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Fucoxanthin inhibits lipopolysaccharide-induced inflammation and oxidative stress by activating nuclear factor E2-related factor 2 via the phosphatidylinositol 3-kinase/AKT pathway in macrophages

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Abstract

Purpose

Anti-inflammatory and antioxidant effects of fucoxanthin (FCX), a xanthophyll carotenoid, have been suggested. However, underlying mechanisms are elusive. The objective of this study was to elucidate the mechanisms by which FCX and its metabolites inhibit lipopolysaccharide (LPS)-induced inflammation and oxidative stress in macrophages.

Methods

The effects of the FCX on mRNA and protein expression of pro-inflammatory cytokines and antioxidant genes, and reactive oxygen species (ROS) accumulation were determined in RAW 264.7 macrophages. A potential role of FCX in the modulation of phosphatidylinositol 3-kinase (PI3K)/AKT/nuclear E2-related factor 2 (NRF2) axis was evaluated.

Results

FCX significantly decreased LPS-induced interleukin (Il)6, Il1b, and tumor necrosis factor α (Tnf) mRNA abundance and TNFα secretion. FCX attenuated LPS or tert-butyl-hydroperoxide-induced ROS accumulation with concomitant increases in the expression of antioxidant enzymes. Also, trolox equivalent antioxidant capacity assay demonstrated that FCX had a potent free radical scavenging property. FCX markedly increased nuclear translocation of NRF2 in LPS-treated macrophages, consequently inducing its target gene expression. Interestingly, the effect of FCX on NRF2 nuclear translocation was noticeably diminished by LY294002, an inhibitor of PI3K, but not by inhibitors of mitogen-activated protein kinases. Phosphorylation of AKT, a downstream element of PI3K, was also markedly increased by FCX. FCX metabolites, such as fucoxanthinol and amarouciaxanthin A, significantly attenuated LPS-induced ROS accumulation and pro-inflammatory cytokine expression.

Conclusion

FCX exerts anti-inflammatory and antioxidant effects by the activation of NRF2 in the macrophages activated by LPS, which is mediated, at least in part, through the PI3K/AKT pathway.

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Abbreviations

ABTS:

2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulphonic acid)

ACXA:

Amarouciaxanthin A

ARE:

Antioxidant response element

BMDM:

Bone marrow-derived macrophages

Cat:

Catalase

FCN:

Fucoxanthinol

FCX:

Fucoxanthin

FAK:

Focal adhesion kinase

Gpx1:

Glutathione peroxidase 1

Hmox1:

Heme oxygenase-1

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

Keap1:

Kelch-like ECH-associated protein 1

LPS:

Lipopolysaccharide

MAPKs:

Mitogen-activated protein kinases

NF-κB:

Nuclear factor κB

NRF2:

Nuclear E2-related factor 2

PI3K:

Phosphatidylinositol 3-kinase

ROS:

Reactive oxygen species

Sod1:

Superoxide dismutase 1

TAC:

Total antioxidant capacity

t-BHP:

Tert-butyl-hydroperoxide

TEAC:

Trolox equivalent antioxidant capacity

TNFα:

Tumor necrosis factor α

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Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1A6A3A03032678) to M-.B. Kim and by funds from the College of Agriculture, Health and Natural Resources at the University of Connecticut to J-.Y. Lee.

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Authors and Affiliations

  1. Department of Nutritional Sciences, University of Connecticut, 27 Manter Rd., Storrs, CT, 06269, USA

    Mi-Bo Kim, Hyunju Kang, Yang Li, Young-Ki Park & Ji-Young Lee

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  1. Mi-Bo Kim
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  2. Hyunju Kang
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  3. Yang Li
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Contributions

MBK: conducted experiments, analyzed data, and wrote the manuscript. HK, YL, and YKP: performed experiments and contributed to manuscript preparation. JYL: designed the study, directed the study, interpreted data, and contributed to manuscript preparation.

Corresponding author

Correspondence to Ji-Young Lee.

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Kim, MB., Kang, H., Li, Y. et al. Fucoxanthin inhibits lipopolysaccharide-induced inflammation and oxidative stress by activating nuclear factor E2-related factor 2 via the phosphatidylinositol 3-kinase/AKT pathway in macrophages. Eur J Nutr 60, 3315–3324 (2021). https://doi.org/10.1007/s00394-021-02509-z

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