PUBLICATION
Pinostrobin ameliorates lipopolysaccharide (LPS)-induced inflammation and endotoxemia by inhibiting LPS binding to the TLR4/MD2 complex
- Authors
- Athapaththu, A.M.G.K., Lee, K.T., Kavinda, M.H.D., Lee, S., Kang, S., Lee, M.H., Kang, C.H., Choi, Y.H., Kim, G.Y.
- ID
- ZDB-PUB-221022-8
- Date
- 2022
- Source
- Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 156: 113874 (Journal)
- Registered Authors
- Keywords
- Inflammation, Myeloid differentiation factor 2, Nuclear factor-κB, Pinostrobin, Toll-like receptor 4
- MeSH Terms
-
- Animals
- Anti-Inflammatory Agents/pharmacology
- Anti-Inflammatory Agents/therapeutic use
- Endotoxemia*/chemically induced
- Endotoxemia*/drug therapy
- Inflammation/chemically induced
- Inflammation/drug therapy
- Inflammation/metabolism
- Lipopolysaccharides/pharmacology
- Molecular Docking Simulation
- NF-kappa B/metabolism
- Toll-Like Receptor 4*/metabolism
- Zebrafish/metabolism
- PubMed
- 36270256 Full text @ Biomed. Pharmacother.
Citation
Athapaththu, A.M.G.K., Lee, K.T., Kavinda, M.H.D., Lee, S., Kang, S., Lee, M.H., Kang, C.H., Choi, Y.H., Kim, G.Y. (2022) Pinostrobin ameliorates lipopolysaccharide (LPS)-induced inflammation and endotoxemia by inhibiting LPS binding to the TLR4/MD2 complex. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 156:113874.
Abstract
Pinostrobin is a natural flavonoid with valuable pharmacological properties, including anti-cancer, anti-viral, and anti-oxidant activities. However, the anti-inflammatory effects of pinostrobin have not been well studied. In this study, we investigated whether pinostrobin attenuates lipopolysaccharide (LPS)-induced inflammation and endotoxemia. Additionally, the target molecule of pinostrobin was identified through molecular docking simulation. Pinostrobin decreased LPS-induced nitric oxide (NO) and prostaglandin E2 production, and reduced the expression of inducible NO synthase and cyclooxygenase-2. Furthermore, pinostrobin inhibited the production of proinflammatory cytokines, including interleukin-12 and tumor necrosis factor-α in LPS-stimulated RAW 264.7 macrophages accompanied by inhibiting nuclear translocation of nuclear factor-κB. The anti-inflammatory effect of pinostrobin was further confirmed in LPS-microinjected zebrafish larvae by diminishing the recruitment of macrophages and neutrophils, and proinflammatory gene expression. Moreover, LPS-microinjected zebrafish larvae showed a decrease in heart rate and an increase in mortality and abnormalities. However, pinostrobin significantly attenuated these adverse effects. Molecular docking showed that pinostrobin fits into myeloid differentiation factor (MD2) and Toll-like receptor 4 (TLR4) with no traditional hydrogen bonds (pose 1). The 2D ligand interaction diagram showed that pinostrobin forms a carbon hydrogen bond with LYS89 in MD2 and many non-covalent interactions, including π-alkyl or alkyl and van der Waals interactions, indicating that pinostrobin hinders LPS binding between MD2 and TLR4 and consequently inhibits TLR4/MD2-mediated inflammatory responses. These data suggest that pinostrobin attenuates LPS-induced inflammation and endotoxemia by binding to the TLR4/MD2 complex.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping