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1.
Biochemistry (Mosc) ; 74(2): 130-6, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19267667

RESUMEN

Pifithrin alpha (PFTalpha), one of the first known low molecular weight modulators of activity of tumor suppressor p53, increases survival of hemopoietic clonogenic cells (evaluated by the criterion of formation of endogenous spleen CFU-C8 colonies in irradiated animals). This effect appeared when PFTalpha was administered either before or after irradiation. Increase in CFU-C8 was also observed after administration of two PFTalpha analogs, derivatives of 2-amino-4,5,6,7-tetrahydrobenzothiazole. These included a parent compound, 2-ATBT (2-amino-4,5,6,7-tetrahydrobenzothiazole), which is used for synthesis of PFTalpha, and a product of its intramolecular cyclization under physiological conditions, cyclo-PFT (2-(4-methylphenyl)imidazo[2,1-b]-5,6,7,8-tetrahydrobenzothiazole). Earlier we found that many low molecular weight compounds increasing number of CFU-C8 (e.g. isothiourea derivatives) demonstrate NO inhibitory activity. Such activity was also found in 2-ATBT and cyclo-PFT by means of EPR spectroscopy of NO. These compounds caused more than twofold inhibition of NO production in vivo. Thus, it has been demonstrated that PFTalpha and its structural analogs increase survival of hemopoietic clonogenic cells in vivo, and NO may play a role in the mechanism of this effect.


Asunto(s)
Benzotiazoles/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Imidazoles/farmacología , Óxido Nítrico/fisiología , Protectores contra Radiación/farmacología , Tolueno/análogos & derivados , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Benzotiazoles/síntesis química , Benzotiazoles/química , Supervivencia Celular/efectos de los fármacos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de la radiación , Imidazoles/síntesis química , Imidazoles/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Óxido Nítrico/biosíntesis , Protectores contra Radiación/síntesis química , Protectores contra Radiación/química , Bazo/citología , Bazo/efectos de los fármacos , Bazo/efectos de la radiación , Relación Estructura-Actividad , Tolueno/síntesis química , Tolueno/química , Tolueno/farmacología
2.
Bull Exp Biol Med ; 145(4): 460-3, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19110594

RESUMEN

The effects of gram-positive bacterial strains (Lactobacillus acidophilus and Lactobacillus rhamnosus) and their subcellular components on the survival of hemopoietic clonogenic cells were evaluated by the formation of endogenous splenic colonies. The effects of these preparations on NO production were studied by the spin-trap paramagnetic resonance spectroscopy. Bacterial preparations from gram-positive bacteria stimulated survival of hemopoietic clonogenic cells, but did not induce NO production in contrast to E. coli LPS.


Asunto(s)
Bacterias Grampositivas/fisiología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/fisiología , Lipopolisacáridos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Bacterias Grampositivas/química , Bacterias Grampositivas/citología , Células Madre Hematopoyéticas/microbiología , Lactobacillus acidophilus/química , Lactobacillus acidophilus/citología , Lactobacillus acidophilus/fisiología , Lacticaseibacillus rhamnosus/química , Lacticaseibacillus rhamnosus/citología , Lacticaseibacillus rhamnosus/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Fracciones Subcelulares/fisiología
3.
Bull Exp Biol Med ; 146(4): 540-2, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19489337

RESUMEN

In vivo experimental studies showed that 1,2-dimethylhydrazine and product of its metabolism in the body azoximethane improve postradiation survival of two types of stem cells in the adult organism: hemopoietic stem cells and intestinal epithelial stem cells. This effect similar to the well-known radioprotective effect of E. coli lipopolysaccharide was observed, when the carcinogen was administered 1 day before gamma-irradiation. Treatment with 1,2-dimethylhydrazine prolonged the mean life-span of mice irradiated in supralethal doses inducing death of the majority of intestinal epithelial stem cells. Nonspecific cyclooxygenase inhibitor indometacin weakened this radioprotective effect of 1,2-dimethylhydrazine. We also found that carcinogen 1,2-dimethylhydrazine improved survival of hemopoietic stem cells. However, in contrast to intestinal epithelial stem cells, indometacin did not inhibit the radioprotective effect of the carcinogen. The radioprotective effect of 1,2-dimethylhydrazine and lipopolysaccharide on stem cells in the presence of indometacin was a sum of individual effects of these preparations and indometacin.


Asunto(s)
1,2-Dimetilhidrazina/farmacología , Células de la Médula Ósea/citología , Carcinógenos/farmacología , Supervivencia Celular/efectos de los fármacos , Mucosa Intestinal/citología , Prostaglandina-Endoperóxido Sintasas/fisiología , Células Madre/efectos de los fármacos , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Inhibidores de la Ciclooxigenasa/farmacología , Rayos gamma , Técnicas In Vitro , Indometacina/farmacología , Ratones , Prostaglandina-Endoperóxido Sintasas/metabolismo , Células Madre/citología , Células Madre/efectos de la radiación
4.
Biochemistry (Mosc) ; 70(1): 8-23, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15701046

RESUMEN

Synthesis of compounds containing a fragment similar to the guanidine group of L-arginine, which is a substrate of nitric oxide synthase (NOS), is the main direction in creating NOS inhibitors. The inhibitory effect of such compounds is caused not only by their competition with the substrate for the L-arginine-binding site and/or oxidizing center of the enzyme (heme) but also by interaction with peptide motifs of the enzyme that influence its dimerization, affinity for cofactors, and interaction with associated proteins. Structures, activities, and relative in vitro and in vivo specificities of various NOS inhibitors (amino acid and non-amino acid) with linear or cyclic structure and containing guanidine, amidine, or isothiuronium group are considered. These properties are mainly analyzed by comparison with effects of the inhibitors on the inducible NOS.


Asunto(s)
Arginina/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Sitios de Unión , Coenzimas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Isoenzimas , Óxido Nítrico Sintasa/química , Óxido Nítrico Sintasa/metabolismo , Relación Estructura-Actividad
5.
Biochemistry (Mosc) ; 70(12): 1310-20, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16417452

RESUMEN

A complex of reactions regulating the number of cells in organs and tissues under normal and pathologic conditions is one of the most important systems of multicellular organisms. In this system, which controls both cell proliferation and clearance, clearance has been given special attention during the last three decades. Some stages of the clearance are known (the choice of "unwanted" cells, their destruction not affecting the surrounding tissue, and, finally, removal of the corpses), and undeniable progress has been achieved in the understanding of the second stage mechanisms, whereas mechanisms of elimination per se of cells or their fragments still continue to be terra incognita. The clearance of such cells is mainly determined by different components of natural and adaptive immunity: phagocytes, complement, opsonins, antigen-presenting cells, etc. Recently specific "danger signals", such as hydrolases, DNA, heat shock proteins, and other potential immunogens released by cells during their elimination have been discovered. Entering the extracellular space, these signals induce inflammation and injury of the surrounding tissues, i.e., autoimmune reactions. Heat shock proteins, in addition to chaperon activity, act as signaling, costimulating, and antigen-carrying molecules in the interactions of dying cells and the immune system.


Asunto(s)
Apoptosis/inmunología , Necrosis/inmunología , Animales , Factores de Coagulación Sanguínea/fisiología , Caenorhabditis elegans , Proteínas de Choque Térmico/fisiología , Humanos , Mediadores de Inflamación/fisiología , Fagocitosis , Receptores de Superficie Celular/fisiología , Transducción de Señal
6.
Bull Exp Biol Med ; 138(4): 397-400, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15665955

RESUMEN

We studied the effect of NO synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine (2-ADT) on the cardiovascular system in rats with endotoxic shock. Blood pressure, heart rate, and respiratory rate were recorded. E. coli lipopolysaccharide decreased blood pressure and heart rate. 2-ADT in a dose of 5 mg/kg normalized these hemodynamic parameters. The normalizing effect of 2-ADT decreased with increasing the dose of this preparation. 2-ADT in high doses (10, 20, and 30 mg/kg) and repeated injections of the preparation caused death of experimental animals.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Hemodinámica/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Respiración/efectos de los fármacos , Choque Séptico/tratamiento farmacológico , Tiazinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Endotoxinas/toxicidad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Ratas , Ratas Wistar , Choque Séptico/fisiopatología , Tiazinas/administración & dosificación , Tiazinas/toxicidad
7.
Biochemistry (Mosc) ; 67(4): 387-408, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11996653

RESUMEN

In all studies on programmed cell death (PCD) and apoptosis as its most showy form, this process was considered to be a paradigmatic antithesis to necrotic cell death. On one hand, a concept on necrosis as a cellular cataclysm, an uncontrolled and passive phenomenon, had been provoked by an enormous bulk of experimental data on its inducibility by superphysiological exposures. On the other hand, much attention was attracted to a rapidly expanding (from nematodes) field of genetic studies on PCD. However, the findings accumulated which suggested a likeness rather than the opposition of the necrotic and apoptotic forms of elimination of "unwanted" cells. 1. Very diverse pathophysiological exposures (stimuli, stresses), such as heat, ionizing radiation, pathogens, cytokines cause both forms of cell death in the same cell population. 2. Anti-apoptotic mechanisms (e.g., Bcl-2) can protect cells from both necrotic and apoptotic destruction. 3. Biochemical interventions (e.g., with inhibitors of poly-(ADP-riboso)-polymerase) into the signal and executive mechanisms of PCD can change the choice of the cell death form. 4. During both necrosis and epigenetic programs of apoptotic cell death that need no macromolecular synthesis (e.g., the CD95-dependent death), the nucleus plays a passive role. Therefore, necrosis, similarly to apoptosis, is suggested to be a form of the programmed cell death. However, for the whole body the physiological consequences of apoptosis and necrosis are quite different. In the case of apoptosis, all constituents of the nucleus and cytoplasm are isolated by an undamaged membrane and then by phagocytes together with the membrane-bound "eat me" markers (phosphatidylserine, etc.). In other words, the elimination of the cell which has realized its apoptotic program remains virtually unnoticed by the body. In the case of necrosis, the cytoplasmic content released into the intercellular space provokes an inflammatory response, i.e., an activation of resident phagocytes and attraction of leukocytes into the necrosis zone. It is suggested that under pathophysiological conditions, the necrotic cell destruction should amplify and catalyze pathological processes. The experimental data available now suggest that a disturbance in the body of optimal balance between the necrotic and apoptotic forms of PCD should be a crucial factor in the development of various pathophysiological processes associated with inflammation (diabetes, arthritis) or with aging (atherosclerosis, neurodegenerative diseases).


Asunto(s)
Necrosis , Animales , Apoptosis/fisiología , Membrana Celular/fisiología , Humanos , Inflamación/patología , Isquemia/patología , Neoplasias/patología , Enfermedades Neurodegenerativas/patología
8.
Bull Exp Biol Med ; 134(4): 338-41, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12533753

RESUMEN

Using the method of electron paramagnetic spectroscopy we demonstrated that thiazine-thiazoline compounds and aminoethyl isothiourea containing the thioamidine group inhibit NO production in the liver of endotoxin-treated mice. Injection of these agents to anesthetized rats increased arterial pressure and enhanced respiration rate. This effect probably reflects inhibition of not only inducible, but also the constitutive synthesis of NO by compounds with thioamidine group.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Óxido Nítrico/antagonistas & inhibidores , Tiazinas/farmacología , Tiazoles/farmacología , Vasoconstrictores/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Endotoxinas , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Wistar , Respiración/efectos de los fármacos , Especificidad de la Especie
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