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Anti-septic Effects of Fisetin In Vitro and In Vivo

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Abstract

Sepsis is a state of disrupted inflammatory homeostasis that is initiated by infection. High mobility group box 1 (HMGB1) protein acting as a late mediator of severe vascular inflammatory conditions, such as sepsis and endothelial cell protein C receptor (EPCR), is involved in vascular inflammation. Fisetin, an active compound from the family Fabaceae, was reported to have antiviral, neuroprotective, and anti-inflammatory activities. Here, we determined the anti-septic effects of fisetin on HMGB1-mediated inflammatory responses and on the shedding of EPCR in vitro and in vivo, for the first time. First, we monitored the effects of post-treatment fisetin on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment fisetin was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. Fisetin also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. Fisetin induced potent inhibition of phorbol-12-myristate 13-acetate (PMA) and CLP-induced EPCR. Fisetin also inhibited the expression and activity of tumor necrosis factor-α converting enzyme, induced by PMA in endothelial cells. In addition, fisetin inhibited the production of tumor necrosis factor-α and the activation of AKT, nuclear factor-κB, and extracellular regulated kinases 1/2 by HMGB1 in HUVECs. Fisetin also down-regulated CLP-induced release of HMGB1, production of interleukin 1β, and reduced septic mortality. Collectively, these results suggest that fisetin may be a candidate therapeutic agent for the treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

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Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korean government [MSIP] (Grant Nos. NRF-2012R1A4A1028835 and 2013–067053).

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea

    Hayoung Yoo & Jong-Sup Bae

  2. Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, 712-715, Republic of Korea

    Sae-Kwang Ku

  3. Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu, 701-724, Republic of Korea

    Min-Su Han

  4. Division of Plant Biosciences, School of Applied BioSciences, College of Agriculture and Life Science, Kyungpook National University, Daegu, 702-701, Republic of Korea

    Kyung-Min Kim

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  1. Hayoung Yoo
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Correspondence to Jong-Sup Bae.

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Hayoung Yoo and Sae-Kwang Ku contributed equally to this work.

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Yoo, H., Ku, SK., Han, MS. et al. Anti-septic Effects of Fisetin In Vitro and In Vivo . Inflammation 37, 1560–1574 (2014). https://doi.org/10.1007/s10753-014-9883-4

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