug based on succinic acid salts was proved - a significant increase in the organic component – the total collagen in bone tissue and the mineral component - the main elements in bone tissue in both young and old senile animals. Evaluation of the dynamics of the content of markers of bone remodeling showed the high effectiveness of the new drug in monotherapy, and in combination with vitamin D3 in the activation of osteogenesis processes in experimental osteoporosis.

Conclusion. The effectiveness of the proposed anti-osteoporotic agent is shown, which is more pronounced in senile rats and is due to a proportional increase in the organic and mineral components of bone tissue.