CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway
Copper oxide nanoparticles (CuO-NPs) induce neurological diseases, including neurobehavioral defects and neurodegenerative diseases. Direct evidence indicates that CuO-NPs induce inflammation in the central nervous system and cause severe neurotoxicity. However, the mechanism of CuO-NP-induced damag...
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MDPI AG
2025-03-01
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| author | Linhui Yang Lina Zhu Bencheng Lin Yue Shi Wenqing Lai Kang Li Lei Tian Zhuge Xi Huanliang Liu |
| author_facet | Linhui Yang Lina Zhu Bencheng Lin Yue Shi Wenqing Lai Kang Li Lei Tian Zhuge Xi Huanliang Liu |
| author_sort | Linhui Yang |
| collection | DOAJ |
| description | Copper oxide nanoparticles (CuO-NPs) induce neurological diseases, including neurobehavioral defects and neurodegenerative diseases. Direct evidence indicates that CuO-NPs induce inflammation in the central nervous system and cause severe neurotoxicity. However, the mechanism of CuO-NP-induced damage to the nervous system has rarely been studied, and the toxicity of different CuO-NP particle sizes and their copper ion (Cu<sup>2+</sup>) precipitation in microglia (BV2 cells) is worth exploring. Therefore, this study investigated CuO-NPs with different particle sizes (small particle size: S-CuO-NPs; large particle size: L-CuO-NPs), Cu<sup>2+</sup> with equal molar mass (replaced by CuCl<sub>2</sub> [Equ group]), and Cu<sup>2+</sup> precipitated in a cell culture solution with CuO-NPs (replaced by CuCl<sub>2</sub> [Pre group]), and examined the mechanism of action of each on BV2 microglia after co-culture for 12 h and 24 h. The activity of BV2 cells decreased, the morphology was damaged, and the apoptosis rate increased in all the exposed groups. Toxicity increased time- and dose-dependently, and was highest in the Equ group, followed by the S-CuO-NPs, L-CuO-NPs, and Pre groups, respectively. Subsequently, we investigated the mechanism of S-CuO-NP-induced cell injury, and revealed that S-CuO-NPs induced oxidative stress and inflammatory response and increased the membrane permeability of BV2 cells. Moreover, S-CuO-NPs reduced the ratio of p-CSF-1R/CSF-1R, p-PLCγ2/PLCγ2, p-extracellular signal-regulated kinase (ERK)/ERK, p-Nrf2/Nrf2, and Bcl-2/Bax protein expression in microglia, and elevated cleaved caspase-3 expression. The CSF-1R/PLCγ2/ERK/Nrf2 apoptotic pathway was activated. The downregulation of CX3CR1, CSF-1R, brain-derived neurotrophic factor (BDNF), and IGF-1 protein expression indicates impairment of the repair and protection functions of microglia in the nervous system. In summary, our results reveal that CuO-NPs promote an increase in inflammatory molecules in BV2 microglia through oxidative stress, activate the CSF-1R/PLCγ2/ERK/Nrf2 pathway, cause apoptosis, and ultimately result in neurofunctional damage to microglia. |
| format | Article |
| id | doaj-art-75d756e70bcb43c4ab078bc418aac43c |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-75d756e70bcb43c4ab078bc418aac43c2025-08-20T02:18:05ZengMDPI AGToxics2305-63042025-03-0113423110.3390/toxics13040231CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 PathwayLinhui Yang0Lina Zhu1Bencheng Lin2Yue Shi3Wenqing Lai4Kang Li5Lei Tian6Zhuge Xi7Huanliang Liu8College of Oceanography and Ecological Science, Shanghai Ocean University, Shanghai 201306, ChinaCollege of Oceanography and Ecological Science, Shanghai Ocean University, Shanghai 201306, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaMilitary Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, ChinaCopper oxide nanoparticles (CuO-NPs) induce neurological diseases, including neurobehavioral defects and neurodegenerative diseases. Direct evidence indicates that CuO-NPs induce inflammation in the central nervous system and cause severe neurotoxicity. However, the mechanism of CuO-NP-induced damage to the nervous system has rarely been studied, and the toxicity of different CuO-NP particle sizes and their copper ion (Cu<sup>2+</sup>) precipitation in microglia (BV2 cells) is worth exploring. Therefore, this study investigated CuO-NPs with different particle sizes (small particle size: S-CuO-NPs; large particle size: L-CuO-NPs), Cu<sup>2+</sup> with equal molar mass (replaced by CuCl<sub>2</sub> [Equ group]), and Cu<sup>2+</sup> precipitated in a cell culture solution with CuO-NPs (replaced by CuCl<sub>2</sub> [Pre group]), and examined the mechanism of action of each on BV2 microglia after co-culture for 12 h and 24 h. The activity of BV2 cells decreased, the morphology was damaged, and the apoptosis rate increased in all the exposed groups. Toxicity increased time- and dose-dependently, and was highest in the Equ group, followed by the S-CuO-NPs, L-CuO-NPs, and Pre groups, respectively. Subsequently, we investigated the mechanism of S-CuO-NP-induced cell injury, and revealed that S-CuO-NPs induced oxidative stress and inflammatory response and increased the membrane permeability of BV2 cells. Moreover, S-CuO-NPs reduced the ratio of p-CSF-1R/CSF-1R, p-PLCγ2/PLCγ2, p-extracellular signal-regulated kinase (ERK)/ERK, p-Nrf2/Nrf2, and Bcl-2/Bax protein expression in microglia, and elevated cleaved caspase-3 expression. The CSF-1R/PLCγ2/ERK/Nrf2 apoptotic pathway was activated. The downregulation of CX3CR1, CSF-1R, brain-derived neurotrophic factor (BDNF), and IGF-1 protein expression indicates impairment of the repair and protection functions of microglia in the nervous system. In summary, our results reveal that CuO-NPs promote an increase in inflammatory molecules in BV2 microglia through oxidative stress, activate the CSF-1R/PLCγ2/ERK/Nrf2 pathway, cause apoptosis, and ultimately result in neurofunctional damage to microglia.https://www.mdpi.com/2305-6304/13/4/231CuO-NPsmicrogliacell apoptosisCSF-1R/PLCγ2/ERK/Nrf2 pathwayfunctional impairment |
| spellingShingle | Linhui Yang Lina Zhu Bencheng Lin Yue Shi Wenqing Lai Kang Li Lei Tian Zhuge Xi Huanliang Liu CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway Toxics CuO-NPs microglia cell apoptosis CSF-1R/PLCγ2/ERK/Nrf2 pathway functional impairment |
| title | CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway |
| title_full | CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway |
| title_fullStr | CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway |
| title_full_unstemmed | CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway |
| title_short | CuO-NPs Induce Apoptosis and Functional Impairment in BV2 Cells Through the CSF-1R/PLCγ2/ERK/Nrf2 Pathway |
| title_sort | cuo nps induce apoptosis and functional impairment in bv2 cells through the csf 1r plcγ2 erk nrf2 pathway |
| topic | CuO-NPs microglia cell apoptosis CSF-1R/PLCγ2/ERK/Nrf2 pathway functional impairment |
| url | https://www.mdpi.com/2305-6304/13/4/231 |
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