Aspects of a Distinct Cytotoxicity of Selenium Salts and Organic Selenides in Living Cells with Possible Implications for Drug Design.

Selenium is traditionally considered as an antioxidant element and selenium compounds are often discussed in the context of chemoprevention and therapy. Recent studies, however, have revealed a rather more colorful and diverse biological action of selenium-based compounds, including the modulation of the intracellular redox homeostasis and an often selective interference with regulatory cellular pathways. Our basic activity and mode of action studies with simple selenium and tellurium salts in different strains of Staphylococcus aureus (MRSA) and Saccharomyces cerevisiae indicate that such compounds are sometimes not particularly toxic on their own, yet enhance the antibacterial potential of known antibiotics, possibly via the bioreductive formation of insoluble elemental deposits. Whilst the selenium and tellurium compounds tested do not necessarily act via the generation of Reactive Oxygen Species (ROS), they seem to interfere with various cellular pathways, including a possible inhibition of the proteasome and hindrance of DNA repair. Here, organic selenides are considerably more active compared to simple salts. The interference of selenium (and tellurium) compounds with multiple targets could provide new avenues for the development of effective antibiotic and anticancer agents which may go well beyond the traditional notion of selenium as a simple antioxidant.

Intracellular diagnostics: hunting for the mode of action of redox-modulating selenium compounds in selected model systems.

Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the "redox link" which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.

Natural selenium particles from Staphylococcus carnosus: Hazards or particles with particular promise?

Various bacteria, including diverse Staphylococci, reduce selenite to yield red selenium particles with diameters in the high nanometer to low micrometer range. Formation and accumulation of such particles in bacteria often results in cell death, triggered by a loss of thiols and formation of disruptive deposits inside the cell. Hence certain pathogenic bacteria are rather sensitive to the presence of selenite, whilst other organisms, such as small nematodes, do not employ this kind of nanotechnology, yet become affected by micromolar concentrations of such naturally generated materials. Selenium particles extracted from cultures of Staphylococcus carnosus and apparently stabilized by their natural protein coating, for instance, show considerable activity against the nematode Steinernema feltiae, Escherichia coli and Saccaromyces cerevisiae. Such natural nano- and micro-particles are also more active than mechanically generated selenium particles and may be applied as antimicrobial materials in Medicine and Agriculture.

Dominant lethal effects of 2,4-D in Biomphalaria glabrata.

Dominant lethal effects of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) were evaluated in the freshwater snail Biomphalaria glabrata. Wild-type snails were exposed during 10 days to 50, 75 and 100ppm of 2,4-D dimethylamine salt (2,4-D DMA) and paired with non-exposed albino snails 1, 11, 25 and 40 days after the exposure. The offspring of the non-exposed albino snails was scored for lethal malformations. One day after the exposure, a significant effect was observed at 75 and 100ppm without a dose-response relationship. After 11 days, the effect was observed only at the highest dose. After 25 days, significant increases in the dominant lethal effects occurred at 50 and 75ppm; effects were directly related to the doses. Background levels of lethal malformations were resumed after 40 days. Although the major and direct measure of dominant lethal mutations is the rate of lethal malformations in the heterozygous offspring of the albino snails, the sensitivity of the assay was substantially increased with the evaluation of all non-viable embryos, that are the sum of those with lethal malformations, identified or not as wild-type.

Inspired by Nature: The Use of Plant-derived Substrate/Enzyme Combinations to Generate Antimicrobial Activity in situ.

The last decade has witnessed a renewed interest in antimicrobial agents. Plants have received particular attention and frequently rely on the spontaneous enzymatic conversion of an inactive precursor to an active agent. Such two-component substrate/enzyme defence systems can be reconstituted ex vivo. Here, the alliin/alliinase system from garlic seems to be rather effective against Saccharomyces cerevisiae, whilst the glucosinolate/myrosinase system from mustard appears to be more active against certain bacteria. Studies with myrosinase also confirm that enzyme and substrate can be added sequentially. Ultimately, such binary systems hold considerable promise and may be employed in a medical or agricultural context.

Evaluation of the toxicity and antiulcerogenic activity of the ethanol extract of Maytenus obtusifolia Mart. leaves / Avaliação da toxicidade e atividade antiulcerogênica do extrato etanólico das folhas de Maytenus obtusifolia Mart

Maytenus obtusifolia é utilizada na medicina popular para o tratamento de úlceras graves, inflamações gerais e câncer. Apesar da importância etnofarmacológica desta espécie, nenhum estudo foi realizado para avaliar a sua toxicidade e atividade antiulcerogênica. Neste estudo, nós avaliamos a toxicidade e propriedade antiulcera do extrato etanólico das folhas de Maytenus obtusifolia (MO-EtOH). O MO-EtOH (10-1000 µg/mL) mostrou baixa toxicidade para as larvas de A. salina com CL50 maior que 1000 µg/mL. O MO-EtOH (2000 mg/kg, p.o.) nγo alterou o peso corporal e peso dos órgãos dos camundongos, mas foi observado um aumento no consumo de água dos machos e uma diminuição do consumo alimentar das fêmeas. Durante o estudo não foram observadas mortes e nem alterações macroscópicas nos órgãos dos camundongos. MO-EtOH (62,5, 125, 250 e 500 mg/kg) e lansoprazol (30 mg/kg) reduziram significativamente o índice ulcerativo para 65,58 ± 8,74, 43,00 ± 9,53, 15,50 ± 7,56, 54,75 ± 8,88 e 36,13 ± 9,55, respectivamente, em comparação com salina 82,13 ± 12,48. Em conclusão, o MO-EtOH apresentou baixa toxicidade e atividade antiulcerogênica, o que confirma o uso popular de M. obtusifolia.

Maytenus obtusifolia is used in folk medicine for the treatment of serious ulcers, general inflammations and cancer. Despite of the ethnopharmacological importance of this species, no study was conducted to evaluate its toxicity and antiulcerogenic activity. In this study, we evaluated the toxicity and antiulcerogenic property of the ethanol extract of the leaves of Maytenus obtusifolia (MO-EtOH). The MO-EtOH (10-1000 µg/mL) showed low toxicity for larvae of A. salina with LC50 higher than 1000 µg/mL. The MO-EtOH (2000 mg/kg, p.o.) did not change the body and organs weight of the mice, but it was observed an increase in the water consumption of males and a decrease in the food consumption of females. During the study no deaths and no macroscopic changes in the organs were observed in the mice. MO-EtOH (62.5, 125, 250 and 500 mg/kg) and lansoprazole (30 mg/kg) significantly reduced the ulcerative index for 65.58 ± 8.74, 43.00 ± 9.53, 15.50 ± 7.56, 54.75 ± 8.88 and 36.13 ± 9.55, respectively, in comparison with saline 82.13 ± 12.48. In conclusion, the MO-EtOH showed low toxicity and antiulcerogenic activity, confirming the popular use of M. obtusifolia.