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CeO2@PAA-LXW7 Attenuates LPS-Induced Inflammation in BV2 Microglia

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Abstract

Microglia are the inherent immune effector cells in the central nervous system (CNS), are activated rapidly when the CNS is stimulated by ischaemia, infection, injury, etc. and participate in and aggravate the development of inflammatory reactions in the CNS. During the process of microglial activation, inflammatory factors such as TNF-α and IL-1β and an abundance of reactive oxygen species (ROS)/reactive nitrogen species (RNS), are released by damaged nerve cells. LXW7 is a small molecule peptide and specifically binds with integrin αvβ3. Cerium oxide nanoparticles (nanoceria) are strong free radical scavengers and are widely used in many studies. In this research, a model of inflammation was established using lipopolysaccharide (LPS) to induce BV2 microglia activation, and the effects of CeO2@PAA (synthetic nanoscale cerium oxide particles), LXW7 and CeO2@PAA-LXW7 were evaluated. We detected the expression level of inflammatory factors, the release of NO in BV2 cells and the generation of intracellular ROS. The expression levels of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) and their phosphorylated proteins were detected in BV2 microglia. We found that CeO2@PAA, LXW7 and CeO2@PAA-LXW7 all effectively inhibited the activation of BV2 microglia, reduced the production of cytokines and the release of NO and reduced the production of intracellular ROS. The three treatments all inhibited the phosphorylation of FAK and STAT3 in BV2 microglia. Regarding these effects, CeO2@PAA-LXW7 was more effective than the other two monotherapies. Our data indicate that CeO2@PAA, LXW7 and CeO2@PAA-LXW7 can exert a neuroprotective function by inhibiting the inflammatory response of LPS-induced BV2 microglia. LXW7 may inhibit the activation of FAK and STAT3 signals in combination with integrin αvβ3 to restrain neuroinflammation and the antioxidative stress effect of cerium oxide; hence, CeO2@PAA-LXW7 can exert a more robust anti-inflammatory and neuroprotective effect via synergistically suppressing the ability of LXW7 to influence the integrin pathway and the free radical-scavenging ability of CeO2@PAA.

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Funding

This study was funded by the Basic Research Project of Peking University Shenzhen Hospital (JCYJ2018012), the Health and Family Planning Commission of Shenzhen Municipality Fund (SZSM201812096) and the Beijing Key Laboratory (BZ0250). The drug synthesis process was supported by the Inner Mongolia University Startup Fund Project (21300-5145152), the Inner Mongolia Education Department Key Project (NJZZ16015) and the Inner Mongolia Natural Science Foundation (2016MS0216).

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Authors and Affiliations

  1. Department of Neurology, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing, 100034, China

    Jingjing Jia & Yining Huang

  2. Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong Province, China

    Jingjing Jia, Jingjing Sun, Sijia Peng, Qizhi Xie & Li Yi

  3. College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot, Inner Mongolia Province, China

    Changyan Li

  4. Department of Phoenix International Medical Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China

    Ting Zhang

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  1. Jingjing Jia
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  2. Changyan Li
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  3. Ting Zhang
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  4. Jingjing Sun
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  8. Li Yi
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Contributions

LY designed the study. CL synthesized the drugs. JJ, TZ and SP performed the studies. JS and QX assisted in part of the experiment. JJ analysed the data and wrote the paper. YH and LY edited the paper. All authors read and approved the final manuscript.

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Correspondence to Yining Huang or Li Yi.

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Jia, J., Li, C., Zhang, T. et al. CeO2@PAA-LXW7 Attenuates LPS-Induced Inflammation in BV2 Microglia. Cell Mol Neurobiol 39, 1125–1137 (2019). https://doi.org/10.1007/s10571-019-00707-2

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