RESUMO
Erectile dysfunction (ED) mechanisms in diabetic patients are multifactorial and often lead to resistance to current therapy. Animal toxins have been used as pharmacological tools to study penile erection. Human accidents involving the venom of Phoneutria nigriventer spider are characterized by priapism. We hypothesize that PnTx2-6 potentiates cavernosal relaxation in diabetic mice by increasing cyclic guanosine monophosphate (cGMP). This effect is neuronal nitric oxide synthase (nNOS) dependent. Cavernosal strips were contracted with phenylephrine (10(-5) M) and relaxed by electrical field stimulation (20 V, 1-32 Hz) in the presence or absence of PnTx2-6 (10(-8) M). Cavernosal strips from nNOS- and endothelial nitric oxide synthase (eNOS)-knockout (KO) mice, besides nNOS inhibitor (10(-5) M), were used to evaluate the role of this enzyme in the potentiation effect evoked by PnTx2-6. Tissue cGMP levels were determined after stimulation with PnTx2-6 in presence or absence of N-nitro-L-arginine methyl ester (L-NAME) (10(-4) M) and ω-conotoxin GVIA (10(-6) M), an N-type calcium channel inhibitor. Results showed that PnTx2-6 enhanced cavernosal relaxation in diabetic mice (65%) and eNOS KO mice, but not in nNOS KO mice. The toxin effect in the cavernosal relaxation was abolished by nNOS inhibitor. cGMP levels are increased by PnTx2-6, however, L-NAME abolished this enhancement as well as ω-conotoxin GVIA. We conclude that PnTx2-6 facilitates penile relaxation in diabetic mice through a mechanism dependent on nNOS, probably via increasing nitric oxide/cGMP production.
Assuntos
Diabetes Mellitus Experimental/complicações , Disfunção Erétil/tratamento farmacológico , Óxido Nítrico Sintase Tipo I/metabolismo , Pênis/efeitos dos fármacos , Peptídeos/uso terapêutico , Venenos de Aranha/uso terapêutico , Animais , GMP Cíclico/metabolismo , Avaliação Pré-Clínica de Medicamentos , Disfunção Erétil/complicações , Disfunção Erétil/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Venenos de Aranha/farmacologia , ômega-Conotoxina GVIARESUMO
The search for new active drugs that can alleviate or cure different diseases is a constant challenge to researchers in the biological area and to the pharmaceutical industry. Historically, research has focused on the study of substances from plants. More recently, however, animal venoms have been attracting attention and studies have been successful in addressing treatment of accidents. Furthermore, venoms and their toxins have been considered good tools for prospecting for new active drugs or models for new therapeutic drugs. In this review, we discuss some possibilities of using different toxins, especially those from arachnid venoms, which have shown some potential application in diseases involving pain, hypertension, epilepsy and erectile dysfunction. A new generation of drugs is likely to emerge from peptides, including those found in animal venoms.(AU)
Assuntos
Venenos de Aranha/uso terapêutico , Peptídeos/uso terapêutico , Epilepsia , Dor , Hipertensão , Disfunção ErétilRESUMO
The search for new active drugs that can alleviate or cure different diseases is a constant challenge to researchers in the biological area and to the pharmaceutical industry. Historically, research has focused on the study of substances from plants. More recently, however, animal venoms have been attracting attention and studies have been successful in addressing treatment of accidents. Furthermore, venoms and their toxins have been considered good tools for prospecting for new active drugs or models for new therapeutic drugs. In this review, we discuss some possibilities of using different toxins, especially those from arachnid venoms, which have shown some potential application in diseases involving pain, hypertension, epilepsy and erectile dysfunction. A new generation of drugs is likely to emerge from peptides, including those found in animal venoms.
Assuntos
Peptídeos/uso terapêutico , Venenos de Aranha/uso terapêutico , Epilepsia , Disfunção Erétil , Hipertensão , DorRESUMO
The use of plants as medicine has been referred to since ancient peoples, perhaps as early as Neanderthal man. Plants are a source of many biologically active products and nowadays they are of great interest to the pharmaceutical industry. The study of how people of different culture use plants in particular ways has led to the discovery of important new medicines. In this work, we verify the possible activity of Musa paradisiaca L. (Musaceae) against the toxicity of snake venoms. Musa paradisiaca, an important source of food in the world, has also been reported to be popularly used as an anti-venom. Interaction of Musa paradisiaca extract (MsE) with snake venom proteins has been examined in this study. Phospholipase A2 (PLA2), myotoxic and hemorrhagic activities, including lethality in mice, induced by crotalidae venoms were significantly inhibited when different amounts of MsE were mixed with these venoms before assays. On the other hand, mice that received MsE and venoms without previous mixture or by separated routes were not protected against venom toxicity. Partial chemical characterization of MsE showed the presence of polyphenols and tannins and they are known to non-specifically inactivate proteins. We suggest that these compounds can be responsible for the in vitro inhibition of the toxic effects of snake venoms. In conclusion, according to our results, using mice as experimental model, MsE does not show protection against the toxic effects of snake venoms in vivo, but if was very effective when the experiments were done in vitro.
Assuntos
Venenos de Crotalídeos/antagonistas & inibidores , Hemorragia/prevenção & controle , Musa/metabolismo , Músculo Esquelético/efeitos dos fármacos , Fosfolipases A/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Venenos de Crotalídeos/química , Venenos de Crotalídeos/toxicidade , Avaliação Pré-Clínica de Medicamentos/métodos , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Frutas/metabolismo , Hemorragia/induzido quimicamente , Masculino , Camundongos , Musa/química , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Neurotoxinas/efeitos adversos , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/química , Fenóis/química , Fenóis/farmacologia , Fosfolipases A/efeitos adversos , Fosfolipases A2 , Extratos Vegetais/química , Plantas Medicinais , Polifenóis , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Taninos/química , Taninos/farmacologiaRESUMO
Casearia sylvestris (Flacourtiaceae) is a plant which grows in the wild. The crude extract and pure substances from this plant induced partial inhibition of the PLA: (phospholipase A2) activity of snake venoms and some purified toxins. C. sylvestris extract efficiently neutralized the hemorrhagic and myotoxic activities caused by crude venoms and toxins.
Assuntos
Casearia/química , Inibidores Enzimáticos/farmacologia , Fosfolipases A/antagonistas & inibidores , Animais , Brasil , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Doenças Musculares/induzido quimicamente , Doenças Musculares/prevenção & controle , Fosfolipases A2 , Extratos Vegetais/farmacologia , Venenos de Serpentes/antagonistas & inibidores , Venenos de Serpentes/enzimologia , Venenos de Serpentes/toxicidadeRESUMO
The authors report a case of a 39-year-old woman with dextrocardia and situs inversus who presented with episodes of complete heart block, managed successfully with a permanent dual chamber endocardial pacemaker.
Assuntos
Dextrocardia/complicações , Bloqueio Cardíaco/complicações , Adulto , Eletrocardiografia , Feminino , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/diagnóstico por imagem , Humanos , Situs Inversus/complicações , UltrassonografiaRESUMO
Aqueous extract from Casearia sylvestris leaves, a typical plant from Brazilian open pastures, was able to neutralize the hemorrhagic activity caused by Bothrops asper, Bothrops jararacussu, Bothrops moojeni, Bothrops neuwiedi and Bothrops pirajai venoms. It also neutralized two hemorrhagic metalloproteinases from Bothrops asper venom. Proteolytic activity on casein induced by bothropic venoms and by isolated proteases, including Bn2 metalloproteinase from B. neuwiedi venom, was also inhibited by the C. sylvestris extract in different levels. The alpha-fibrinogen chain was partially protected against degradation caused by B. jararacussu venom, when this venom was incubated with C. sylvestris extract. We also observed that this extract partially increased the time of plasma coagulation caused by B. jararacussu, B. moojeni and B. neuwiedi venoms. C. sylvestris extract did not induce proteolysis in any substrate assayed.
Assuntos
Bothrops/fisiologia , Venenos de Crotalídeos/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Extratos Vegetais/farmacologia , Animais , Caseínas/metabolismo , Venenos de Crotalídeos/enzimologia , Fibrinogênio/metabolismo , Fibrinólise/efeitos dos fármacos , Hemorragia/patologia , Hemorragia/prevenção & controle , Metaloendopeptidases/metabolismo , Dermatopatias/patologia , Dermatopatias/prevenção & controleRESUMO
The crude aqueous extract from the leaves of Casearia sylvestris, a plant found in Brazilian open pastures, was assayed for its ability to inhibit phospholipase A2 (PLA2) activity and some biological activities of bee and several snake venoms, and of a number of isolated PLA2s. The extract induced partial inhibition of the PLA2 activity of venoms containing class I, II and III PLA2s. When tested against the purified toxins, it showed the highest efficacy against class II PLA2s from viperid venoms, being relatively ineffective against the class I PLA2 pseudexin. In addition, C. sylvestris extract significantly inhibited the myotoxic activity of four Bothrops crude venoms and nine purified myotoxic PLA2s, including Lys-49 and Asp-49 variants. The extract was able to inhibit the anticoagulant activity of several isolated PLA2s, with the exception of pseudexin. Moreover, it partially reduced the edema-inducing activity of B. moojeni and B. jararacussu venoms, as well as of myotoxins MjTX-II and BthTX-I. The extract also prolonged the survival time of mice injected with lethal doses of several snake venoms and neutralized the lethal effect induced by several purified PLA2 myotoxins. It is concluded that C. sylvestris constitutes a rich source of PLA2 inhibitors.
Assuntos
Antitoxinas/farmacologia , Venenos de Abelha/metabolismo , Fosfolipases A/antagonistas & inibidores , Fosfolipases A/metabolismo , Extratos Vegetais/farmacologia , Rosales/química , Venenos de Serpentes/metabolismo , Animais , Anticoagulantes/farmacologia , Venenos de Abelha/antagonistas & inibidores , Venenos de Crotalídeos/metabolismo , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Eletroforese em Gel de Poliacrilamida , Masculino , Camundongos , Fosfolipases A2 , Venenos de Serpentes/antagonistas & inibidores , Fatores de TempoRESUMO
A basic serine protease which is active on casein and fibrinogen was purified from Bothrops moojeni venom using a single step chromatography on a CM-Sepharose fast flow column. The enzyme, MOO3, was not hemorrhagic and presented only a trace of blood-clotting activity. Synthetic chromogenic substrates (azoacasein and azoalbumin) where not hydrolyzed by MOO3. Using polyacrylamide gel electrophoresis at pH 4.3, MOO3 showed as a single protein band. Using sodium dodecyl sulfate-polyacrylamide electrophoresis, MOO3 behaved as a single-chain protein with an approximate mol. weight of 27,000, both in the presence and absence of beta-mercaptoethanol. Its pI was 7.8 by electrofocusing. The enzyme did not contain neutral carbohydrates and its N-terminal amino acid was alanine. The amino acid composition showed 249 residues/mole, a high content of hydrophilic amino acids and 14 half-cystine residues, which should account for 7 disulfide bonds. The protease cleaved the A-alpha chain faster than the B-beta of bovine fibrinogen and showed no effect on the delta-chain. Specific esterolytic activity of MOO3 on alpha-N-tosyl-l-arginine methyl ester was 29.64 mumol min-1 x mg-1. MOO3 represented 1.42% (w/w) of the initial desiccated venom. Its proteolytic activity was inhibited by beta-mercaptoethanol, leupeptin, phenylmethylsulphonyl fluoride and ethylenediamine tetraacetate.
Assuntos
Bothrops/metabolismo , Serina Endopeptidases/química , Venenos de Serpentes/enzimologia , Animais , Caseínas/metabolismo , Bovinos , Cromatografia por Troca Iônica , Eletroforese em Gel de Poliacrilamida , Fibrinogênio/metabolismo , Serina Endopeptidases/isolamento & purificação , Inibidores de Serina Proteinase/farmacologia , Especificidade por SubstratoRESUMO
Glucocorticoid excess is associated with a blunted GH response to GHRH. IGF-I levels in hypercortisolism are controversial and have been reported as low, normal or high. The aim of this study was to evaluate longitudinally time-dependent changes in the GH response to GHRH, IGF-I, IGFBP-3 and albumin values in patients during corticotherapy. Six patients received GHRH before and after one week and one month of prednisone administration (20-60 mg/d, orally). IGF-I, IGFBP-3 and albumin were determined in each test, at time 0. Ten normal controls were also evaluated in one occasion. There were no differences in basal GH values, GH response to GHRH, IGF-I and IGFBP-3 levels between controls and patients before starting corticotherapy. Albumin (g/l; mean+/-SE) values were lower in patients before treatment (31+/-4) than in controls (43+/-1). After one week of prednisone administration there was a significant decrease in peak GH (microg/l) levels (before: 18.8+/-7.4; 1 week: 5.0+/-1.3), which was maintained after one month (8.1+/-3.5). IGF-I (microg/l) levels increased significantly, from 145+/-23 to 205+/-52 after one week of therapy, reaching levels of 262+/-32 after one month. IGFBP-3 (mg/l) values did not increase significantly (before: 2.1+/-0.2; 1 week: 2.5+/-0.3; 1 month: 2.8+/-0.2). Albumin levels showed a significant rise both after one week (36+/-4) and one month (42+/-3) of corticotherapy. In summary, we observed a marked decrease in the GH response to GHRH after one week and one month of prednisone administration associated with an increase in circulating IGF-I and albumin values. The physiological implications of these findings are still uncertain. It is possible that glucocorticoids increase hepatic IGF-I and albumin synthesis, although other mechanisms may have a role.