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1.
Dokl Biochem Biophys ; 513(1): 319-323, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37700213

RESUMO

Previously, it was shown that the non-conventional toxin WTX from the venom of the cobra Naja kaouthia, when administered intravenously, caused a decrease in blood pressure (BP) and an increase in heart rate (HR) in rats [13]. To identify the site of the toxin molecule responsible for these effects, we studied the influence of synthetic peptide fragments of the WTX on BP and HR in normotensive male Sprague-Dawley rats under general anesthesia induced by Telazol and Xylazine. It was found that peptides corresponding to the WTX central polypeptide loop, stabilized by a disulfide bond, at intravenous injection at concentrations from 0.1 to 1.0 mg/mL caused a dose-dependent decrease in BP, with the HR increasing only in the first 5-10 min after administration. Thus, WTX fragments corresponding to the central polypeptide loop reproduce the decrease in blood pressure caused by the toxin.


Assuntos
Venenos Elapídicos , Peptídeos , Ratos , Masculino , Animais , Pressão Sanguínea , Sequência de Aminoácidos , Ratos Sprague-Dawley , Venenos Elapídicos/química , Venenos Elapídicos/farmacologia , Peptídeos/farmacologia , Anestesia Geral , Fragmentos de Peptídeos/farmacologia
3.
Dokl Biochem Biophys ; 503(1): 47-51, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35538277

RESUMO

The data available to date indicate that the activation of nicotinic acetylcholine receptors (nAChR) of α7 type can reduce heart damage resulting from ischemia and subsequent reperfusion. We have studied two new synthetic D-analogs of 6-bromohypaphorine, which are selective agonists of α7 nAChR, in a rat model of myocardial ischemia. Acute myocardial infarction in animals was induced by occlusion of the left coronary artery with its subsequent reperfusion under mechanical lung ventilation. It was found that one of the analogs was more active, and treatment with it at the onset of reperfusion statistically reduced infarct size. This analog also prevented changes in the concentration of potassium and sodium ions in the blood, occurring during occlusion/reperfusion injury. The data obtained indicate that hypaphorine analogs are promising for the development of drugs that reduce the adverse effects of myocardial infarction.


Assuntos
Traumatismos Cardíacos , Infarto do Miocárdio , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Receptores Nicotínicos , Animais , Infarto do Miocárdio/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Ratos , Reperfusão , Triptofano/análogos & derivados
4.
Dokl Biochem Biophys ; 503(1): 98-103, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35538287

RESUMO

To search for compounds with antiprotozoal activity, effects of snake venoms on the ciliates Tetrahymena pyriformis was studied. T. pyriformis from subkingdom of Protozoa, including the protozoal pathogens, was used as a model organism to select the venoms that are the most active against parasitic protozoans. Various concentrations of venoms were added to the cells, and the cells that survived after 24 h were counted. Among the six snake species from the Viperidae family, the venom of the viper Vipera berus, which completely killed the cells at 49 µg/mL, was the most active. Among four species from the Elapidae family, the previously studied cobra venoms containing cytotoxins with strong antiprotozoal activity as well as the venom of krait Bungarus multicinctus (10 µg/mL) were the most active. The venoms of the pit vipers and Nikolsky's viper did not show any activity at 12.5 mg/mL. Thus, the venoms of V. berus and B. multicinctus are promising for the isolation of new antiprotozoal compounds.


Assuntos
Tetrahymena pyriformis , Viperidae , Animais , Bungarus , Venenos Elapídicos , Elapidae , Venenos de Serpentes , Venenos de Víboras
5.
Biochimie ; 194: 127-136, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34979156

RESUMO

Оligoarginines were recently discovered (Lebedev et al., 2019 Nov) as a novel class of nicotinic acetylcholine receptors (nAChRs) inhibitors, octaoligoarginine R8 showing a relatively high affinity (44 nM) for the α9/α10 nAChR. Since the inhibition of α9/α10 nAChR by α-conotoxin RgIA and its analogs is a possible way to drugs against neuropathic pain, here in a mice model we compared R8 with α-conotoxin RgIA in the effects on the chemotherapy-induced peripheral neuropathy (CIPN), namely on the long-term oxaliplatin induced neuropathy. Tests of cold allodynia, hot plate, Von Frey and grip strength analysis revealed for R8 and α-conotoxin RgIA similar positive effects, expressed most prominently after two weeks of administration. Histological analysis of the dorsal root ganglia sections showed for R8 and RgIA a similar partial correction of changes in the nuclear morphology of neurons. Since α9/α10 nAChR might be not the only drug target for R8, we analyzed the R8 action on rat TRPV1 and TRPA1, well-known nociceptive receptors. Against rTRPV1 at 25 µM there was no inhibition, while for rTRPA1 IC50 was about 20 µM. Thus, involvement of rTRPA1 cannot be excluded, but in view of the R8 much higher affinity for α9/α10 nAChR the latter seems to be the main target and the easily synthesized R8 can be considered as a potential candidate for a drug design.


Assuntos
Conotoxinas , Neuralgia , Receptores Nicotínicos , Animais , Conotoxinas/farmacologia , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Oxaliplatina/toxicidade , Peptídeos , Ratos
6.
Dokl Biochem Biophys ; 507(1): 334-339, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36786997

RESUMO

The effects of extracts of ten plant species from Russia and five species from Vietnam on the growth and survival of ciliates Tetrahymena pyriformis were studied. T. pyriformis belongs to the subkingdom Protozoa, which also includes pathogens of protozoan infections. Extraction of dried plants was carried out with acidic and alkaline aqueous solutions, as well as with an aqueous ethanol. Various amounts of extracts were added to the ciliate cells, and the number of cells survived after incubation for 1 and 24 h was recorded. We found that our samples of several plants, including wormwood, harmala, and licorice, similarly to those studied earlier, exhibit antiprotozoal activity, which may indicate that the secondary metabolites are the same in plants from different regions. Using the ciliate T. pyriformis as a model organism, the presence of antiprotozoal activity in extracts of lilac, chondrilla, cinquefoil, hop, and elm was shown for the first time.


Assuntos
Antiprotozoários , Extratos Vegetais , Plantas , Federação Russa , Plantas/química , Antiprotozoários/química , Antiprotozoários/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Tetrahymena pyriformis/efeitos dos fármacos
7.
Dokl Biochem Biophys ; 491(1): 81-84, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32483757

RESUMO

Using electrophysiology, the effect of nicotinic acetylcholine receptor (nAChR) ligands on acetylcholine-induced depolarization in the neurons of Helix lucorum snail was studied. It was found that the α-conotoxin PnIA [R9, L10], a selective antagonist of α7 nAChR, and α-cobratoxin (antagonist of α7 and muscle-type nAChR) suppressed neuronal depolarization. Fluorescence microscopy showed staining of the neurons with fluorescently labeled α-bungarotoxin; this staining was reduced by pretreatment with α-cobratoxin. Induced depolarization was also suppressed by α-conotoxin RgIA, a selective inhibitor of α9 nAChR. In contrast to Lymnaea stagnalis nAChR, which are weakly sensitive to neurotoxin II and α-conotoxin GI, antagonists of muscle-type nAChR, H. lucorum receptors were most effectively inhibited by these antagonists. The results obtained, as well as the previously found sensitivity of the receptors studied in this work to muscarinic receptor ligands, indicate an unusual atypical pharmacological profile of H. lucorum nAChR.


Assuntos
Neurônios/metabolismo , Receptores Colinérgicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Acetilcolina/metabolismo , Animais , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bungarotoxinas/metabolismo , Caracois Helix , Ligantes , Microscopia Confocal , Microscopia de Fluorescência , Neurotoxinas/metabolismo , Piridinas/farmacologia , Transdução de Sinais
8.
Dokl Biochem Biophys ; 491(1): 89-92, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32483759

RESUMO

Blockade of α6, α3ß2, α9α10, and α7 subtypes of nicotinic acetylcholine receptors slows tumor growth in vivo, increases cytotoxic activity of splenocytes from tumor-bearing mice, and, to some extent, reduces the viability of Ehrlich carcinoma cells in vitro. These data indicate that nicotinic acetylcholine receptors are involved in oncogenesis, affecting the survival of tumor cells, inter alia, via modulation of the antitumor immunity.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Ehrlich/metabolismo , Antagonistas Nicotínicos/farmacologia , Baço/citologia , Animais , Antineoplásicos/química , Carcinogênese , Proliferação de Células , Sobrevivência Celular , Conotoxinas/metabolismo , Camundongos , Transplante de Neoplasias , Antagonistas Nicotínicos/química , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores
9.
Dokl Biochem Biophys ; 491(1): 93-97, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32483760

RESUMO

The antioxidant activity and protective effect in the toxicity model of H2O2 were studied for arachidonic (AA-CHOL), docosahexaenoic (DHA-CHOL), linoleic (Ln-CHOL), and oleic (Ol-CHOL) fatty acids, as well as arachidonoyl dicholine (AA-diCHOL) and O-arachidonoyl bistetramethylaminoisopropanol (ABTAP). AA-CHOL, DHA-CHOL and Ln-CHOL provided a 20% increase in cell survival. AA-CHOL, AA-diCHOL, Ol-CHOL, and ABTAP had a radical-scavenging effect in the ABTS test, approximately equal to the activity of a standard radical scavenger Trolox.


Assuntos
Antioxidantes/química , Ácidos Araquidônicos/química , Colina/química , 2-Propanol/química , Ácido Araquidônico/química , Linhagem Celular Tumoral , Cromanos/química , Ácidos Docosa-Hexaenoicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Ácidos Graxos , Radicais Livres/química , Humanos , Peróxido de Hidrogênio/química , Ácido Linoleico/química , Ácido Oleico/química
10.
Dokl Biochem Biophys ; 488(1): 338-341, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31768855

RESUMO

Four dimeric disintegrins were isolated from the venom of the steppe viper V. ursinii using liquid chromatography. Disintegrins prevented adhesion of MCF7 cells to fibronectin, which indicates their interaction with integrin receptors of the αVß1 type. According to mass spectrometry data, the molar masses of disintegrins are about 14 kDa. The method of peptide mapping established the structure of a new heterodimeric disintegrin weighing 13 995.5 Da and shows that it belongs to the class of RGD/KGD-containing disintegrins.


Assuntos
Desintegrinas/química , Multimerização Proteica , Proteínas de Répteis/química , Venenos de Víboras/química , Viperidae , Animais , Desintegrinas/farmacologia , Humanos , Células MCF-7 , Receptores de Vitronectina/metabolismo , Proteínas de Répteis/farmacologia , Venenos de Víboras/farmacologia
11.
Dokl Biochem Biophys ; 487(1): 251-255, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31559591

RESUMO

Three-finger snake neurotoxins are selective antagonists of some nicotinic acetylcholine receptor subtypes and are widely used to study these receptors. The peptide neurotoxin azemiopsin, recently isolated from the venom of Azemipos feae, is a selective blocker of muscle-type nicotinic acetylcholine receptor. In order to reduce their toxicity and increase resistance under physiological conditions, we have encapsulated these toxins into nanomaterials. The study of nanomaterials after interaction with neurotoxins by the methods of transmission electron microscopy and dynamic light scattering revealed an increase in the size of nanoparticles, which indicates the inclusion of neurotoxins in nanomaterials.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Neurotoxinas/química , Antagonistas Nicotínicos/química , Polissacarídeos/química , Receptores Nicotínicos/metabolismo , Sulfatos/química , Cápsulas , Neurotoxinas/toxicidade , Antagonistas Nicotínicos/toxicidade , Tamanho da Partícula , Venenos de Serpentes/química
12.
Dokl Biochem Biophys ; 487(1): 282-286, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31559598

RESUMO

The study of the influence of cobra Naja oxiana cardiotoxins on the contractility of the rat papillary muscles and its rhythmoinotropic characteristics has shown that the presence of toxins induces a slight contractility decrease in the stimulation frequency range up to 0.1 Hz. In the stimulation frequency range from 0.1 to 0.5 Hz, a positive inotropic effect is found. However, the positive inotropic effect is replaced by a negative one with further increase in the frequency up to 3 Hz. In the presence of cardiotoxins, the positive force-frequency relationship in the region of 1-3 Hz, characteristic of healthy rat myocardium, disappears and the relationship becomes completely negative. L-type calcium channel blocker nifedipine does not affect the changes induced by toxins, while a high concentration (10 mM) of calcium prevents the effects of cardiotoxins on the muscle. The results obtained show that the impairment of the force-frequency relationship occurs long before the development of irreversible damage in the myocardium and may be the first sign of the pathological action of cardiotoxins.


Assuntos
Proteínas Cardiotóxicas de Elapídeos/farmacologia , Coração/efeitos dos fármacos , Coração/fisiologia , Contração Miocárdica/efeitos dos fármacos , Naja naja , Animais , Relação Dose-Resposta a Droga , Ratos
13.
Dokl Biochem Biophys ; 479(1): 127-130, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29779115

RESUMO

Genes encoding two three-finger toxins TFT-AF and TFT-VN, nucleotide sequences of which were earlier determined by cloning cDNA from venom glands of vipers Azemiops feae and Vipera nikolskii, respectively, were expressed for the first time in E. coli cells. The biological activity of these toxins was studied by electrophysiological techniques, calcium imaging, and radioligand analysis. It was shown for the first time that viper three-finger toxins are antagonists of nicotinic acetylcholine receptors of neuronal and muscle type.


Assuntos
Músculos/metabolismo , Neurônios/metabolismo , Receptores Nicotínicos/metabolismo , Proteínas Recombinantes/metabolismo , Toxinas Biológicas/metabolismo , Viperidae/genética , Animais , Sinalização do Cálcio , Linhagem Celular Tumoral , Humanos , Músculos/citologia , Neurônios/citologia , Proteínas Recombinantes/genética , Toxinas Biológicas/genética
14.
Dokl Biochem Biophys ; 483(1): 313-315, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30607728

RESUMO

Arginine-containing peptides R3, R8, and R16 were obtained by solid-phase peptide synthesis, and their binding to nicotinic acetylcholine receptors (nAChRs) of muscle and neuronal (α7) types was studied by competitive radioligand assay with the use of 125I-α-bungarotoxin. The resulting peptides exhibited a significantly greater binding activity with respect to the muscle-type nAChRs than to the α7 receptor. Thus, we have discovered a new class of nAChR ligands. The affinity of the synthesized oligoarginines for nAChR depended on the number of amino acid residues in the chain. The highest affinity was exhibited by the R16 peptide, which contained 16 arginine residues.


Assuntos
Peptídeos , Receptor Nicotínico de Acetilcolina alfa7/química , Animais , Ligantes , Peptídeos/síntese química , Peptídeos/química , Torpedo
15.
Dokl Biochem Biophys ; 476(1): 316-319, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29101740

RESUMO

Low-molecular-weight compounds with anticoagulant activity were isolated from the scorpion Heterometrus laoticus venom. The determination of the structure of the isolated compounds by nuclear magnetic resonance and mass spectrometry showed that one of the isolated compounds is adenosine, and the other two are dipeptides leucyl-tryptophan and isoleucyl-tryptophan. The anticoagulant properties of adenosine, which is an inhibitor of platelet aggregation, is well known, but its presence in scorpion venom is shown for the first time. The ability of leucyl-tryptophan and isoleucyl-tryptophan to slow down blood clotting and their presence in scorpion venom are also established for the first time.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Venenos de Escorpião/química , Escorpiões , Animais , Camundongos , Peso Molecular
16.
Dokl Biochem Biophys ; 475(1): 264-266, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28864897

RESUMO

A new three-finger toxin nakoroxin was isolated from the cobra Naja kaouthia venom, and its complete amino acid sequence was established. Nakoroxin belongs to the group of "orphan" toxins, data on the biological activity of which are practically absent. Nakoroxin shows no cytotoxicity and does not inhibit the binding of α-bungarotoxin to nicotinic acetylcholine receptors of muscle and α7 types. However, it potentiates the binding of α-bungarotoxin to the acetylcholine-binding protein from Lymnaea stagnalis. This is the first toxin with such an unusual property.


Assuntos
Venenos Elapídicos/química , Toxinas Biológicas/química , Toxinas Biológicas/isolamento & purificação , Sequência de Aminoácidos , Toxinas Biológicas/metabolismo
17.
Dokl Biochem Biophys ; 475(1): 253-255, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28864899

RESUMO

Fluorescent derivatives are widely used to study the structure and functions of proteins. Quantum dots (QDs), fluorescent semiconductor nanocrystals, have a high quantum yield and are much more resistant to bleaching compared to organic dyes. Conjugates of α-neurotoxins with QDs were used for visualization of human α7 acetylcholine receptors heterologously expressed in GH4C1 pituitary adenoma cells. Specific staining of cells by the conjugated toxins was observed.


Assuntos
Neurotoxinas/química , Neurotoxinas/metabolismo , Pontos Quânticos/química , Venenos de Serpentes/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Linhagem Celular Tumoral , Humanos , Imagem Molecular
18.
Biomed Khim ; 63(3): 241-247, 2017 May.
Artigo em Russo | MEDLINE | ID: mdl-28781257

RESUMO

A role of nicotinic acetylcholine receptors (nAChR) in the development of Parkinson's disease (PD) has been investigated using two mouse models corresponding to the presymptomatic stage and the early symptomatic stage of PD. Quantitative determination of nAChR in the striatum and substantia nigra (SN) was performed using the radioactive derivatives of epibatidine, -conotoxin MII, and -bungarotoxin as ligands. The number of ligand-binding sites changed differently depending on their location in the brain, the stage of the disease and the receptor subtype. Epibatidine binding decreased in the striatum to 66% and 70% at the presymptomatic and early symptomatic stages, respectively, whereas in SN a 160% increase was registered at the presymptomatic stage. The -conotoxin MII binding on striatal dopaminergic axonal terminals at the presymptomatic stage decreased by 20% and at the symptomatic stage it demonstrated a further decrease. The increase in -bungarotoxin binding at the presymptomatic stage and a decrease at the early symptomatic stage was observed in the striatum. In SN, the level of -bungarotoxin binding decreased at the presymptomatic stage and kept constant at the symptomatic stage. The significant decrease in the expression of Chrna4 and Chrna6 genes encoding 4 and 6 nAChR subunits was observed in SN at the early symptomatic stage, while a 13-fold increase in expression of the Chrna7 gene encoding the 7 nAChR subunit was detected at the presymptomatic stage. The data obtained suggest possible involvement of nAChR in compensatory mechanisms at early PD stages.


Assuntos
Corpo Estriado/metabolismo , Doença de Parkinson Secundária/genética , Receptores Nicotínicos/genética , Substância Negra/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/genética , Animais , Doenças Assintomáticas , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bungarotoxinas/farmacologia , Conotoxinas/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Ligantes , Camundongos , Agonistas Nicotínicos/farmacologia , Especificidade de Órgãos , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/fisiopatologia , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Piridinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Nicotínicos/metabolismo , Transdução de Sinais , Substância Negra/efeitos dos fármacos , Substância Negra/fisiopatologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
19.
Dokl Biochem Biophys ; 474(1): 178-182, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28726106

RESUMO

Compounds activating γ-aminobutyric acid type A receptor were isolated from the toad Bufo bufo venom as a result of chromatographic separation. Analysis of the structure of these compounds by mass spectrometry and nuclear magnetic resonance showed that they are arginine derivatives of dicarboxylic acids and represent suberylarginine, pimeloylarginine, and adipoylarginine.


Assuntos
Arginina/química , Bufo bufo , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacologia , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/farmacologia , Glândula Parótida/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ácidos Dicarboxílicos/metabolismo , Agonistas de Receptores de GABA-A/metabolismo , Células HEK293 , Humanos , Ligantes
20.
Dokl Biochem Biophys ; 472(1): 52-55, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28421441

RESUMO

Two low-molecular-weight compounds were isolated from the parotid gland secret of the toad Bufo bufo, which by absorption spectra and HPLC-MS/MS chromatography data correspond to di- and trimethyl derivatives of serotonin (5-hydorxytryptamine): bufotenine (confirmed by counter synthesis) and bufotenidine (5-HTQ). In experiments on competitive radioligand binding, these compounds showed a higher affinity and selectivity for neuronal α7 nicotinic acetylcholine receptors compared with the muscular cholinergic receptors. The most efficient compound in terms of binding value was bufotenine, the efficiency of 5-HTQ was an order of magnitude lower, and the minimal activity was exhibited by serotonin.


Assuntos
Venenos de Anfíbios/farmacologia , Serotonina/análogos & derivados , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Venenos de Anfíbios/química , Animais , Bufo bufo , Linhagem Celular , Ligantes , Ligação Proteica , Ratos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos
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