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An Active Drimane-Type Lactone from Polygonum jucundum Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice Through TLR4-MAPKs Signaling Pathway

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Abstract

The herbs of Polygonum jucundum Lindex. (Polygonaceae) is a traditional Chinese medicine for inflammatory diseases. 2α-Hydroxyl-3β-angeloylcinnamolide (HAC), a drimane-type sesquiterpenoid, was the major active compound of the ethanol extract of P. jucundum which inhibited the production of inflammatory mediators. However, the biological mechanism of HAC for anti-inflammatory activity has not been reported. In the current study, we investigated whether HAC could suppress the production of inflammatory mediators in lipopolysaccharide (LPS)-induced acute lung injury in mice (ALI) through downregulation of Toll-like receptor 4 (TLR4) and activations of mitogen-activated protein kinases (MAPKs) and inducible protein nitric oxide synthase (iNOS). Moreover, our data indicated that HAC inhibits the overexpression of iNOS and TLR4 in LPS-treated RAW264.7, and also inhibits MAPK signal. These findings suggest that HAC shows anti-inflammatory effects in ALI mice through suppressing TLR4-mediated MAPK pathway in activated macrophages. In addition, six derivatives of HAC obtained by structure modification were investigated for their inhibitory effects on the production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α), suggesting that the acetylation could increase the inhibition of HAC on TNF-α release in LPS-treated RAW264.7 cells. In summary, all these results showed that HAC may be a potential anti-inflammatory lead compound for the treatment of acute lung injury.

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Acknowledgements

We would like to thank the National Natural Science Foundation (8157355, 30700060 for C.F. Zhang) and the National New Drug Innovation Major Project of China (2011ZX09307-002-02 for M. Zhang) for the financial support for this research.

Author information

Correspondence to Mian Zhang or Chaofeng Zhang.

Ethics declarations

All experimental protocols were approved by the Animal Studies Committee of China Pharmaceutical University and animal handling followed the dictates of the National Animal Welfare Law of China.

Conflict of Interest

The authors declare that they have no conflict of interest.

Statement of Authorship

In this paper, Yang Hu, Lijun Tao, and Mian Zhang undertake the synthesis and pharmacology experiments, Hui Tan and Kuniyoshi Shimizu help to study the anti-inflammation action in vitro. Yang Hu and Fei Zhang have contributed to the X-ray structure analysis. Chaofeng Zhang, the corresponding author, undertakes the design of this project, QSAR analysis, and logic train of thought.

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Hu, Y., Tao, L., Tan, H. et al. An Active Drimane-Type Lactone from Polygonum jucundum Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice Through TLR4-MAPKs Signaling Pathway. Inflammation 40, 1204–1213 (2017). https://doi.org/10.1007/s10753-017-0563-z

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Key Words

  • 2α-Hydroxyl-3β-angeloylcinnamolide
  • Toll-like receptor 4
  • Mitogen-activated protein kinases
  • Acute lung injury
  • Anti-inflammation