Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca2+ Levels and ROS/p53/p38 Axis

Vlašić, Ignacija; Krstačić-Galić, Antonio; Horvat, Anđela; Oršolić, Nada; Sadžak, Anja; Mandić, Lucija; Šegota, Suzana; Jazvinšćak Jembrek, Maja (2025) Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca2+ Levels and ROS/p53/p38 Axis. Antioxidants, 14 (1). ISSN 2076-3921

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Abstract

Although commonly appreciated for their anti-oxidative and neuroprotective properties, flavonoids can also exhibit pro-oxidative activity, potentially reducing cell survival, particularly in the presence of metal ions. Disrupted copper homeostasis is a known contributor to neuronal dysfunction through oxidative stress induction. This study investigated the effects of myricitrin (1–20 μg/mL) on copper-induced toxicity (0.5 mM CuSO4) in the neuroblastoma SH-SY5Y cell line. At non-toxic concentrations, myricitrin exacerbated copper’s toxic effects. The myricitrin-induced decrease in survival was accompanied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase activity, and a lower GSH/GSSG ratio. In combination with copper, myricitrin also activated caspase-3/7, promoted nuclear chromatin changes, and compromised membrane integrity. At the protein level, myricitrin upregulated p53 and PUMA expression. The toxic effects of myricitrin were alleviated by the p38 inhibitor SB203580, the intracellular calcium chelator BAPTA-AM, and the NMDA receptor blocker MK-801, highlighting the significant role of the ROS/p53/p38 axis in cell death and the critical involvement of calcium ions in apoptosis induction. The atomic force microscopy was used to assess the surface morphology and nanomechanical properties of SH-SY5Y cells, revealing changes following myricitrin treatment. This research highlights the toxic potential of myricitrin and emphasizes the need for caution when considering flavonoid supplementation in conditions with elevated copper levels.

Item Type:	Article
Uncontrolled Keywords:	flavonol; metal-induced neurotoxicity; pro-oxidative activity; apoptosis; atomic force microscopy
Subjects:	BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions:	Division of Molecular Medicine Division of Physical Chemistry
Projects:	Project title Project leader Project code Project type Zaštitni mehanizmi i učinci flavonoida ugrađenih u nanonosače u modelnim membranama i neuronima-NanoFlavNeuroProtect Suzana Šegota IP-2016-06-8415 HRZZ
Depositing User:	Ana Zečević
Date Deposited:	28 Apr 2025 07:18
URI:	http://fulir.irb.hr/id/eprint/9758
DOI:	10.3390/antiox14010046

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