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Vol 21, No 2 (2023)

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Reviews

Circular RNAs — a modern perspective on the molecular mechanisms of neurologic diseases in humans and prospects for therapeutic agents

Shabanov P.D., Vashchenko V.I., Savelieva L.P., Romashova Y.E.

Abstract

In mammals, the brain exhibits significantly higher expression levels of various noncoding RNAs (ncRNAs) compared to other organs. Among these, circular RNAs (circRNAs) have recently emerged as a distinct class of ncRNAs. CircRNAs are formed by back-splicing and fusion of exons, introns, or both, resulting in covalently closed loops. Abundant in the brain, circRNAs levels increase during development and persist into adulthood. The functional significance and mechanisms of circRNA action are subjects of ongoing search, with indications that they regulate the transcription of host genes and sequestration of miRNAs and RNA binding proteins. Some circRNAs have also shown potential for translation, giving rise to peptides. In a healthy brain, circRNA expression and abundance are carefully regulated spatiotemporally. However, altered expression of circRNAs is associated with several disorders, including brain tumor growth and acute and chronic neurodegenerative disorders. This is believed to be through their impact on mechanisms such as angiogenesis, neuronal plasticity, autophagy, apoptosis, and inflammation. The unique properties of circRNAs make them promising molecular biomarkers, especially in the context of neurodegenerative diseases. This review provides a comprehensive overview of circRNAs, focusing on their role in the pathogenesis of major neurodegenerative disorders, namely, Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, schizophrenia, and amyotrophic lateral sclerosis (ALS). Additionally, it discusses the potential utility of circRNAs in biomarker discovery for these debilitating conditions.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):95-133
pages 95-133 views

Alkaline hydrogen peroxide solutions: expectorant, pyolytic, mucolytic, haemolytic, oxygen-releasing, and decolorizing effects

Fisher E.L., Urakov A.L., Samorodov A.V., Bashirov I.I., Shabanov P.D.

Abstract

The local action of hydrogen peroxide solutions on such dense biological masses, such as pus, mucus, sputum, and blood clots, is influenced not only by the concentration of the hydrogen peroxide but also by the alkalinity of the solution and the temperature of the interaction medium. Increasing the solution’s temperature from 24°C–26°C to 45°C–55°C and its alkalinity from pH 7.0 to 8.4–8.5 enhances the pyolytic, mucolytic, hemolytic, bleaching, and oxygen-releasing activity of hydrogen peroxide solutions. Simple heating achieves the desired level of hyperthermia, while the addition of sodium bicarbonate provides the indicated alkalinity.

Hyperthermia, according to the laws of physics, reduces the viscosity of biological masses, increasing their fluidity, permeability to the antiseptic solution, miscibility, and solubility in it. Furthermore, hyperthermia accelerates the rate of chemical, physicochemical, and biochemical processes, according to the Arrhenius law. The elevated temperature of interacting media speeds up the alkaline saponification process of proteins and protein-lipid complexes, which constitute the colloidal basis of biological masses. Additionally, hyperthermia intensifies the enzymatic decomposition of hydrogen peroxide into water and oxygen gas, facilitated by the enzyme catalase present in most biological masses. The released molecular oxygen generates gas bubbles that mimic cold boiling, leading to the “explosion” of biological masses, transforming them into a fluffy white foam.

Oxygen in an alkaline environment oxidizes biological pigments, including hemoglobin and its metabolites of different colors, resulting in their discoloration.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):135-150
pages 135-150 views

Original articles

Emotiogenic effects of antorex, a novel OX1R antagonist, on emotional manifestations of anxiety and compulsiveness in rats

Lebedev A.A., Lukashkova V.V., Pshenichnaya A.G., Bychkov E.R., Lebedev V.A., Rusanovsky V.V., Shabanov P.D.

Abstract

BACKGROUND: In recent years, research has focused on understanding the role of orexins and their receptors in regulating the emotions, motivations and brain reinforcing systems. Orexin plays a crucial role in the extrahypothalamic system of corticotropin-releasing hormone, making it a potential target for developing pharmacological agents to treat phobic spectrum disorders.

AIM: The study aims to analyze the effect of the new OX1R antagonist, antorex, on emotional manifestations of anxiety in rats.

MATERIALS AND METHODS: The experiments involved 38 Wistar male rats. Antorex, at a concentration of 1 µg/µl (or water as control), was intranasally administered in a volume of 20 µl (10 µl in each nostril). A battery of behavioral tests was employed, including the elevated plus maze, open field, marble test, intruder-resident test and anxiety-phobic state assessment.

RESULTS: In the elevated plus maze test, antorex showed moderate anxiolytic activity, as evidenced by the increase in the time spent in the light arm compared to the control group. The marble test revealed a decrease in the number of buried balloons after antorex administration, indicating a reduction in obsessive-compulsive state of anxiety. The anxiety-phobic state assessment test demonstrated a decrease in the avoidance reaction to the hand’s action. In the “open field” test, a decrease in motor activity was observed.

CONCLUSIONS: The OX1R antagonist antorex demonstrated an anxiolytic and sedative effect, reducing compulsive behavior without affecting the communicative activity. These findings support the potential use of drugs that modulate orexin regulation as a novel approach in the treatment of phobic spectrum disorders.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):151-158
pages 151-158 views

Study of the effects of kisspeptin analogs on the behavior of Danio rerio

Goltz V.A., Lebedev A.A., Blazhenko A.A., Lebedev V.A., Kazakov S.V., Bayramov A.A., Khokhlov P.P., Bychkov E.R., Pyurveev S.S., Shabanov P.D.

Abstract

BACKGROUND: This study aims to analyze the behavioral effects of mammalian Kiss1 kisspeptin analogs, Clone (USA): KS4, KS5, KS6, KS7, KS8, KS9, and Kiss10, on Danio rerio (zebrafish). The peptides have structural variations in the final four amino acids.

MATERIALS AND METHODS: Kisspeptins were dissolved in aquarium water and administered in two doses: 1) 0.01 mg per 1000 ml of water, and 2) 0.1 mg per 1000 ml of water. Phenazepam, an anxiolytic, was also dissolved in water and used in three doses: 1) 0.1 mg per 1000 ml, 2) 0.5 mg per 1000 ml, and 3) 1 mg per 1000 ml. The study compared kisspeptines with anxiolytics using phenazepam as an example in the novelty test. The fish’s response to novelty in the viewing tank was assessed, including diving to the bottom, increased freezing, and decreased movement in the upper half of the tank. Fish residence time in the lower part of the tank after phenazepam administration decreased, especially at a dose of 0.5 and 1 mg/l.

RESULTS: Kisspeptin analogues decreased the indices characterizing the anxious state of the fish. Against the background of Kiss1 kisspeptin analogues, the average fish path length differed significantly in contrast to the effects of phenazepam. KS4 at a dose of 0.1 mg/l showed a 1.4-fold decrease in the number of freezing, in the freezing time, in the trajectory length and 1.5-fold increase in the number of transitions to the upper part of the tank. The dose of 0.01 mg/l decreased the number of freezing, freezing time, and trajectory length by 1,5-3 times. KS5 at a dose of 0.1 mg/l decreased the number of freezing, the freezing time, the trajectory length and the number of transitions to the upper part of the tank by 1.2–1.6 times. The dose of 0.01 mg/l decreased the number of freezing, freezing time, trajectory length by 2.8–3 times. KS6 at a dose of 0.1 mg/l decreased the number of freezing, the freezing time, and the trajectory length by 2–2.5 times. The number of transitions to the upper part of the aquarium increased 2.5 times. The dose of 0.01 mg/ml decreased the number of freezing, freezing time, and trajectory length by 1.7–2.2 times. KS7 at a dose of 0.1 mg/l decreased the number of freezing, freezing time, and trajectory length by 1.3–2 times. The number of movements to the top of the aquarium increased 1.6-fold. The dose of 0.01 mg/l decreased the number of freezing, freezing time, trajectory length by 1.6 times. KS8 at a dose of 0.1 mg/l decreased the number of freezing, the freezing time, and the trajectory length by 1.6 times. The dose of 0.01 mg/l decreased the number of freezing, the freezing time, and the trajectory length by 1.8–2.3 times. KS9 at a dose of 0.1 mg/l decreased the number of freezing, the freezing time, and the trajectory length by 1.2–2 times. The dose of 0.01 mg/l reduced the number of freezing, the freezing time, and the trajectory length by 1.6 times. In Kiss10 at a dose of 0.1 mg/l, there was a 1.4–1.6-fold decrease in the number of freezing, in freezing time, and in trajectory length. There was a 2.7-fold increase in the transitions to the upper part of the aquarium. The dose of 0.01 mg/l decreased the number of freezing, freezing time, and trajectory length by 1.3–1.7 times. We observed a 1.3-fold increase in the number of trajectories. Summarizing the obtained indicators, we came to the conclusion that kisspeptin analogues were not inferior in their effect to the effects obtained after taking the tranquilizer phenazepam. Among mammalian kisspeptin analogues, KS6 at a dose of 0.1 mg/L showed the best performance.

CONCLUSIONS: The study concludes that mammalian Kiss1 kisspeptin analogs and Kiss10 reduce anxiety-phobic reactions to novelty in Danio rerio. The effects of the studied kisspeptin analogs are lower than those of phenazepam. Kisspeptin is involved not only in the modulation of serotonin-dependent behavior in Danio rerio but also in the GABA-ergic system, resembling benzodiazepine-type tranquilizers. The results support the hypothesis that kisspeptin may be involved in the regulation of anxiety-phobic states, likely playing a role in maintaining the emotional aspects of reproductive behavior, such as sexual motivation and arousal.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):159-169
pages 159-169 views

Clinical pharmacology

The influence of peptide bioregulators on the resistance of the organism to adverse effects

Kim A.E.

Abstract

The article explores the potential of using peptide bioregulators-cytomedins to enhance the body’s resistance against adverse environmental influences. The study examines scientific literature on the general mechanisms of action of peptide bioregulators, their main clinical effects, and applications. Furthermore, it analyzes the results of research on their activity in individuals with signs of asthenia and reduced immunoreactivity under various adverse conditions, such as hypoxia, hyperthermia, and exposure to aviation and space flight factors, deep-sea diving, and the challenging environment of the Arctic zone.

The research indicates that a single intranasal administration of cortexin, epithalamin, thymogen, and prostatilen in low doses contributes to an increase in the tolerance of adverse effects. Additionally, their short-term use shows delayed positive effects, reflecting their impact on the level of nonspecific resistance of the organism. The specific effects of these drugs depend on the type of adverse effect and the organ tropism of each drug.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):171-177
pages 171-177 views

Plasma adiponectin as a predictor of the effectiveness of coronary heart disease therapy in patients with metabolic syndrome

Firova E.M., Tanyanskiy D.A.

Abstract

BACKGROUND: Adiponectin, an adipose tissue protein, plays a crucial role in the development of metabolic syndrome and atherosclerosis. As a potential therapeutic target, this adipokine can be considered in the context of treatment strategies.

AIM: The aim of this study was to assess the correlation between changes in plasma adiponectin concentration during coronary heart disease therapy and the effectiveness of the treatment, as well as to examine the relationship between initial adiponectin levels and treatment outcomes in patients with metabolic syndrome.

MATERIALS AND METHODS: The study included 31 patients with coronary heart disease and metabolic syndrome (age 59.7 ± 5.9 years, 21 women) which underwent the reexamination after 2–3 years. Most patients received statins (n = 26), while some received fibrates (n = 4) and hypoglycemic drugs (n = 4). Additionally, the patients were on hypotensive and antithrombotic therapies. The effectiveness of coronary heart disease therapy was assessed by evaluating changes in the functional class of angina pectoris and exercise tolerance measured through cycle ergometry. Plasma samples were collected at the initial and reexamination periods to determine glucose, insulin, adiponectin, leptin, and lipidogram parameters.

RESULTS: The study revealed improvements in insulin sensitivity and plasma lipid spectrum, along with reduced levels of plasma leptin and increased adiponectin levels during the course of therapy. In addition, some patients showed enhanced exercise tolerance. Among the biochemical parameters, changes in insulin resistance during therapy correlated with improvements in exercise performance indicators during cycle ergometry (r = −0.32…−0.36, p < 0.05). Moreover, multiple regression analysis indicated that the initial adiponectin concentration independently determined changes in inotropic reserve and the amount of work performed (β = 0.44, p = 0.04 and β = 0.64, p = 0.008).

CONCLUSIONS: The study’s findings regarding the association of plasma adiponectin concentration with changes in exercise tolerance during coronary heart disease therapy suggest the potential for developing specific approaches to raise adiponectin levels in the future.

Reviews on Clinical Pharmacology and Drug Therapy. 2023;21(2):179-189
pages 179-189 views


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