Radix Glycyrrhizae extract and licochalcone a exert an anti-inflammatory action by direct suppression of toll like receptor 4

Min Cai; You-Cai Xu; Bo Deng; Jun-Bang Chen; Ting-Fang Chen; Ke-Feng Zeng; Si Chen; Sui-Hui Deng; Zhang-Bin Tan; Wen-Jun Ding; Shuang-Wei Zhang; Bin Liu; Jing-Zhi Zhang

doi:10.1016/j.jep.2022.115869

Radix Glycyrrhizae extract and licochalcone a exert an anti-inflammatory action by direct suppression of toll like receptor 4

J Ethnopharmacol. 2023 Feb 10;302(Pt A):115869. doi: 10.1016/j.jep.2022.115869. Epub 2022 Oct 26.

Authors

Min Cai¹, You-Cai Xu², Bo Deng³, Jun-Bang Chen⁴, Ting-Fang Chen⁵, Ke-Feng Zeng⁶, Si Chen⁷, Sui-Hui Deng⁸, Zhang-Bin Tan⁹, Wen-Jun Ding¹⁰, Shuang-Wei Zhang¹¹, Bin Liu¹², Jing-Zhi Zhang¹³

Affiliations

¹ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China; Guangzhou Emergency Medical Command Center, Guangzhou, 510030, China. Electronic address: [email protected].
² Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
³ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
⁴ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
⁵ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
⁶ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
⁷ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
⁸ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
⁹ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
¹⁰ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
¹¹ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
¹² Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].
¹³ Department of Traditional Chinese Medicine, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China. Electronic address: [email protected].

PMID: 36309116
DOI: 10.1016/j.jep.2022.115869

Abstract

Ethnopharmacological relevance: Radix Glycyrrhizae (GL), a herbal medicine that is widely available, has shown advantages for a variety of inflammatory diseases. Toll like receptor 4 (TLR4) pathway has been shown to play a key role in the progression of inflammation.

Aim of the study: The purpose of this study was to investigate the involvement of TLR4 in the anti-inflammatory mechanism of GL extract and its active constituent on acute lung injury (ALI).

Materials and methods: A model of inflammation produced by lipopolysaccharide (LPS) was established in C57BL/6 mice and macrophages derived from THP-1. To screen the active components of GL, molecular docking was used. Molecular dynamics and surface plasmon resonance imaging (SPRi) were used to study the interaction of a specific drug with the TLR4-MD2 complex. TLR4 was overexpressed by adenovirus to confirm TLR4 involvement in the anti-inflammatory activities of GL and the chosen chemical.

Results: We observed that GL extract significantly reduced both LPS-induced ALI and the production of pro-inflammatory factors including TNF-α, IL-6 and IL-1β. Additionally, GL inhibited the binding of Alexa 488-labeled LPS (LPS-488) to the membrane of THP-1 derived macrophages. GL drastically reduce on the expression of TLR4 and the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-B (NF-κB). Furthermore, molecular docking revealed that Licochalcone A (LicoA) docked into the LPS binding site of TLR4-MD2 complex. MD2-LicoA binding conformation was found to be stable using molecular dynamic simulations. SPRi indicated that LicoA bound to TLR4-MD2 recombinant protein with a KD of 3.87 × 10^-7 M. LicoA dose-dependently reduced LPS-488 binding to the cell membrane. LicoA was found to significantly inhibit LPS-induced lung damage and inflammation. Furthermore, LicoA inhibited TLR4 expression, MAPK and NF-κB activation in a dose-dependent manner. The inhibitory effects of GL and LicoA on LPS-induced inflammation and TLR4 signaling activation were partly eliminated by TLR4 overexpression.

Conclusion: Our findings imply that GL and LicoA exert inhibitory effects on inflammation by targeting the TLR4 directly.

Keywords: Inflammation; Licochalcone A; Radix Glycyrrhizae; Toll like receptor.

MeSH terms

Acute Lung Injury* / chemically induced
Acute Lung Injury* / drug therapy
Acute Lung Injury* / metabolism
Animals
Anti-Inflammatory Agents / adverse effects
Inflammation / chemically induced
Lipopolysaccharides / toxicity
Lymphocyte Antigen 96 / metabolism
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
NF-kappa B / metabolism
Toll-Like Receptor 4* / metabolism

Substances

Toll-Like Receptor 4
Lipopolysaccharides
NF-kappa B
licochalcone A
Lymphocyte Antigen 96
Anti-Inflammatory Agents