Cytotoxic effect of carbohydrate derivatives of digitoxigenin involves modulation of plasma membrane Ca2+ -ATPase.

Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na+ /K+ -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi-synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin-α-L-rhamno-pyranoside (1) and digitoxigenin-α-L-amiceto-pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi-26-VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P-type ATPases; Na+ /K+ -ATPase, sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA), and plasma membrane Ca2+ -ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi-26-VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na+ /K+ -ATPase, PMCA and SERCA, the modulation of these P-type ATPases was completely absent in Wi-26-VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.

The Janus face of ouabain in Na+ /K+ -ATPase and calcium signalling in neurons.

Na+ /K+ -ATPase, a transmembrane protein essential for maintaining the electrochemical gradient across the plasma membrane, acts as a receptor for cardiotonic steroids such as ouabain. Cardiotonic steroids binding to Na+ /K+ -ATPase triggers signalling pathways or inhibits Na+ /K+ -ATPas activity in a concentration-dependent manner, resulting in a modulation of Ca2+ levels, which are essential for homeostasis in neurons. However, most of the pharmacological strategies for avoiding neuronal death do not target Na+ /K+ -ATPase activity due to its complexity and the poor understanding of the mechanisms involved in Na+ /K+ -ATPase modulation. The present review aims to discuss two points regarding the interplay between Na+ /K+ -ATPase and Ca2+ signalling in the brain. One, Na+ /K+ -ATPase impairment causing illness and neuronal death due to Ca2+ signalling and two, benefits to the brain by modulating Na+ /K+ -ATPase activity. These interactions play an essential role in neuronal cell fate determination and are relevant to find new targets for the treatment of neurodegenerative diseases. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

Antiglycation, antioxidant and cytotoxicity activities of crude extract of Turnera ulmifolia L. before and after microencapsulation process.

Turnera ulmifolia L. is used in folk medicine and it is known to have anti-hyperglycemic effect on the organism in order to reduce complications in diabetic patients. Glycation process is directly related to oxidative stress, acting as an important endogenous source, inducing the production of free radicals, and thus increasing the production of reactive oxygen species. The encapsulation technology on natural compounds can minimize and even mitigate the risk of loss of biological activity in order to maintain their activities against oxidative stress and glycation. The present study aimed to evaluate the antiglycation and antioxidant activities of T. ulmifolia extract before and after encapsulation and cytotoxicity of the crude extract. This study presents important information about the biological activities, highlighting antioxidant and antiglycation potential and no cytotoxicity of Turnera ulmifolia crude extract, a species of genus Turnera that has been poorly studied. T. ulmifolia crude extract presented flavonoids as main active compounds. The results showed a promising activity in scavenging free and peroxyl radicals, chelating iron ions and inhibiting BSA glycation. In addition, this study showed the possible encapsulation of bioactive compounds using maltodextrin as wall material.

The role of Na+/K+-ATPase during chick skeletal myogenesis.

The formation of a vertebrate skeletal muscle fiber involves a series of sequential and interdependent events that occurs during embryogenesis. One of these events is myoblast fusion which has been widely studied, yet not completely understood. It was previously shown that during myoblast fusion there is an increase in the expression of Na+/K+-ATPase. This fact prompted us to search for a role of the enzyme during chick in vitro skeletal myogenesis. Chick myogenic cells were treated with the Na+/K+-ATPase inhibitor ouabain in four different concentrations (0.01-10 µM) and analyzed. Our results show that 0.01, 0.1 and 1 µM ouabain did not induce changes in cell viability, whereas 10 µM induced a 45% decrease. We also observed a reduction in the number and thickness of multinucleated myotubes and a decrease in the number of myoblasts after 10 µM ouabain treatment. We tested the involvement of MEK-ERK and p38 signaling pathways in the ouabain-induced effects during myogenesis, since both pathways have been associated with Na+/K+-ATPase. The MEK-ERK inhibitor U0126 alone did not alter cell viability and did not change ouabain effect. The p38 inhibitor SB202190 alone or together with 10 µM ouabain did not alter cell viability. Our results show that the 10 µM ouabain effects in myofiber formation do not involve the MEK-ERK or the p38 signaling pathways, and therefore are probably related to the pump activity function of the Na+/K+-ATPase.

Δ²,³-ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases.

Looking at a new putative target for the large spectrum antiparasitic drug ivermectin, we recently showed that avermectin-derived drugs are active against promastigote and amastigote forms of Leishmania amazonensis at low micromolar concentrations. However, we then reported that at this concentration range ivermectin is also able to inhibit three important mammalian P-type ATPases so that unacceptable adverse effects could occur if this drug were used at such high doses therapeutically. The present work aimed to test the activity of ten ivermectin analogs on these rat ATPases in search of a compound with similar leishmanicidal activity but with no effect on the mammalian (host) ATPases at effective concentrations. We synthesized three new ivermectin analogs for testing on rat SERCA (1a and 1b), Na+, K+-ATPase (α1 and α2/α3 isoforms) and H+/K+-ATPase activity, along with seven analogs already characterized for their leishmanicidal activity. Our main finding is that one of the prepared derivatives, Δ²,³-ivermectin ethyl secoester 8, is equipotent to ivermectin 1 for the in vitro leishmanicidal effects but is nearly without effect on the rat ATPases, indicating that it could have a better therapeutic index in vivo and could serve as a candidate for hit-to-lead progression. This conclusion is further supported by the fact that compound 8 produced only 6% (vs 77% for ivermectin) inhibition of the human kidney enzyme at 5 µM, a concentration corresponding to the IC50 for the activity against L. amazonensis amastigotes.

Diferenciaçäo sexual dos vertebrados: contribuiçäo de fatores somáticos e ambientais / Sexual differentiation of vertebrates: contribution of somatic and environmental factors

Há vários séculos a questäo da determinaçäo sexual dos animais é debatida. No entanto, um verdadeiro avanço no entendimento de como e quais fatores estäo ou podem estar envolvidos neste evento foi alcançado somente há algumas décadas. O presente trabalho descreve e discute os fatores genéticos, ambientais (temperatura, concentraçäo de íons, pH, dentre outros) e hormonais que estabelecem o padräo sexual do embriäo indiferenciado de animais pertencentes às várias classes de vertebrados.

Parkinsonismo: aspéctos clínicos, biológicos e terapêuticos / Parkinsonism: clinical, biological and therapeutical aspects

O parkinsonismo idiopático (doença de Parkinson) e secundário, ou seja, que apresenta etiologia conhecida (pós-encefalítico, por toxinas, por drogas ou por algumas doenças degenerativas) såo processos neurodegenerativos que afetam progressivamente as funçÆes motoras normais do indivíduo. Neste trabalho, os aspéctos clínicos, etiológicos, fisiopatológicos e principalmente a descriçåo do arsenal farmacológico e as medidas utilizadas no combate ou retardo medicamentoso do parkinsonismo såo abordados e discutidos

Evidências científicas da eficácia clínica do tratamento homeopático em reumatologia / Scientific evidences of the clinical efficacy of homeopathic treatment in rheumatology

A homeopatia é largamente aceita como método nao científico de tratamento em que a melhora dos sintomas do paciente se deve exclusivamente a fatores psicológicos inespecíficos, ou seja, a uma resposta placebo. Entretanto, vários pesquisadores têm feito esforços no sentido de verificar se a homeopatia é uma ferramenta eficaz no controle de enfermidades. Em reumatologia, alguns ensaios clínicos vêm sendo realizados para avaliar a eficácia de medicamentos homeopáticos no tratamento de certas doenças reumáticas. No entanto, apesar desses estudos terem sido efetuados para solucionar a controvérsia existente entre homeopatia e alopatia, os resultados obtidos nao revelam de forma definitiva se a atividade curativa do medicamento homeopático realmente existe, já que resultados contraditórios sao observados. Apesar das evidências serem relativamente positivas, novas investigaçoes sao necessárias para comprovaçao, com regidez e imparcialidade científica, do valor terapêutico da homeopatia

Mecanismos da hipertensåo arterial essencial / Mechanisms of the essential arterial hypertention

No presente trabalho foram discutidos os processos fisiopatológicos e etiopatogênicos da Hipertensåo Arterial Essencial (HAE), explicitando-se fatores genéticos (defeito no transporte de íons, alteraçÆes no mecanismosrenina-angiotensina-aldosterona, resposta aumentada ao estresse e as recém-concebidas "structural upward resettings") envolvidos, buscando-se a aproximaçåo do real encadeamento lógico dos eventos que ocorrem nesta afecçåo. Após esta abordagem, foram levantadas questÆes referentes às perspectivas futuras sobre o esclarecimento dos mecanismos responsáveis pelo desenvolvimento e instalaçåo da HAE

Açöes farmacológicas dos antidepressivos / Pharmacological actions of antidepressant drugs

Vários aspectos das drogas antidepressivas säo abordados no presente artigo. Assim, a toxicologia e/ou as características terapêuticas e principalmente o mecanismo de açäo säo apresentados para os antidepressivos tricíclicos, atípicos, aos inibidores da monoaminoxidase, lítio e outros fármacos utilizados no tratamento de distúrbios associados à depressäo

Farmacologia das sulfoniluréias / Pharmacology of sulfonylureas

No presente estudo foi descrita e evidenciada a farmacologia das sulfoniluréias, no tratamento do diabetes mellitus do tipo II (insulino-independente). Apesar da sempre crescente utilizaçäo destas drogas na terapia do diabetes, principalmente pela sua praticidade e rapidez, näo se pode deixar de esquecer o balanço entre as dosagens, contra-indicaçöes e o aspecto geral, físico e mental do paciente. Além disso, so cuidados gerais, a orientaçä para uma dieta equilibrada, a prática de exercício e os cuidados com a higiene pessoal do indivíduo diabético sä necessários para que o tratamento alcance o sucesso esperado

Farmacologia dos nitratos / Pharmacology of nitrates

Os nitratos säo drogas utilizadas nas afecçoes cardiovasculares, desde o século passado. Quimicamente säo ésteres de ácido nìtrico (HNO) ou nitroso (HNO) apresentando as ligaçöes C-O-N. Estes fármacos atuam promovendo vasodilataçöes periférica e coronária, levando deste modo a um aumento da oferta e a uma diminuiçäo do consumo de O. Assim, apresentam grande aplicaçäo na terapia da angina. Os mecanismos de açäo dos nitratos ainda näo se encontram totalmente esclarecidos, necessitando-se assim de novos estudos que visem ampliar o grau de conhecimento sobre a farmacodinâmica destes compostos, desta forma tornando seu uso mais eficaz na terapia cardiovascular

Estudo comparativo das drogas nifedipina, verapamil e nitroglicerina no infarto agudo do miocárdio (IAM) / Comparative study of nifedipine, verapamil and nitroglycerin in acute myocardial infarction (AMI)

O objetivo do presente estudo foi comparar os efeitos das drogas nifedipina, verapamil e nitroglicerina sobre ratos infartados, pela oclusäo, durante 10 minutos, da artéria coronária esquerda. Costatou-se que as drogas têm efeitos protetores sobre o miocárdio isquêmico, sendo a açäo da nifedipina um pouco superior às duas outras substâncias. Apesar destes resultados, há necessidade de novas pesquisas, para que seja apontada a droga mais eficaz na terapia pós-infarto do miocárdio

Estudo epidemiologico da hipertensao arterial e dos fatores de risco cardiovascular em Bangu, Rio de Janeiro, Brasil / Epidemiological study of the hypertension and cardiovascular risk factors in Bangu, Rio de Janeiro, Brasil

Uma analise epidemiologica realizada na localidade de Bangu,zona oeste da cidade do Rio de Janeiro,RJ-Brasil,objetivou avaliar a prevalencia de hipertensao arterial e dos fatores de risco cardiovascular nesta populacao.Participaram deste estudo 500 individuos,sendo constatada uma prevalencia relativamente alta de hipertensao(29,7 por cento ,19,9 por cento e 25,2 por cento para homens,mulheres e ambos,respectivamente)A hipertensao sistolica isolada tambem foi prevalente(11,9 por cento,7,8 por cento e 10,0 por cento para homens,mulheres e ambos respectivamente)A vida sedentaria foi o principal fator de risco cardiovascular,seguida pela obesidade e dieta.Os dados disponiveis no presente estudo sao similares aos obtidos em outras investigacoes nacionais e internacionais,podendo ser utilizados na elaboracao de programas de saude relacionados a prevencao desta doenca.