Toxicidade de fisetina e seu mecanismo de ação sobre leveduras do complexo Cryptococcus neoformans e dermatófitos
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2016-02-29
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Universidade Federal de Goiás
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Increases in antimicrobial resistance and the side effects of available antifungal drugs have increased the need to develop new and more effective antifungal agents. Among the compounds extracted from plants, flavonoids have been considered to be possible sources of new therapeutics for fungal, bacterial and viral infections. The antifungal mechanism of action and toxicity of fisetin, flavonoid with antifungal activity previously established for the Cryptococcus neoformans species complex and dermatophytes were determined. The action of this flavonoid was evaluated by quantitation of ergosterol, cell viability by flow cytometry and by changes in fungal morphology visualized by scanning electron microscopy. The fisetin toxicity was determined in vitro through the evaluation of hemolytic and myelotoxic potential and in vivo by acute oral toxicity. Hepatotoxicity of this flavonoid in hepatocellular carcinoma cell line (Hepg2) was performed by determination of mitochondrial viability using the MTT reduction method, evaluation of cellular and nuclear morphology by staining with May-Grunwald-Giemsa and Hoechst 33342 and analysis of viability and death cell by method of phosphatidylserine externalization. The obtained results have allowed to verify that the yeast subjected to the action of the fisetin showed a content ergosterol reduction, changes in cellular metabolism viewed in flow cytometry. Fungal cells treated with fisetin and observed by scanning electron microscopy showed in the analysis of yeast C. neoformans complex, retraction in the cell cytoplasm and in the dermatophytes there have been changes in hyphae and sharp reduction of conidia. The toxicological analysis of fisetin, observed a low potential hemolytic and an absence of damage on the granulocyte-macrophage progenitors cells. Animals treated with fisetin did not show behavioral changes, with liver and kidneys macroscopically normal. The cytotoxicity assessment observed on HepG2 cells in different concentrations of the compound showed cell viability with a range of 65.9% to 18.5% at concentrations from 3.12 to 400 μg/mL fisetin, suggesting that the action this flavonoid on the HepG2 cell line is concentration-dependent. Rare cellular and nuclear morphological changes, with few cells in apoptosis were observed in HepG2 cells in the presence of fisetin. In conclusion, although many cytotoxicity assays and mechanism of action must be made to introduce fisetin as a new drug, the present results show a favorable profile to conduct the study and development of this substance in the treatment of cryptococcosis and dermatophytosis.
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COSTA, M. P. Toxicidade de fisetina e seu mecanismo de ação sobre leveduras do complexo Cryptococcus neoformans e dermatófitos. 2016. 84 f. Dissertação (Mestrado em Medicina Tropical e Saúde Publica) - Universidade Federal de Goiás, Goiânia, 2016.