[Genetic aspects of type 1 glucagon peptide agonists clinical efficacy: A review].

A review of publications devoted to the analysis of genetic polymorphisms of the gene encoding the glucagon-like peptide type 1 receptor and some other genes directly and indirectly involved in the implementation of its physiological action is presented. The aim of the study: to search for information on genes polymorphism that can affect the effectiveness of glucagon-like peptide type 1 agonists. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was based on PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic source eLIBRARY.RU from 1993 to 2022. The several genes polymorphisms (GLP1R, TCF7L2, CNR1, SORCS1, WFS1, PPARD, CTRB1/2) that may affect the course and therapy of type 2 diabetes mellitus, metabolic syndrome and obesity, was described. Single nucleotide substitutions in some regions of these genes can both decrease and increase the clinical efficacy of the treatment of diabetes mellitus and metabolic syndrome with the help of type 1 glucagon-like peptide agonists: exenatide, liraglutide. Data on the role of genetic variations in the structure of the products of these genes in the effectiveness of other type 1 glucacone-like peptide agonists have not been found.

[Clinical effectiveness and pharmacokinetics of gliflozin from the point of view of individual genetic characteristics: A review].

A review of publications devoted to the analysis of genetic polymorphisms and features of the functioning of genes that affect the pharmacokinetics and pharmacodynamics of sodium-glucose cotransporter-2 inhibitors (SGLT2i) is presented. Objective of the study was to reveal information about genes whose polymorphism may affect the effectiveness of SGLT2i. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was carried out in the PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic libraries eLIBRARY.RU from 1993 to 2022. Polymorphisms in the structure of several genes (SLC5A2, UGT1A9, ABCB1, PNPLA3) have been described that may affect the treatment of type 2 diabetes mellitus complicated by diseases such as chronic heart failure, chronic kidney disease, or non-alcoholic fatty liver disease. The information found on the genetic features of the development of the effects of SGLT2i is limited to a description of the differences in their pharmacokinetics. The relevance of currently available pharmacogenetic studies is largely constrained by small sample sizes.

Blockade of Dopamine D2 Receptors as a Novel Approach to Stimulation of Notch1+ Endothelial Progenitor Cells and Angiogenesis in C57BL/6 Mice with Pulmonary Emphysema Induced by Proteases and Deficiency of α1-Antitrypsin.

We studied the effects of spiperone, a selective blocker of dopamine D2 receptors, on the model of pulmonary emphysema provoked by administration of elastase and D-galactosamine hydrochloride to female C57BL/6 mice and characterized by activation of proteases in the lungs and systemic deficiency of its inhibitor α1-antitrypsin. In this model, spiperone prevented the development of inflammatory reaction and reduced the area of emphysematous expanded alveolar tissue. The expression of angiogenic marker CD31 in the lungs increased under these conditions. Regeneration of the damaged microvascular bed under the action of spiperone resulted from recruiting of Notch1+ endothelial progenitor cells (CD45-CD31+CD34+) into the lungs and blockade of the inhibitory effect of dopamine on phosphorylation of VEGF-2 receptors in endothelial cells of different maturity. In addition, spiperone produced a protective effect on hepatocytes and restored the production and secretion of α1-antitrypsin by these cells.

Pericytes and Smooth Muscle Cells Circulating in the Blood as Markers of Impaired Angiogenesis during Combined Metabolic Impairments and Lung Emphysema.

The changes in endothelial progenitor cells and progenitor cells of angiogenesis, pericytes and smooth muscle cells, were studied in female C57BL/6 mice with a combination of metabolic impairments induced by injections of sodium glutamate and lung emphysema modeled by the administration of cigarette smoke extract. It was observed that sodium glutamate significantly enhances pathological changes in the lungs (inflammation and lung emphysema) induced by the administration of cigarette smoke extract. Recruiting of endothelial progenitor cells (CD45-CD31+CD34+ and CD31+CD34+CD146-) and progenitor cells of angiogenesis (CD45-CD117+CD309+) was registered in the injured lungs. Angiogenesis impairment induced by combined exposure is related to altered migration of pericytes (CD31-CD34-CD146+) and smooth muscle cells (CD31-CD34+CD146+) in emphysema-like enlarged lung tissue.

Endothelial Progenitor Cells and Notch-1 Signaling as Markers of Alveolar Endothelium Regeneration in Pulmonary Emphysema.

We studied the effects of elastase, cigarette smoke extract, D-galactosamine hydrochloride, and tyrosine kinase inhibitor SU5416 on endothelial progenitor cells and angiogenesis precursors, as well as on Notch-1 expression by immature endothelial cells. Simultaneously with pulmonary emphysema, different damaging factors with diverse mechanisms of action caused pathological changes in the microvascular network of the lungs and destroyed the alveolar endothelium in female C57Bl/6 mice. D-galactosamine hydrochloride disturbed mobilization of endothelial progenitor cells expressing VEGFR (CD45-CD309+) and angiogenesis progenitors (CD45-CD309+CD117+) and their migration into emphysema expanded lungs. Elastase inhibited VEGFR-expressing endothelial progenitor cells, while cigarette smoke extract inhibited cells with CD45-CD31+CD34+ phenotype. In pulmonary emphysema provoked by elastase or D-galactosamine hydrochloride, angiogenesis was provided by endothelial cells with CD45-CD31+CD34+ phenotype, whereas in emphysema modeled with SU5416 or cigarette smoke extract, it was provided by the endothelial VEGFR-expressing cells and mature CD31+ endothelial cells, respectively. Replenishment of immature endothelial cells damaged by elastase and SU5416 involved Notch-1+ angiogenesis precursors and Notch-1+ endothelial progenitor cells with VEGFR.

Role of Endogenous Agonists of Opioid Receptors in the Regulation of Heart Resistance to Postischemic Reperfusion Injury.

Intravenous injection of nonselective antagonists of opioid receptors (OR) naltrexone (5 mg/kg) and naloxone methiodide (5 mg/kg), selective δ1-OR antagonist BNTX (0.7 mg/kg), selective δ2-OR blocker naltriben (0.3 mg/kg), selective κ-OR antagonist norbinaltorphimine (2 mg/kg), and selective blocker of ORL1 opioid receptors JTC-801 (0.1 mg/kg) produced no effect on reperfusion injury to the heart in rats narcotized with α-chloralose. In contrast, selective µ-OR antagonist CTAP (1 mg/kg) limited the infarct size, although this effect was not observed at a lower CTAP concentration of 0.1 mg/kg. Probably, the myocardial infarct size-limiting effect of CTAP was associated with activation of the non-opioid receptors. It was hypothesized that endogenous OR agonists did not affect heart resistance to reperfusion injury in unadapted rats.

Effects of Pegylated Glucagon-Like Peptide-1 Analogue in C57Bl/6 Mice under Optimal Conditions and During Streptozotocin-Induced Diabetes.

Biological activity of a new pegylated form of an of glucagon-like peptide-1 (GLP-1) analogue pegGLP-1 was studied in C57Bl/6 mice under normal conditions and during modeling of streptozotocin-induced type I diabetes mellitus. pegGLP-1 differs from GLP-1 (7-37) by polyethylene glycol residue covalently bound to His7, Lys26, and Lys34 of the GLP-1 molecule. It was shown that single intragastrical administration of pegGLP-1 induced an increase in GLP-1 level in blood serum of healthy mice. The maximum level of this parameter was observed in 4-8 h. pegGLP-1 elimination half-time was 8.5 h and mean retention time was 15 h. Administration of pegGLP-1 to animals with modeled type I diabetes mellitus was followed by an increase in the levels of GLP-1 and insulin in blood serum, produced a hypoglycemic effect, and improved the parameters of glucose-tolerance test. Biological activity of pegGLP-1 was higher than activity of GLP-1.

Response of Inflammatory Mediators, Extracellular Matrix Proteins and Stem and Progenitor Cells to Emphysema.

Inflammation, extracellular matrix proteins (hydroxyproline, connective tissue growth factor, collagen, and fibronectin), stem and progenitor cells (multipotent mesenchymal stromal cells, Clara cells, angiogenesis, precursors, endothelial and epithelial cells) were studied in female C57Bl/6 mice with experimental elastase-induced emphysema. Diffuse emphysema reduced the number of endothelial (CD45(-)CD31(+)CD34(+)) and epithelial (CD45(-)CD117(+)CD49f(+)) cells, induced microcirculation disturbances, and decreased the area occupied by the connective tissue. Emphysematous changes in the lungs were accompanied by infiltration of the alveolar septa with macrophages and lymphocytes, increase in the serum and lung concentrations of transforming growth factor-ß, IL-1ß, IL-2, IL-5, IL-10, and IL-13, and lung concentration of IL-17. In the lungs, inflammation was associated with marked increase in the number of multipotent mesenchymal stromal cells CD90(+)CD73(+)CD106(+)CD44(+)) and Clara cells (CD45(-)CD34(-)CD31(-)Sca1(+)) and overexpression of extracellular matrix proteins (hydroxyproline, connective tissue growth factor, collagen, fibronectin) and Clara cells protein. On the other hand, elastase reduced the number of angiogenic precursor cells (CD45(-)CD117(+)Flk1(+)).

[Influence of a drug with anticonvulsant action on the level of bioelectric activity and ion content in brain structures].

1-[(3-chlorophenyl)phenylmethyl]urea--a compound possessing anticonvulsant activity, which has been selected by screening among 100 linear and cyclic urea derivatives, produces synchronization of spontaneous bioelectric activity, increased convulsion threshold in the motor cortex, dorsal hippocampus, and basolateral nuclei of amygdala, increased the index of low-frequency flicker acquisition, and reduced response to high-frequency oscillations in the visual cortex of rabbits. This compound also increased the extracellular content of sodium ions and reduced intracellular content of potassium ions in the motor cortex, dorsal hippocampus, and amygdala.

[Influence of neuroprotectors with choline-positive action on the level of brain-injury markers during acute ischemic stroke].

Choline-positive neuroprotectors citicoline and choline alfoscerate decreased blood concentration of protein S100 in clinical trial on 52 patients in the first days after acute ischemic stroke. Neuroprotective therapy has also produced stabilization of blood-brain barrier.

[The effect of phospholipid hepatoprotectors on lipid peroxidation in liver and content of cytokines in the blood in experimental pathology caused by isoniazid].

The purpose--to investigate the influence of hepatoprotective agents of phospholipids'structure essentiale, eplir and its combinations with amber acid on rats liver functional state, lipoperoxidation and bioenergetics, also tumor necrosis factor-a and interleukin-10 blood content in experimental isoniazid intoxication. These agents demonstrated antioxidant action, decreased the common and indirect bilirubine, tumor necrosis factor-alpha blood content, aminotransferase and alkaline phosphatase activity, increased the interleukin-10 blood content. Isonoazid uncoupled the substrate oxidation with ADP phosphorylation and inhibited the respiratory activity of liver mitochondrions. Essentiale and eplir increased the coupling of oxidation with ATP synthesis, in combination with amber acid improved kinetic characteristics of liver mitochondrions.

[Endothelium-protective effects of vinpocetine, pentoxifylline and enalapril in patients with chronic brain ischemia].

The influence of vinpocetine, pentoxifylline and enalapril on endothelium functions has been studied in a group of in 172 patients with chronic brain ischemia. The endothelium-protective effect of drugs was manifested as the inhibition of the Willebrand factor output during arteriovenous occlusion test and as the renewal of endothelium-depended vasodilation. The extent of neurologic deficit reduction correlated with decrease in the activated endothelium-depended output of the Willebrand factor.

[ROLE OF OPIOID RECEPTORS IN THE REGULATION OF RESISTANCE OF HEART TO IMPACT OF ISCHEMIA-REPERFUSION].

Activation of m-, d1-, d2- and k1-opioid receptors increases cardiac resistance to ischemia-reperfusion. The cardioprotective effect of opioids in many cases appears to be associated with the activation of the peripheral OR. However, when it comes to non-peptide agonists OR able to cross the blood-brain barrier, we cannot exclude the involvement of central opioid receptors in cardioprotection. Endogenous opioids are not involved in the regulation of cardiac tolerance to ischemia- reperfusion in non-adapted animals. Stimulation of k1- and d1-OP may exert delayed cardioprotective effect. Activation d- and k1-OP reduces the intensity of cardiomyocyte apoptosis after reperfusion. The results of studies related to the inotropic effect of opioids during reperfusion of the heart remain highly controversial.

[The effect of ethomersol on local cerebral blood flow and edema of the brain tissue in chronic ischemia]. / Vliianie étomerzola na lokal'nyi mozgovoi krovotok i otek mozgovoi tkani v usloviiakh khronicheskoi ishemii.

The effects of ethomersole (50 mg/kg orally during 10 days) on local cerebral blood flow and cerebral tissue impedance were investigated in rats after left carotid artery ligation and right carotid artery narrowing (blood flow was decreased to 50%). Under these conditions, ethomersole accelerated the blood flow recovery, levelled blood flow asymmetry between the hemispheres, decreased the development of brain edema. In in vitro experiments ethomersole demonstrated a pronounced limitation of cerebral lipid peroxidation.

[Endothelium-dependent vasodilation in patients with cerebrovascular disease]. / Sostoianie éndoteliizavisimoi vazodiliatsii u bol'nykh tserebrovaskuliarnoi bolezn'iu.

The aim of the study was to examine changes in vasodilatory endothelial function in early cerebrovascular disease of atherosclerotic genesis. All the examinees underwent ultrasonic investigation, test for reactive hyperemia of the brachial artery to evaluate vasodilatory function of the endothelium. Disturbances in the flow-dependent vasodilation were detected at initial stages of the disease, aggravated with the progress of cerebrovascular disease and therefore could serve the earliest, objective indicator of atherosclerotic process.

[An effect of vinpocetine (cavinton) on endothelium function in patients with chronic cerebral ischemia].

The influence of vinpocetine (cavinton) on endothelium function in 87 patients with chronic cerebral ischemia has been studied. Vinpocetine exerts an endothelium protective effect which appears as a partial renewal of endothelium-dependent vasodilatation and inhibition of rejection of Willebrand factor during arteriovenous occlusion test. Leveling of neurological deficit by vinpocetine depends on the extent of renewal of endothelium-dependent vasodilatation.