Toxins

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Open AccessArticle

Development of an in Vitro Potency Assay for Anti-anthrax Lethal Toxin Neutralizing Antibodies

by Gail Whiting, Michael Baker and Sjoerd Rijpkema

Toxins 2012, 4(1), 28-41; https://doi.org/10.3390/toxins4010028 - 19 Jan 2012

Cited by 1 | Viewed by 7275

Lethal toxin (LT) of Bacillus anthracis reduces the production of a number of inflammatory mediators, including transcription factors, chemokines and cytokines in various human cell lines, leading to down-regulation of the host inflammatory response. Previously we showed that the reduction of interleukin-8 (IL-8) [...] Read more.

Lethal toxin (LT) of Bacillus anthracis reduces the production of a number of inflammatory mediators, including transcription factors, chemokines and cytokines in various human cell lines, leading to down-regulation of the host inflammatory response. Previously we showed that the reduction of interleukin-8 (IL-8) is a sensitive marker of LT-mediated intoxication in human neutrophil-like NB-4 cells and that IL-8 levels are restored to normality when therapeutic monoclonal antibodies (mAb) with toxin-neutralising (TN) activity are added. We used this information to develop cell-based assays that examine the effects of TN therapeutic mAbs designed to treat LT intoxication and here we extend these findings. We present an in vitro assay based on human endothelial cell line HUVEC jr2, which measures the TN activity of therapeutic anti-LT mAbs using IL-8 as a marker for intoxication. HUVEC jr2 cells have the advantage over NB-4 cells that they are adherent, do not require a differentiation step and can be used in a microtitre plate format and therefore can facilitate high throughput analysis. This human cell-based assay provides a valid alternative to the mouse macrophage assay as it is a more biologically relevant model of the effects of toxin-neutralising antibodies in human infection. Full article

(This article belongs to the Special Issue Anthrax Toxin)

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Open AccessReview

Inhibitors of the Cellular Trafficking of Ricin

by Julien Barbier, Céline Bouclier, Ludger Johannes and Daniel Gillet

Toxins 2012, 4(1), 15-27; https://doi.org/10.3390/toxins4010015 - 06 Jan 2012

Cited by 32 | Viewed by 10679

Abstract

Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic [...] Read more.

Throughout the last decade, efforts to identify and develop effective inhibitors of the ricin toxin have focused on targeting its N-glycosidase activity. Alternatively, molecules disrupting intracellular trafficking have been shown to block ricin toxicity. Several research teams have recently developed high-throughput phenotypic screens for small molecules acting on the intracellular targets required for entry of ricin into cells. These screens have identified inhibitory compounds that can protect cells, and sometimes even animals against ricin. We review these newly discovered cellular inhibitors of ricin intoxication, discuss the advantages and drawbacks of chemical-genetics approaches, and address the issues to be resolved so that the therapeutic development of these small-molecule compounds can progress. Full article

(This article belongs to the Special Issue Ricin Toxin)

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Open AccessArticle

Investigations into the Toxicology of Spirolides, a Group of Marine Phycotoxins

by Rex Munday, Michael A. Quilliam, Patricia LeBlanc, Nancy Lewis, Pamela Gallant, Sandra A. Sperker, H. Stephen Ewart and Shawna L. MacKinnon

Toxins 2012, 4(1), 1-14; https://doi.org/10.3390/toxins4010001 - 30 Dec 2011

Cited by 68 | Viewed by 8654

Abstract

Spirolides are marine phycotoxins produced by the dinoflagellates Alexandrium ostenfeldii and A. peruvianum. Here we report that 13-desmethyl spirolide C shows little cytotoxicity when incubated with various cultured mammalian cell lines. When administered to mice by intraperitoneal (ip) injection, however, this substance was [...] Read more.

Spirolides are marine phycotoxins produced by the dinoflagellates Alexandrium ostenfeldii and A. peruvianum. Here we report that 13-desmethyl spirolide C shows little cytotoxicity when incubated with various cultured mammalian cell lines. When administered to mice by intraperitoneal (ip) injection, however, this substance was highly toxic, with an LD₅₀ value of 6.9 µg/kg body weight (BW), showing that such in vitro cytotoxicity tests are not appropriate for predicting the in vivo toxicity of this toxin. Four other spirolides, A, B, C, and 20-methyl spirolide G, were also toxic to mice by ip injection, with LD₅₀ values of 37, 99, 8.0 and 8.0 µg/kg BW respectively. However, the acute toxicities of these compounds were lower by at least an order of magnitude when administration by gavage and their toxic effects were further diminished when administered with food. These results have implications for future studies of the toxicology of these marine toxins and the risk assessment of human exposure. Full article

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Toxins, Volume 4, Issue 1 (January 2012) – 3 articles , Pages 1-41

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