Reviews on Clinical Pharmacology and Drug Therapy

Glycosphingolipids chemically linked to sialic acids play an important role as structural scaffold molecules of the outer membranes of nerve cells in humans and animals. Progress in research on gangliosides and sialidases (i.e., enzymes involved in ganglioside hydrolysis) may make a substantial contribution to the development of promising pharmacological agents for various fields of medicine. This article presents a review of methods used both previously and at present for the qualitative and quantitative analysis of various types of gangliosides in biological samples, as well as of the activity of sialidases that degrade them. Russian and international scientific data was analyzed. Chromophores obtained with sodium periodate (NaIO₄) and tert-butyl hydroperoxide from both sialic acids and 2-deoxyribose can remain stable for several hours at room temperature, whereas when heated to 100°C they degrade within a few minutes. However, when the reaction mixture is exposed to alkaline solutions, only the chromophores derived from sialic acids degrade to a colorless state, whereas the chromophore derived from 2-deoxyribose retains its color. In addition, it should be noted that the contributions of N-acetylneuraminic acid and N-glycolylneuraminic acid to the formation of the above-mentioned chromophores also differs. This is evidenced by the fact that the molar absorption coefficient of N-glycolylneuraminic acid is 19% lower than that of N-acetylneuraminic acid, which may indicate differences in the bond strength of the acetyl and glycolyl groups in sialic acids. Thus, the methods developed to date make it possible not only to perform highly sensitive and selective qualitative and quantitative assay of various gangliosides present in biological samples, but also to effectively determine the activity of sialidases involved in hydrolysis of these gangliosides. However, because this requires quite complex, expensive, and technically demanding high-performance liquid chromatography with fluorescence detection, the more widely accepted approach in routine biochemical studies of gangliosides and sialidases remains the simpler optical-chemical method based on the use of thiobarbituric acid.

Resistance of tumor cells to cell death because of high level of aerobic glycolysis, compared with normal tissues, is a distinctive feature of cancer cells (Warburg effect). Recent studies have identified metabolism-related forms of cell death as unique types of regulated necrosis arising from imbalance in cellular metabolism. Necrosis plays an essential role in the development and homeostasis of nearly all multicellular organisms. In addition, dysregulation of cell death contributes to a wide range of pathological conditions. Historically, apoptosis was considered the principal programmed pathway of cell destruction, whereas necrosis was defined as an uncontrolled form of cell death. However, studies conducted over recent decades have revealed several important forms of regulated cell death that constitute part of the mechanisms of degenerative diseases, inflammatory disorders, and cancer. Growing understanding of these regulated, non-apoptotic cell death pathways opens new perspectives for therapeutic strategies. This article describes cell death mediated by regulated pathways, including necroptosis, ferroptosis, cuproptosis, autophagy-related cell death, lysosome-dependent cell death, and disulfidptosis. The mechanisms of metabolic cell death are discussed, and their potential in cancer therapy is explored. The complexity of metabolic cell death pathways is emphasized, and innovative ideas are proposed for understanding their therapeutic prospects in cancer treatment. The role of small-molecule inhibitors, regulatory pathways, and the prospects for anticancer drug development are also discussed.

It has been shown that the grass, stems, leaves and inflorescences of wild and cultivated cannabis[1] contain cannabinoids, which, like synthetic cannabinoids, have a hallucinogenic effect. The continuing increase in the abuse of hallucinogens from the group of natural and synthetic cannabinoids among young people, the widespread use of cultivated and wild cannabis, as well as the medical use of cannabinoids as drugs in the treatment of cancer and mental disorders, pose a risk of developing mental dependence and the prevalence of drug addiction in society. It is indicated that among drug addicts and youth, the names cannabis[1], marijuana[1] and hashish[1] refer to drugs made from cannabis[1] herb (Cannabis sativa or Cannabis indica). Due to the fact that cannabinoids are not destroyed by high temperature (they do not burn in fire) and hydrochloric acid of gastric juice, they retain a hallucinogenic effect when inhaled as part of smoke and ingested as part of extracts. Most often, the cannabis is used to produce smoking mixtures known as spice, aroma mix, macon, as well as resin known as hashish[1]. Hashish and the glandular trichomes of the flowering tops of female cannabis plants contain more cannabinoids than other cannabis[1] plant products. It is indicated that inhalation of smoke from smoking mixtures into the body and enteral administration of liquid cannabis[1] extract causes drug addicts to improve their mood and allow them to have fun. The main cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). It has been shown that after inhaling smoke with natural or synthetic cannabinoids, the narcotic effect in drug addicts begins to develop after 15–20 s, reaches its maximum value after 10–30 min and lasts up to 1–3 h, but can be prolonged by repeated smoke inhalation (smoking). After ingestion of cannabinoids in effective doses, the narcotic effect can begin to develop after 30–60 min, after which it usually reaches a maximum after 1.5–2.0 h and lasts up to 6 h (sometimes longer). At the same time, a person experiences dizziness, weakness throughout the body, auditory and visual hallucinations, loses coordination in movements and the ability to think correctly.

[1] A substance prohibited in the Russian Federation.

BACKGROUND: Rodent models of polycystic ovary syndrome, including those induced by dehydroepiandrosterone, are widely used to study the pathogenesis of this disorder; however, ovarian steroidogenesis and ovulation markers in this model remain insufficiently characterized. There are no data on the ability of luteinizing hormone receptor agonists to stimulate ovulation in rats with this model of polycystic ovary syndrome, which is important for assisted reproductive technologies.

AIM: This study aimed to investigate ovarian steroidogenesis, ovulation markers, and ovarian morphology in infantile female rats with dehydroepiandrosterone-induced polycystic ovary syndrome, and to assess the effects of the allosteric agonist TP03, 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, on these parameters.

METHODS: Female Wistar rats, starting at 23–26 days of age, were treated with dehydroepiandrosterone for 6 weeks (6 mg/100 g/day, subcutaneously). The following parameters were assessed: body and ovarian weight, serum levels of testosterone, progesterone, and estradiol (enzyme-linked immunosorbent assay), ovarian gene expression (reverse-transcription polymerase chain reaction), and ovarian morphology (number of tertiary and preovulatory follicles, corpora lutea, and follicular cysts) by microscopy. Rats with polycystic ovary syndrome were stimulated with an ovulation-inducing drug at a dose of 15 IU/rat, followed by TP03 at a dose of 25 mg/kg 48 h later; the studied parameters were evaluated 16 h later.

RESULTS: In dehydroepiandrosterone-induced rats, ovarian weight, the number of tertiary follicles and corpora lutea of previous cycles, progesterone levels, and the expression of genes responsible for steroidogenesis (Star, Cyp11a1, Cyp17a1) and ovulation (Adamts-1, Vegf-a) were decreased, whereas testosterone levels were increased and follicular cysts were detected in the ovaries, consistent with the pathogenesis of polycystic ovary syndrome. Treatment with ovulation-inducing drugs increased ovarian weight, progesterone levels, and Cyp17a1 gene expression, and stimulated ovulation, leading to the formation of corpora lutea. Luteinized unruptured follicles were also detected in the ovaries; this finding was associated with decreased expression of the ADAMTS-1 metalloproteinase and VEGF-A genes involved in follicular rupture.

CONCLUSION: Treatment of infantile rats with dehydroepiandrosterone-induced polycystic ovary syndrome using TP03 induces ovulation; however, along with normal corpora lutea, luteinized unruptured follicles are formed as a result of decreased expression of genes involved in follicular rupture.

BACKGROUND: Antimicrobial peptides are considered a promising strategy for the development of combinations effective against antibiotic-resistant bacteria.

AIM: This work aimed to investigate the potential for enhancing the antibacterial activity of synthetic analogs of natural peptides and expanding their spectrum when used in combination with conventional antibiotics, antiseptics, and silver nanoparticles.

METHODS: Antimicrobial activity was determined using the serial dilution in a liquid nutrient medium containing microorganisms, whereas the nature of combined action was assessed using serial dilutions by the checkerboard method. A hemolysis assay was used to evaluate the toxicity of the tested substances.

RESULTS: The most frequent synergistic effects were identified for combinations of peptides PG-1, ChBac3.4, and PR-39 with AgNP-A1, AgNP-A2, and poviargol; RC, MC, and RFR ChBac3.4-1-NH2 with the antibiotics amikacin, gentamicin, and erythromycin; and PG-1, ChBac3.4, and RFR ChBac3.4(1–14) with the antiseptics amidopropyl betaine and chlorhexidine against antibiotic-resistant bacteria. The hemolysis assay demonstrated the safety of the tested combinations at concentrations substantially exceeding antimicrobial levels.

CONCLUSION: The data confirm the high potential of the combined use of antimicrobial peptides, antibiotics, silver nanoparticles, and antiseptics to enhance antibacterial activity, supporting further development and clinical implementation of preparations based on PG-1 and PR-39, MC and PR-39, and RFR Bac3.4(1–14) and Bac5(20–43) for the treatment of wound infections.