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1.
Chem Res Toxicol ; 27(10): 1696-706, 2014 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-25285689

RESUMO

Hapalindoles make up a large group of bioactive metabolites of the cyanobacterial order Stigonematales. 12-epi-Hapalindole E isonitrile, 12-epi-hapalindole C isonitrile, 12-epi-hapalindole J isonitrile, and hapalindole L from Fischerella are acutely toxic for insect larvae; however, the biochemical targets responsible for the biological activities of hapalindoles are not understood. We describe here the electron impact mass spectra of these four hapalindole congeners; their structures were confirmed by nuclear magnetic resonance spectroscopy. In combination with the presented mass spectra of (15)N-labeled species and their retention times on a gas chromatography capillary column, a rapid and reliable determination should be possible in future research. The bioactivity of these hapalindoles was tested on mammalian cells focusing on their effects in the BE(2)-M17 excitable human neuroblastoma cell line. The fluorescent dye Alamar Blue was applied to monitor cytotoxicity, fura-2 to evaluate changes in the cytosolic calcium concentrations, and bis-oxonol to detect effects on membrane potential. Data showed that the hapalindoles did not affect cell viability of the neuroblastoma cells, even when they were incubated for 72 h. Neither depolarization nor initiation of calcium influx was observed in the cells upon hapalindole treatment. However, the data provide evidence that hapalindoles are sodium channel-modulating neurotoxins. They inhibited veratridine-induced depolarization in a manner similar to that of neosaxitoxin. Our data suggest hapalindoles should be added to the growing number of neurotoxic secondary metabolites, such as saxitoxins and anatoxins, already known in freshwater cyanobacteria. As stable congeners, hapalindoles may be a risk in freshwater ecosystems or agricultural water usage and should therefore be considered in water quality assessment.


Assuntos
Cianobactérias/química , Alcaloides Indólicos/química , Canais de Sódio/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cianobactérias/metabolismo , Fura-2/química , Fura-2/toxicidade , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Alcaloides Indólicos/toxicidade , Espectroscopia de Ressonância Magnética , Potenciais da Membrana/efeitos dos fármacos , Isótopos de Nitrogênio/química , Ratos , Saxitoxina/análogos & derivados , Saxitoxina/toxicidade , Canais de Sódio/química
2.
Zygote ; 6(2): 113-23, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9770776

RESUMO

Ion-sensitive fluorophores are commonly used for quantitative measurements of intracellular ion concentrations. However, both the method of intracellular loading--which for many fluorophores involves endogenous esterase-mediated removal of hydrophobic groups such as acetoxymethyl esters (AM)--and fluorescence excitation of fluorophores in the cell, can produce toxic metabolites and reactive species. Techniques used to measure intracellular ion concentrations in mammalian eggs and embryos are being increasingly employed, yet little information is available about any detrimental effects of the use of fluorophores. We have therefore used in vitro fertilisation (IVF) to assess potential fluorophore toxicity in mouse eggs, and whole cell patch-clamp recordings to detect fluorophore-associated membrane damage in zygotes. Four fluorophores were examined: SNARF-1 and BCECF (pH indicators), Fura-2 (Ca2+) and MQAE (Cl-). Cleavage of AM groups alone had no effect either on the success of IVF or on membrane electrical properties of mouse zygotes. Intracellularly loaded BCECF, SNARF-1 and Fura-2 followed by fluorescence excitation were not cell-toxic under the conditions examined. In contrast, MQAE demonstrated significant toxicity both alone and in combination with fluorescence excitation.


Assuntos
Corantes Fluorescentes/toxicidade , Óvulo/efeitos dos fármacos , Zigoto/efeitos dos fármacos , Animais , Benzopiranos , Fertilização in vitro , Fluoresceínas/toxicidade , Fura-2/toxicidade , Camundongos , Naftóis/toxicidade , Técnicas de Patch-Clamp , Compostos de Quinolínio/toxicidade , Rodaminas/toxicidade , Espectrometria de Fluorescência
3.
Neurosci Lett ; 162(1-2): 169-72, 1993 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-8121621

RESUMO

Membrane-permeating, fluorescent Ca2+ indicators have been used to investigate the role of increased intracellular Ca2+ (Ca2+i) levels in excitotoxic neuronal injury, but their ability to chelate Ca2+i and their own toxic effects in some cells could obscure this relationship. N-Methyl-D-aspartate (NMDA)-stimulated Ca2+i responses and toxicity were measured in neuron-enriched rat cerebrocortical cultures loaded with either fluo-3 or fura-2. Ca2+i responses signaled by both indicators were similar in magnitude, and neither indicator reduced NMDA toxicity, measured by lactate dehydrogenase (LDH) release. Fluo-3 and fura-2 appear to be suitable for comparative studies of NMDA-induced Ca2+i responses and excitotoxicity.


Assuntos
Compostos de Anilina/toxicidade , Cálcio/metabolismo , Córtex Cerebral/metabolismo , Corantes Fluorescentes/toxicidade , Fura-2/toxicidade , Neurônios/efeitos dos fármacos , Xantenos/toxicidade , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Feminino , Histocitoquímica , L-Lactato Desidrogenase/metabolismo , N-Metilaspartato/toxicidade , Gravidez , Ratos , Ratos Sprague-Dawley
4.
J Biochem Toxicol ; 6(4): 299-303, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1774771

RESUMO

The effect of intracellular calcium chelators on rabbit renal proximal tubule (RPT) cell death induced by t-butyl hydroperoxide (TBHP) and H2O2 was examined. Preincubation of RPT suspensions with 50 microM QUIN 2/AM completely prevented TBHP (0.5 mM) and H2O2 (2 mM) induced cell death [i.e., release of lactate dehydrogenase (LDH)]. QUIN 2/AM, BAPTA/AM, EGTA/AM, and FURA 2/AM, at 5 microM, decreased LDH release (at 6 hr) from 41% to 4%, 21%, 26%, and 33%, and decreased lipid peroxidation (at 1 hr) from 1.0 to 0.1, 0.4, 0.6, and 0.8 nmol MDA/mg protein, respectively, after TBHP exposure. Since oxidant-induced lipid peroxidation and cell death are iron-dependent in this model, these results suggest that the intracellular calcium chelators inhibit cell death by chelating iron.


Assuntos
Cálcio/metabolismo , Quelantes/toxicidade , Túbulos Renais Proximais/efeitos dos fármacos , Aminoquinolinas/toxicidade , Animais , Morte Celular/efeitos dos fármacos , Ácido Egtázico/análogos & derivados , Ácido Egtázico/toxicidade , Fura-2/toxicidade , Técnicas In Vitro , Líquido Intracelular/metabolismo , Ferro/metabolismo , Túbulos Renais Proximais/citologia , Coelhos
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