Antidotal effect of cyclosporine A against α-amanitin toxicity in CD-1 mice, at clinical relevant doses

Garcia, Juliana; Carvalho, Alexandra T. P.; Neves, Ricardo Pires das; Malheiro, Rui F.; Rodrigues, Daniela Ferreira; Figueiredo, Pedro; Bovolini, António; Duarte, José Alberto; Costa, Vera Marisa; Carvalho, Félix

doi:10.1016/j.fct.2022.113198

Cited by 6 publications

(2 citation statements)

References 55 publications

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“…In this study, we focused on 4 h interval between AMA injection and ICG treatment since this 4 h interval was the same as that used in previous studies to mimic actual human poisoning and treatment scenarios 5 , 52 , 68 . Therefore, this will facilitate us to compare our results with others on how ICG is effective in treating AMA toxicity.…”

Section: Discussionmentioning

confidence: 99%

Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity

Wang

Wan

et al. 2023

Nat Commun

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The “death cap”, Amanita phalloides, is the world’s most poisonous mushroom, responsible for 90% of mushroom-related fatalities. The most fatal component of the death cap is α-amanitin. Despite its lethal effect, the exact mechanisms of how α-amanitin poisons humans remain unclear, leading to no specific antidote available for treatment. Here we show that STT3B is required for α-amanitin toxicity and its inhibitor, indocyanine green (ICG), can be used as a specific antidote. By combining a genome-wide CRISPR screen with an in silico drug screening and in vivo functional validation, we discover that N-glycan biosynthesis pathway and its key component, STT3B, play a crucial role in α-amanitin toxicity and that ICG is a STT3B inhibitor. Furthermore, we demonstrate that ICG is effective in blocking the toxic effect of α-amanitin in cells, liver organoids, and male mice, resulting in an overall increase in animal survival. Together, by combining a genome-wide CRISPR screen for α-amanitin toxicity with an in silico drug screen and functional validation in vivo, our study highlights ICG as a STT3B inhibitor against the mushroom toxin.

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Section: Discussionmentioning

confidence: 99%

Identification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity

Wang

Wan

et al. 2023

Nat Commun

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“…The mechanisms of these antidotes are not completely elucidated but appear to involve inhibition of oxidative stress and/or the blockade of OATP1B3 [ 18 ]. Other known OATP1B3 inhibitors are the immunosuppressant cyclosporin and the antibiotic rifampicin [ 9 ], which have been shown to inhibit amanitin-induced cellular damage [ 9 , 19 ]. A recent study evaluated the effects of N-acetylcysteine, silibinin, and benzylpenicillin on clinical outcomes of amatoxin poisonings.…”

Section: Introductionmentioning

confidence: 99%

Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells

Hof,

Visser,

de Jong

et al. 2024

Toxins

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Amanita phalloides poisonings account for the majority of fatal mushroom poisonings. Recently, we identified hematotoxicity as a relevant aspect of Amanita poisonings. In this study, we investigated the effects of the main toxins of Amanita phalloides, α- and β-amanitin, on hematopoietic cell viability in vitro. Hematopoietic cell lines were exposed to α-amanitin or β-amanitin for up to 72 h with or without the pan-caspase inhibitor Z-VAD(OH)-FMK, antidotes N-acetylcysteine, silibinin, and benzylpenicillin, and organic anion-transporting polypeptide 1B3 (OATP1B3) inhibitors rifampicin and cyclosporin. Cell viability was established by trypan blue exclusion, annexin V staining, and a MTS assay. Caspase-3/7 activity was determined with Caspase-Glo assay, and cleaved caspase-3 was quantified by Western analysis. Cell number and colony-forming units were quantified after exposure to α-amanitin in primary CD34+ hematopoietic stem cells. In all cell lines, α-amanitin concentration-dependently decreased viability and mitochondrial activity. β-Amanitin was less toxic, but still significantly reduced viability. α-Amanitin increased caspase-3/7 activity by 2.8-fold and cleaved caspase-3 by 2.3-fold. Z-VAD(OH)-FMK significantly reduced α-amanitin-induced toxicity. In CD34+ stem cells, α-amanitin decreased the number of colonies and cells. The antidotes and OATP1B3 inhibitors did not reverse α-amanitin-induced toxicity. In conclusion, α-amanitin induces apoptosis in hematopoietic cells via a caspase-dependent mechanism.

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