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Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper

Sadžak, Anja; Vlašić, Ignacija; Kiralj, Zoran; Batarelo, Marijana; Oršolić, Nada; Jazvinšćak Jembrek, Maja; Kušen, Ines; Šegota, Suzana (2021) Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper. Molecules, 26 (4). ISSN 1420-3049

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Abstract

Oxidative stress (OS) induced by the disturbed homeostasis of metal ions is one of the pivotal factors contributing to neurodegeneration. The aim of the present study was to investigate the effects of flavonoid myricetin on copper-induced toxicity in neuroblastoma SH-SY5Y cells. As determined by the MTT method, trypan blue exclusion assay and measurement of ATP production, myricetin heightened the toxic effects of copper and exacerbated cell death. It also increased copper-induced generation of reactive oxygen species, indicating the prooxidative nature of its action. Furthermore, myricetin provoked chromatin condensation and loss of membrane integrity without caspase-3 activation, suggesting the activation of both caspase-independent programmed cell death and necrosis. At the protein level, myricetin-induced upregulation of PARP-1 and decreased expression of Bcl-2, whereas copper-induced changes in the expression of p53, p73, Bax and NME1 were not further affected by myricetin. Inhibitors of ERK1/2 and JNK kinases, protein kinase A and L-type calcium channels exacerbated the toxic effects of myricetin, indicating the involvement of intracellular signaling pathways in cell death. We also employed atomic force microscopy (AFM) to evaluate the morphological and mechanical properties of SH-SY5Y cells at the nanoscale. Consistent with the cellular and molecular methods, this biophysical approach also revealed a myricetin-induced increase in cell surface roughness and reduced elasticity. Taken together, we demonstrated the adverse effects of myricetin, pointing out that caution is required when considering powerful antioxidants for adjuvant therapy in copper-related neurodegeneration.

Item Type: Article
Uncontrolled Keywords: myricetin ; prooxidative activity ; copper toxicity ; atomic force microscopy ; elasticity ; roughness
Subjects: BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions: Division of Molecular Medicine
NMR Center
Projects:
Project titleProject leaderProject codeProject type
Zaštitni mehanizmi i učinci flavonoida ugrađenih u nanonosače u modelnim membranama i neuronimaŠegota, SuzanaIP-2016-06-8415HRZZ
Depositing User: Suzana Šegota
Date Deposited: 09 Mar 2021 12:55
Last Modified: 06 Aug 2021 13:38
URI: http://fulir.irb.hr/id/eprint/6344
DOI: 10.3390/molecules26040845

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