RESUMEN

A primary in vitro analysis of the anticholinesterase properties of substituted 1,3-dihydro-2-oxo-1H-benzimidazol-2-ones was performed along with in silico calculation of their oral toxicity. These compounds are analogs of BIMU-8, a well-known agonist of serotonin 5-HT4 receptors, and are supposed to combine the functions of cholinesterase inhibitors and serotonin receptor agonists. Biochemical analysis showed the ability of the obtained chemicals to inhibit acetyl- and butyrylcholinesterase. A compound with minimal toxicity, high inhibitory ability against butyrylcholinesterase, and low inhibitory ability against acetylcholinesterase has been identified, which is of greatest interest for further experimental development.

Asunto(s)

Enfermedad de Alzheimer , Butirilcolinesterasa , Humanos , Receptores de Serotonina , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad

RESUMEN

[This corrects the article DOI: 10.1134/S0022093022010203.].

RESUMEN

The development of drugs for the therapy of COVID-19 is one of the main problems of modern physiology, biochemistry and pharmacology. Taking into account the available information on the participation of mast cells and the role of histamine in the pathogenesis of COVID-19, as well as information on the positive role of famotidine in the prevention and treatment of coronavirus infection, an experiment was carried out using famotidine in a mouse model. We used a type A/PR/8/34 (H1N1) virus adapted to mice. The antiviral drug oseltamivir (Tamiflu), which belongs to the group of neuraminidase inhibitors, was used as a reference drug. The use of famotidine in combination with oseltamivir can increase survival, improve the dynamics of animal weight, reduce the level of NKT cells and increase the level of naive T-helpers. Further studies of famotidine in vivo should be aimed at optimizing the regimen of drug use at a higher viral load, as well as with a longer use of famotidine.

RESUMEN

Being one of the main proteins in the human body and many animal species, albumin plays a crucial role in the transport of various ions, electrically neutral molecules and in maintaining the colloidal osmotic pressure of the blood. Albumin is able to bind almost all known drugs, many nutraceuticals and toxic substances, determining their pharmaco- and toxicokinetics. However, albumin is not only the passive but also the active participant of the pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities. Due to the thiol group of Cys34, albumin can serve as a trap for reactive oxygen and nitrogen species, thus participating in redox processes. The interaction of the protein with blood cells, blood vessels, and also with tissue cells outside the vascular bed is of great importance. The interaction of albumin with endothelial glycocalyx and vascular endothelial cells largely determines its integrative role. This review provides information of a historical nature, information on evolutionary changes, inflammatory and antioxidant properties of albumin, on its structural and functional modifications and their significance in the pathogenesis of some diseases.

RESUMEN

We studied the effect of different doses of ammonium chloride (ACl) and ammonium carbonate (ACr) on immunological parameters of the peripheral blood in rats during high-intensity exercise. Changes in the absolute and relative numbers of granulocytes, lymphocytes, natural killers, naive and mature effector cells one day after the end of the forced swimming cycle were found by using a hematological analyzer and a flow cytometer. Immunological indicators were analyzed relative to swimming duration on the last day of ultimate load. The revealed changes indicate the onset of the effector phase of the development of the inflammatory processes in the positive control group (physiological saline) and in rats receiving a higher dose of ACr (20 mg/kg), while administration of ACl prevented the development of inflammatory processes and shifts in the physiological balance of lymphocyte subpopulations. Immunological profiling indicates that ACl in a dose of 20 mg/kg most effectively improved physical performance in our forced swimming model.

Asunto(s)

Compuestos de Amonio/química , Compuestos de Amonio/farmacología , Natación , Animales , Sistema Inmunológico/efectos de los fármacos , Condicionamiento Físico Animal/métodos , Ratas

RESUMEN

Endothelial cells (ECs) line the blood vessels and lymphatic vessels, as well as heart chambers, forming the border between the tissues, on the one hand, and blood or lymph, on the other. Such a strategic position of the endothelium determines its most important functional role in the regulation of vascular tone, hemostasis, and inflammatory processes. The damaged endothelium can be both a cause and a consequence of many diseases. The state of the endothelium is indicated by the phenotype of these cells, represented mainly by (trans)membrane markers (surface antigens). This review defines endothelial markers, provides a list of them, and considers the mechanisms of their expression and the role of the endothelium in certain pathological conditions.

RESUMEN

We compared the effects of two doses of ammonium chloride and ammonium carbonate (10 and 20 mg/kg) on the duration of swimming and blood lactate level. Ammonium chloride in a dose of 20 mg/kg was more efficient than in a dose of 10 mg/kg. The efficiency of ammonium carbonate in a dose of 10 mg/kg was similar to that of ammonium chloride in a dose of 20 mg/kg. Increasing the dose of ammonium carbonate to 20 mg/kg led to a decrease in the duration of swimming. On the last day of the experiment, lactate level in 5 min after exhausting load was maximum in control rats, while in rats treated with 10 mg/kg ammonium carbonate and 20 mg/kg ammonium chloride it was lower by 27 and 33%, respectively. In the control group, the amplitude of the decrease in lactate concentration in 1 h after load was 2-fold greater than in the group receiving ammonium chloride in a dose of 20 mg/kg and 1.6-fold greater that in groups treated with ammonium carbonate in a dose of 10 mg/kg and ammonium chloride in a dose of 20 mg/kg.

Asunto(s)

Compuestos de Amonio/farmacología , Ácido Láctico/sangre , Rendimiento Físico Funcional , Estrés Psicológico , Natación/fisiología , Cloruro de Amonio/farmacología , Compuestos de Amonio/química , Animales , Carbonatos/farmacología , Masculino , Ratas , Ratas Wistar , Sales (Química)/farmacología , Estrés Psicológico/sangre , Estrés Psicológico/fisiopatología , Natación/psicología

RESUMEN

Ammonium, an end-product of catabolism, in low doses can promote adaptation of metabolic pathways in erythrocytes under conditions of extreme physical exercise. We compared the effects of two ammonium salts, ammonium chloride and ammonium carbonate, in two doses on biochemical parameters of rat erythrocytes 1 day after extreme physical exercise in a 4-week cycle of forced swimming. Of 16 analyzed parameters, the maximum number of significant shifts from the control was revealed in the groups of rats receiving ammonium chloride in doses of 20 and 10 mg/kg, and the minimal number of differences was found in groups treated with ammonium carbonate in the same doses. The comparison of the levels of reduced glutathione and 2.3-bisphosphoglicerate and activities of 5'-nucleotidase and Ca2+- and Na/K-ATPases attested to more rigorous control of the mechanism of oxygen delivery to tissues by erythrocytes after administration of ammonium chloride in a dose of 20 mg/kg.

Asunto(s)

Adaptación Fisiológica/efectos de los fármacos , Cloruro de Amonio/farmacología , Antioxidantes/farmacología , Carbonatos/farmacología , Eritrocitos/efectos de los fármacos , Esfuerzo Físico , 2,3-Difosfoglicerato/agonistas , 2,3-Difosfoglicerato/metabolismo , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , Adaptación Fisiológica/fisiología , Animales , ATPasas Transportadoras de Calcio/genética , ATPasas Transportadoras de Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Eritrocitos/citología , Eritrocitos/metabolismo , Expresión Génica/efectos de los fármacos , Glutatión/agonistas , Glutatión/metabolismo , Estrés Oxidativo/efectos de los fármacos , Condicionamiento Físico Animal , Ratas , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Natación

RESUMEN

We studied the role of calcium-regulating structures of slow- (m. soleus, SOL) and fast-twitch (m. extensor digitorum longus, EDL) skeletal muscles of rats during adaptation to exhausting physical activity and the possibility of modulating this adaptation with decaffeinated green tea extract. It was established that EDL adaptation is mainly aimed at Са2+ elimination from the sarcoplasm by Са-ATPase and its retention in the reticulum by calsequestrin. Administration of green tea extract increased endurance due to involvement of slow-twitch muscles whose adaptation is associated with enhanced expression of all the studied genes responsible for the regulation of Ca2+ balance.

Asunto(s)

Calcio/metabolismo , Fibras Musculares de Contracción Lenta/metabolismo , Extractos Vegetales/farmacología , Activación Transcripcional/efectos de los fármacos , Animales , Camellia sinensis/química , Evaluación Preclínica de Medicamentos , Masculino , Redes y Vías Metabólicas , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Condicionamiento Físico Animal , Ratas Wistar , Transcriptoma

RESUMEN

Hydrogen peroxide at concentrations below cytotoxic ones causes an increase in the cytoplasmic calcium concentration in human umbilical vein endothelial cells as a result of calcium release from intracellular stores. Two-pore calcium channel blocker trans-NED19 partially suppresses the increase in the level of calcium ions in the cells in response to the addition of hydrogen peroxide. The staining of endothelial cells with the fluorescent stereoisomer cis-NED19 and LysoTracker confirmed the localization of two-pore calcium channels in lysosomes and endolysosomal vesicles.

Asunto(s)

Canales de Calcio/metabolismo , Calcio/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Células Endoteliales de la Vena Umbilical Humana/citología , Peróxido de Hidrógeno/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Carbolinas/farmacología , Humanos , Piperazinas/farmacología , Porosidad

RESUMEN

The metabolic profile of plasma of white non-linear rats was investigated under normal conditions and after chronic inhalational exposure to low doses of aliphatic hydrocarbons with the number of carbon atoms from 6 to 10. Metabolic profile was determined with combination of gas chromatography-mass spectrometry and high performance, high resolution liquid chromatography-mass spectrometry with subsequent use of chemometrical methods for data treatment and presentation. It was shown that continuous 90-day exposure to a mixture of C6-C10 saturated hydrocarbons at concentration of 160 ± 20.5 mg/m³ results in various impairments of metabolic processes in liver and kidneys. Exposure to hydrocarbons at doses of 31.4 ± 5.6 mg/m³ and 5.2 ± 1.8 mg/m³ evoked significantly smaller changes. Novel metabolic markers of the toxic effect of low concentrations of C6-C10 aliphatic hydrocarbons were revealed. The ratio of concentrations of pyrophosphoric and oxalic acids in rat blood plasma was found to be the most sensitive marker called <>. A hypothesis is put forward about the redox balance violation as the leading pathogenetic mechanism of neuropathies and concomitant pathologies associated with hydrocarbon chronic intoxication.

Asunto(s)

Hidrocarburos Acíclicos/toxicidad , Riñón/metabolismo , Hígado/metabolismo , Metaboloma/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Riñón/patología , Hígado/patología , Oxidación-Reducción/efectos de los fármacos , Ratas

RESUMEN

The blocker of two-pore channels trans-NED 19 and hydrogen peroxide were found to inhibit histamine-induced relaxation of rat-aorta. The degree of inhibition depended on histamine concentration. The relaxation in response to I µM histamine of rat aorta preconstricted with 30 mM KCI, serotonin, or endothelin- 1, was completely abolished by 30 µM trans-NED 19. On the other hand, trans-NED 19 decreased the relaxation of the aorta in the presence of 10 µM histamine only by 2.1-fold to 2.4-fold, and there was almost no inhibition by trans-NED 19 of the relaxationinduced by 100 ptM histamine.) Relaxation of precontracted with serotonin aorta in response to 10 and 100 µM histamine was reduced by hydrogen peroxide (200 M) by 10- and 2.5-fold, respectively. Suppression of aorta relaxation by trans-NED 19 and H202 correlated with their inhibitory effect on the histamine-induced increase in the cytoplasmic free calcium concentration in human umbilical vein endothelial cells. With the use of a fluorescent probe LysoTracker, the cis-NED19 binding sites were demonstrated to be localized in endolysosomes of the endothelial cells. These data indicate that two-pore calcium channels participate in the histamine-induced endothelium-dependent relaxation of rat aorta. Furthermore, their functional role is exhibited much more clearly at low histamine concentrations. We suggest that hydrogen peroxide evokes depletion of intracellular calcium depots thereby suppressing the response to histamine.

Asunto(s)

Aorta/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Carbolinas/farmacología , Células Endoteliales/metabolismo , Peróxido de Hidrógeno/farmacología , Piperazinas/farmacología , Vasodilatación/efectos de los fármacos , Animales , Aorta/fisiopatología , Histamina/farmacología , Masculino , Ratas , Ratas Wistar

RESUMEN

Albumin molecule, unlike molecules of many other plasma proteins, is not covered with carbohydrate shell. It plays a crucial role in maintaining of colloid osmotic pressure of the blood, and is able to bind and transport various endogenous and exogenous molecules. The enzymatic activity of albumin, the existence and the role of which most researchers are still skeptical to accept, is of the main interest to us. In this review, a history of the issue is traced, with particular attention to the esterase activity of albumin. The kinetic and thermodynamic characteristics of the interaction of albumin with some substrates are adduced, and possibility of albumin being attributed to certain groups of Enzyme Nomenclature is considered.

Asunto(s)

Esterasas/química , Esterasas/metabolismo , Albúmina Sérica/química , Albúmina Sérica/metabolismo , Humanos , Cinética , Unión Proteica , Especificidad por Sustrato

RESUMEN

Oral administration of green tea extract in a dose of 6 mg/kg twice a day (before and after exercise) over 2 weeks significantly increased swimming times on week 1 and 2 in comparison with control animals receiving water. The 7-day and final exhaustive running in rats was accompanied by a significant decrease in spleen weight and iron serum levels associated with developed reticulocytosis. Administration of green tea extract in a dose of 12 mg/kg once a day (before exercise) for 2 weeks did not affect the duration of the running, but prevented the decrease in serum iron and spleen weight, that, along with a significantly increased concentration of reduced glutathione in erythrocytes, can indicate a normalizing effect of green tea extract on hemopoiesis and stimulating effect on the antioxidant system of erythrocytes.

Asunto(s)

Antioxidantes/farmacología , Condicionamiento Físico Animal , Extractos Vegetales/farmacología , Bazo/efectos de los fármacos , Animales , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Glutatión/sangre , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Reticulocitosis/efectos de los fármacos , Bazo/metabolismo , Té

RESUMEN

The ratio of early apoptosis and late apoptosis (necrosis) in the cultured human umbilical vein endothelial cells was estimated after exposure to hydrogen peroxide (H2O2) in vitro trying to keep them close to the physiological conditions (high cell density, high serum content, H2O2 concentration not over 500 µM). Cell viability was assessed using flow cytometry and simultaneous staining with fluorescent dyes PO-PRO-1 to detect early apoptotic cells, and DRAQ7 to detect late apoptotic and necrotic cells. The data obtained suggest that the primary mechanism of cytotoxic response is apoptosis. The critical concentration of H2O2 causing the death of the cell population in a dense monolayer is 250 µM. Lower concentrations of H2O2 (up to 200 µM) cause death of individual cells; however, viability of endothelial cell population is retained, and response to calcium activating agonists does not change compared with control cells.

Asunto(s)

Apoptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Necrosis/inducido químicamente , Antraciclinas , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptosis/genética , Benzoxazoles , Biomarcadores/metabolismo , Calcio/metabolismo , Agonistas de los Canales de Calcio/farmacología , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Factor VIII/genética , Factor VIII/metabolismo , Citometría de Flujo , Colorantes Fluorescentes , Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Indoles/farmacología , Necrosis/genética , Necrosis/metabolismo , Necrosis/patología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Tiofenos/farmacología

RESUMEN

Serotonin in cardiovascular system plays an important role in blood coagulation, allergy, and inflammation, as well as in blood vessel tone regulation. In this review, the mechanisms of serotonin effects upon the cells of blood vessels are considered and the list of main agonists and antagonists is presented. The signaling pathways activated by serotonin and their interaction in normal and pathological states are described.

Asunto(s)

Sistema Cardiovascular/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Transducción de Señal/fisiología , Animales

RESUMEN

Previously it was found that sodium fluoroacetate (SF) inhibited the growth of the Ehrlich cancer by means of monotherapy and enhanced the antitumor effect of cyclophosphamide (CP) in experiments with autochthonous subcutaneous tumors induced by benzo (a) pyrene. In this study a comparison of the antitumor activity of SF and metformin showed that both substances did not have significant effect in monotherapy but enhanced the effect of CP, increasing the percentage of tumors with the same or reduced volume. Besides, SF, unlike metformin increased the average duration of effect. The data obtained promoted further study of the mechanism of the antitumor effect of SF and the search effective combination with already known antitumor drugs.

Asunto(s)

Antineoplásicos/farmacología , Ciclofosfamida/farmacología , Fluoroacetatos/farmacología , Metformina/farmacología , Sarcoma Experimental/tratamiento farmacológico , Animales , Sinergismo Farmacológico , Ratones , Ratones Endogámicos , Factores de Tiempo

RESUMEN

It is known that albumin is able to cut ester bonds in organophosphates (OPs). Amino acids responsible for esterase and pseudo-esterase activity of albumin towards OPs are still not determined. The purpose of this study is to identify the potential sites of esterase activity of albumin by the example of its interaction with soman using molecular modeling methods. The structures of the protein complexes with soman was determined by molecular docking procedure, the stability of the complexes were simulated using molecular dynamics method. It has been determined that productive sorption of soman near Tyr411 is possible only after deprotonation of the tyrosine. Tyr150 binds soman more efficiently than Tyr411; deprotonation of Tyr150 does not affect the binding efficiency, but affects on the stability of the complexes. The true esterase activity of albumin Tyr150 in relation to soman is proposed. It is shown that Ser193 can also be responsible for the esterase activity of albumin. We hypothesize that deprotonation of catalytic amino acid in one of the sites could be initiated by ligand binding in other sites (allosteric regulation).

Asunto(s)

Esterasas/química , Modelos Moleculares , Albúmina Sérica/química , Soman/química , Sitios de Unión , Catálisis , Esterasas/metabolismo , Humanos , Cinética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Albúmina Sérica/metabolismo , Soman/toxicidad , Tirosina/química

RESUMEN

Effects of biogenic and abiogenic disulphides on viability of human umbilical vein endothelial cells in culture has been investigated using three methods: the neutral red uptake assay, quantification of intracellular ATP, and modifications of Mosmann method, the essence of which is the reduction of tetrazolium salts, MTT and MTS, by cells. 2,2'-dithio-bis(N,N-diethyl)ethanamine (DS) was used as an abiogenic disulphide. As for biogenic disulphides, we used GSSG and garlic oil (GO), the principal component of which is diallyl disulphide (DADS). It has been found that DS and GO have a similar cytotoxic effect upon the endothelial cells (EC50 - 0.6 mM). GSSG in concentrations up to 1 mM did not effect the viability of endothelial cells. It has been demonstrated for the first time that DS and GO can serve as mediators of plasma membrane oxidoreductase activity, tetrazolium salts being as the substrate; this may cause false-negative effect. Thus, the Mosmann method has serious limitations when testing the cytotoxicity of disulphides, though can be used in studying the mechanism of action of disulphides.

Asunto(s)

Compuestos Alílicos/farmacología , Artefactos , Membrana Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Sulfuros/farmacología , Adenosina Trifosfato/antagonistas & inhibidores , Adenosina Trifosfato/biosíntesis , Membrana Celular/química , Membrana Celular/enzimología , Supervivencia Celular/efectos de los fármacos , Dietilaminas/farmacología , Disulfuros/farmacología , Disulfuro de Glutatión/farmacología , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/enzimología , Humanos , Rojo Neutro/metabolismo , Oxidación-Reducción , Oxidorreductasas/metabolismo , Sales de Tetrazolio/metabolismo , Tiazoles/metabolismo

RESUMEN

The run of trained rats until exhaustion affected changes of red-ox balance in red blood cells (RBC) and deteriorated the acid stability of RBC. The oral administration of quercetin, 20 mg/kg, caused expansion of oxidative stress in RBC and a significant decrease in RBC acid stability. Pro-oxidant activity of quercetin could contribute accelerated intravascular hemolysis. It was accompanied by a significant reticulocytosis compared with a control group of rats no fed on antioxidant but exposed to run. Green tea extract (GTE) oral administration, 12 mg/kg, resulted in preventing oxidative stress in RBC, increasing in acid stability of RBC and reducing reticulocytosis. Thus, prooxidant activity of quercetin and the high antioxidant efficacy of GTE are indicative of the advantages of the complex preparations containing several antioxidant compounds. Such complex preparations may counteract an oxidative stress and save mechanical stability of erythrocytes under exhausted run.

Asunto(s)

Antioxidantes/farmacología , Camellia sinensis/química , Eritrocitos/efectos de los fármacos , Esfuerzo Físico , Extractos Vegetales/farmacología , Animales , Hemólisis , Masculino , Quercetina/toxicidad , Ratas , Ratas Wistar