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Nanoceria potently reduce superoxide fluxes from mitochondrial electron transport chain and plasma membrane NADPH oxidase in human macrophages

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Abstract

Cerium oxide nanoparticles, also known as nanoceria, possess antioxidative and anti-inflammatory activities in animal models of inflammatory disorders, such as sepsis. However, it remains unclear how nanoceria affect cellular superoxide fluxes in macrophages, a critical type of cells involved in inflammatory disorders. Using human ML-1 cell-derived macrophages, we showed that nanoceria at 1–100 μg/ml potently reduced superoxide flux from the mitochondrial electron transport chain (METC) in a concentration-dependent manner. The inhibitory effects of nanoceria were also shown in succinate-driven mitochondria isolated from the macrophages. Furthermore, nanoceria markedly mitigated the total intracellular superoxide flux in the macrophages. These data suggest that nanoceria could readily cross the plasma membrane and enter the mitochondrial compartment, reducing intracellular superoxide fluxes in unstimulated macrophages. In macrophages undergoing respiratory burst, nanoceria also strongly reduced superoxide flux from the activated macrophage plasma membrane NADPH oxidase (NOX) in a concentration-dependent manner. Token together, the results of the present study demonstrate that nanoceria can effectively diminish superoxide fluxes from both METC and NOX in human macrophages, which may have important implications for nanoceria-mediated protection against inflammatory disease processes.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CDCL:

Coelenterazine hcp-derived chemiluminescence

DEPMPO:

5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide

EPR:

Electron paramagnetic resonance

FBS:

Fetal bovine serum

FCCP:

Carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone

LDCL:

Lucigenin-derived chemiluminescence

METC:

Mitochondrial electron transport chain

NOX:

NADPH oxidase

PBS:

Phosphate-buffered saline

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TPA:

12-O-Tetradecanoylphorbol 13-acetate

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Acknowledgements

This study was supported in part by a grant from the National Institutes of Health (GM124652). The EPR facility used in this study was supported by an Institutional Development Grant (IDG-1018) from the North Carolina Biotechnology Center (Research Triangle Park, NC). The Berthold LB9505 luminometer was provided by Dr. Michael A. Trush from The Johns Hopkins University (Baltimore, MD).

Funding

This study was supported in part by a Grant (GM124652) from the National Institutes of Health, Bethesda, MD, and an Institutional Development Grant (IGD-1018) from the North Carolina Biotechnology Center, Research triangle Park, NC.

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Authors and Affiliations

  1. Department of Pharmacology, Jerry Wallace School of Osteopathic Medicine, Campbell University, Buies Creek, NC, 27506, USA

    Y. Robert Li

  2. Department of Physiology and Pathophysiology, Jerry Wallace School of Osteopathic Medicine, Campbell University, Buies Creek, NC, 27506, USA

    Hong Zhu

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Both authors contributed to the study conception, design, performance, data analysis, and writing. Both authors read and approved the final manuscript.

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Correspondence to Y. Robert Li.

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Li, Y.R., Zhu, H. Nanoceria potently reduce superoxide fluxes from mitochondrial electron transport chain and plasma membrane NADPH oxidase in human macrophages. Mol Cell Biochem 476, 4461–4470 (2021). https://doi.org/10.1007/s11010-021-04246-7

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