Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis
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 throu...
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2025-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/1/46 |
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| author | Ignacija Vlašić Antonio Krstačić-Galić Anđela Horvat Nada Oršolić Anja Sadžak Lucija Mandić Suzana Šegota Maja Jazvinšćak Jembrek |
| author_facet | Ignacija Vlašić Antonio Krstačić-Galić Anđela Horvat Nada Oršolić Anja Sadžak Lucija Mandić Suzana Šegota Maja Jazvinšćak Jembrek |
| author_sort | Ignacija Vlašić |
| collection | DOAJ |
| description | 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 CuSO<sub>4</sub>) 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. |
| format | Article |
| id | doaj-art-fd53d517cd214f5482a451f57f978434 |
| institution | Kabale University |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj-art-fd53d517cd214f5482a451f57f9784342025-01-24T13:19:17ZengMDPI AGAntioxidants2076-39212025-01-011414610.3390/antiox14010046Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 AxisIgnacija Vlašić0Antonio Krstačić-Galić1Anđela Horvat2Nada Oršolić3Anja Sadžak4Lucija Mandić5Suzana Šegota6Maja Jazvinšćak Jembrek7Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaDepartment of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, CroatiaDivision of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaDepartment of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, CroatiaDivision of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, CroatiaDivision of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, CroatiaDivision of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, CroatiaDivision of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, CroatiaAlthough 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 CuSO<sub>4</sub>) 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.https://www.mdpi.com/2076-3921/14/1/46flavonolmetal-induced neurotoxicitypro-oxidative activityapoptosisatomic force microscopy |
| spellingShingle | Ignacija Vlašić Antonio Krstačić-Galić Anđela Horvat Nada Oršolić Anja Sadžak Lucija Mandić Suzana Šegota Maja Jazvinšćak Jembrek Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis Antioxidants flavonol metal-induced neurotoxicity pro-oxidative activity apoptosis atomic force microscopy |
| title | Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis |
| title_full | Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis |
| title_fullStr | Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis |
| title_full_unstemmed | Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis |
| title_short | Neurotoxic Effect of Myricitrin in Copper-Induced Oxidative Stress Is Mediated by Increased Intracellular Ca<sup>2+</sup> Levels and ROS/p53/p38 Axis |
| title_sort | neurotoxic effect of myricitrin in copper induced oxidative stress is mediated by increased intracellular ca sup 2 sup levels and ros p53 p38 axis |
| topic | flavonol metal-induced neurotoxicity pro-oxidative activity apoptosis atomic force microscopy |
| url | https://www.mdpi.com/2076-3921/14/1/46 |
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