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Vol 20, No 4 (2022)

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Reviews

Circular RNAs in eukaryotic cells: origin, characteristics, mechanisms of molecular functioning in human malignant diseases

Vashchenko V.I., Chuklovin A.B., Shabanov P.D.

Abstract

Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with limited functionality.

However, recent advances in highthroughput genomic technology have allowed circRNAs to be characterized in detail and revealed their important functions in controlling various biological and molecular processes, the most essential being gene regulation. Due to structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA 2 biology. Unlike linear RNAs, circRNAs are produced differentially by backsplicing exons or “lariat” introns from a pre-messenger RNA (mRNA) forming covalently closed loop-like molecules missing 3' poly-(A) tail or 5' cap structures, thus rendering them resistant to exonuclease-mediated degradation.

Previous studies have revealed multiple roles of circRNAs as “sponges” for miRNA and RNA-binding proteins (RBP), as well as regulators of transcription, translation, and splicing events. Recent advances in the field suggest that the circRNAs are involved in many human disorders, including cancer and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, due to their aberrant expression in different pathological conditions. The circRNAs are stable in cells, owing to their circular structure. Participation of circRNAs in programmed cellular destruction by autophagy is discussed in details. The autophagy is a catabolic process which promotes decomposition and recycling of harmful or redundant biological macromolecules and initiates destruction of ageing cells. Processes how circRNAs influence a course of a disease, including an autophagy are in detail discussed, specifying that it joins at the beginning and upon development of various illnesses, and it can influence drug resistance (for example, antitumor efficiency of Cisplatin).

The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular actions of circRNAs and their usage as potential therapeutic targets in different human malignancies.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(4):335-384
pages 335-384 views

The possibilities of chiral drugs

Lenskaya K.V., Kurbanov R.A., Bagaturiya G.O., Grishin V.V., Proshin S.N.

Abstract

In world practice, most drugs are chiral compounds, and about 90% of the latter are synthesized as racemates, which consist of an equimolar mixture of two enantiomers. Despite the fact that they have the same chemical structure, most of the isomers of chiral drugs show noticeable differences in safety and efficacy: pharmacology, toxicology, pharmacokinetics, metabolism.

The aim of our study is to analyze the literature data concerning the nomenclature, pharmacology, toxicology and mechanisms of action of currently used chiral drugs.

The analysis revealed the need to develop a method of chiral separation and analysis of racemic drugs in the pharmaceutical industry. This process plays a particularly important role in the clinic, to exclude an undesirable isomer from the drug from the point of view of pharmacotherapy, as well as to select the optimal course of treatment and maximum pharmacological effect.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(4):385-393
pages 385-393 views

Biochemical mechanisms of the energy-protective action of blockers of slow high-threshold L-type calcium channels

Vorobieva V.V., Levchenkova O.S., Shabanov P.D.

Abstract

This review discusses information about the structure and function of calcium channels in the plasma membrane and mitochondria of the heart, and pharmacological methods for modulating their conductance. Experimental data are presented that characterize the change in the energy metabolism of cardiomyocytes against the background of the transformation of the conductivity of L-type calcium channels of the cell membrane in a non-invasive model of vibration-mediated (56 sessions of total vertical vibration, with a frequency of 44 Hz and an amplitude of 0.5 mm) hypoxia.

It was shown that in animals treated with calcium channel blocker adalat (nifedipine INN) against the background of vibration, the rate of endogenous respiration (Ve), measured by the polarographic method using a closed Clark electrode in native homogenate of rabbit myocardial tissue, remained at the level of intact animals and amounted to 16.3 ± 4.3 ng-O atom/ min · mg of protein, amytal sensitivity increased by 39% (p < 0.05) compared to the group of vibrated animals, low-natality decreased by 40% (p < 0.05). The dynamics of the rate of substrate respiration (Vac and Vglu + mal) in the group with adalat returned to that of intact animals, which indicated the restoration of the physiological predominance of the activity of theNADH – CoQ-reductase complex in redox reactions. It was found that the blockade of transport of Ca2+ ions at the level of high-threshold (HVA) voltage-dependent ion channels of the L-type of the cell membrane, normalizing the activity of the I enzyme-substrate complex of the respiratory chain and regulatoryly restraining the hyperactivity of succinate dehydrogenase in zone II of the enzyme-substrate complex, has an energy-protective effect. Adalat prevented a low-energy shift and the development of bioenergetic hypoxia in the myocardial tissue of experimental animals.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(4):395-405
pages 395-405 views

Sacubitril/valsartan as a component of therapy for chronic heart failure

Danilov A.I., Evseev A.V., Evseeva M.A., Pavluchenkova O.V., Pereverzev V.A.

Abstract

Chronic heart failure is in the vast majority of cases the outcome of many cardiovascular diseases. Despite significant achievements in the early diagnosis and treatment of cardiological pathology, the prevalence of chronic heart failure is steadily increasing, increasing the material costs of the healthcare system. Experts explain this aspect by the aging of the population of the developed countries of the world due to an increase in life expectancy. The presented review highlights the possibilities of using sacubitril/valsartan in clinical practice in order to inhibit the progression of chronic heart failure.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(4):407-413
pages 407-413 views

Original articles

Effects of agonists of melanocortin receptors MC3Rand MC4R on components of sexual behavior of male rats reared in condition of chronic social isolation

Tissen l.Y., Magarramova L.A., Ayzup M.D., Lebedev A.A., Shabanov P.D.

Abstract

BACKGROUND: Melanocortins, including α-melanocyte stimulating hormone (MSH), βMSH, γMSH, and adrenocorticotropic hormone, are products of the polypeptide proopiomelanocortin. These products bind to five different melanocortin receptors (MC1R, MC2R, MC3R, MC4R, MC5R) with different affinities. Because MC3R and MC4R are the major types expressed in the brain, these two receptors can mediate the behavioral effects of melanocortins.

AIM: To clear the role of MC4R in sexual behavior of male rats after social isolation from relatives.

MATERIALS AND METHODS: In the present study, 40 naive male Wistar rats divided into 4 groups, 3 of which were grown in complete social and partial sensory isolation, received saline, PT-141 (MC3R/MC4R agonist) in a dose 0.3 µg intraperitoneally, and THIQ (MC4R agonist) in a dose 0.1 µg intranasally. Behavioral effects were registered in a cage with unreachable reinforcement in which the female in the estrus phase, separated by a transparent perforated barrier, was kept for 10 minutes under red light. Blood samples were taken 30 minutes after administration from the tail vein. Testosterone concentrations were measured by ELISA.

RESULTS: Social isolation had no significant effect on latent time before trying to reach a female but decreased the time spent near the cage with a female. Isolated animals did not show genital grooming acts during the experiment. PT-141 decreased the latent time to approach the female, increased the time spent near the female cage, and stimulated genital grooming. THIQ decreased the latent time to reach a female and stimulated genital grooming. At the same time, THIQ had no effect on the time spent near the female cage. Social isolation reduced testosterone levels more than twice compared to controls. The administration of PT-141 and THIQ had no effect on testosterone concentration.

CONCLUSIONS: The results confirm the depressing effect of chronic social isolation stress on the sexual motivation of male rats and demonstrate different roles of melanocortin MC3R/MC4R receptors in the realization of sexual behavior.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(4):415-420
pages 415-420 views

Clinical pharmacology

JAK-inhibitors: clinical pharmacology and application perspectives

Doktorova S.A., Rafalskiy V.V., Grabovetskaya Y.Y., Korenev S.V.

Abstract

BACKGROUND: For the last decade, physicians and researchers have been actively developing and investigating a novel targeted synthetic disease-modifying antirheumatic drugs. The application of drugs that affect the JAK-STAT pathway and multiple proinflammatory cytokines certainly has great potential for the treatment of different inflammatory diseases. This review provides articles from the past 10 years describing these small-molecule inhibitors: clinical pharmacology, safety, adverse effects and application. There is a growing body of literature that recognises the importance of JAK inhibitors as attractive pharmacological alternative to biologics.

AIM: The article aims to explore clinical pharmacology of JAK inhibitors, safety, drug interactions, comparison with biologic disease-modifying antirheumatic drugs and perspective applications for these drugs.

MATERIALS AND METHODS: The research data in this review is drawn from five main sources: PubMed, Scopus, Medline, GoogleScholar, eLibrary. A search was conducted for the period from 2012 to 2022 in Russian and English, by combinations of words: janus kinase inhibitors, disease-modifying antirheumatic drugs, safety, adverse effects, autoimmune diseases, pharmacokinetics, pharmacodynamics.

RESULTS: The most important clinically relevant findings were that these small-molecule inhibitors have a main advantages like oral administration, rapid therapeutics effect and less of patients-non-responders to therapy. On the other hand, JAK inhibitors have a classic pharmacokinetics and pharmacodynamics, this allows to study such parameters using standard methods.

CONCLUSIONS: In this review, the aim was to assess clinical pharmacology of JAK inhibitors, safety, comparison withbiologic disease-modifying antirheumatic drugs and perspective applications for these drugs. In general, it seems that the safety issues of JAK inhibitors unresolved, in particular the development of thromboembolic complications, infectiousdiseases, and malignancies. This is an important issue for future research.

Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(4):421-434
pages 421-434 views


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