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Therapeutic Action of Honokiol on Postoperative Ileus via Downregulation of iNOS Gene Expression

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Abstract

Postoperative ileus is a common complication after intra-abdominal surgery. Nitric oxide produced by macrophages in the inflamed gastrointestinal tract plays a crucial role in the pathogeny of postoperative ileus. Honokiol, extracted from the bark of Magnolia spp., is a natural compound with a biphenolic structure. In the present study, we examined the effect of honokiol on postoperative ileus and discussed its site of action. Postoperative ileus model mice were generated by surgical intestinal manipulation. Mice were administered honokiol (10 mg kg−1, per os) 1 h before and after intestinal manipulation. Gastrointestinal transit, leukocyte infiltration, and messenger RNA (mRNA) expression of inflammatory mediators were measured in postoperative ileus model mice with or without honokiol. We also investigated the inflammatory effect of honokiol in lipopolysaccharide-stimulated peritoneal macrophages. Gastrointestinal transit was delayed in postoperative ileus model mice and honokiol recovered the impaired transit. Honokiol significantly inhibited leukocyte infiltration and upregulation of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) and inducible nitric oxide synthase in the ileal muscle layer of postoperative ileus model mice. In peritoneal macrophages activated by lipopolysaccharide, honokiol significantly inhibited the upregulated mRNA expression of proinflammatory cytokines and inducible nitric oxide synthase. Honokiol significantly recovered gastrointestinal dysmotility and inhibited intestinal inflammation in postoperative ileus. Moreover, honokiol was suggested to have effects on macrophages, namely, inhibiting mRNA expression of proinflammatory cytokines and inducible nitric oxide synthase. Taken together, honokiol represents a potential novel therapeutic agent for postoperative ileus.

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Abbreviations

BSA:

Bovine serum albumin

FITC:

Fluorescein isothiocyanate

GABAAR:

Gamma-aminobutyric acid A receptor

HNK:

Honokiol

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IM:

Intestinal manipulation

iNOS:

Inducible NOS

LPS:

Lipopolysaccharide

MnSOD:

Manganese superoxide dismutase

MPO:

Myeloperoxidase

OSCP:

Oligomycin-sensitivity-conferring protein

POI:

Postoperative ileus

ROS:

Reactive oxygen species

TBS:

Tris-buffered saline

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Japan (MH: 24248050 and HO: 25221205).

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Authors and Affiliations

  1. Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan

    Taiki Mihara, Shoma Mikawa, Noriyuki Kaji, Hiroshi Ozaki & Masatoshi Hori

  2. Department of Clinical Research, Oriental Medicine Research Center, Tokyo, 108-8642, Japan

    Mari Endo & Tetsuro Oikawa

  3. Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan

    JAN Tong-Rong

Authors
  1. Taiki Mihara
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  2. Shoma Mikawa
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Contributions

Author Contributions

MH and TM conceived and designed the experiments. TM performed all of the experiments. TM and MH wrote the manuscript. SM, NK, ME, TO, HO, Jan TR, and MH reviewed and discussed the data.

Corresponding author

Correspondence to Masatoshi Hori.

Ethics declarations

All animal experiments were performed according to the Guide for Animal Use and Care published by the University of Tokyo and were approved by the Institutional Review Board of the University of Tokyo (approval code P10-482).

Conflict of Interest

The authors declare that they have no conflicts of interest.

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Mihara, T., Mikawa, S., Kaji, N. et al. Therapeutic Action of Honokiol on Postoperative Ileus via Downregulation of iNOS Gene Expression. Inflammation 40, 1331–1341 (2017). https://doi.org/10.1007/s10753-017-0576-7

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