Biomedicine & Pharmacotherapy

0753-3322

156 (2022) 113874

SCIE

[논문]Pinostrobin ameliorates lipopolysaccharide (LPS)-induced inflammation and endotoxemia by inhibiting LPS binding to the TLR4/MD2 complex

Athapaththu Mudiyanselage Gihan Kavinda Athapaththu, Gi-Young Kim

Athapaththu, 김기영

Kyeong Tae Lee , Mirissa Hewage Dumindu Kavinda, Seunghun Lee, Sanghyuck Kang, Mi-Hwa Lee, Chang-Hee Kang , Yung Hyun Choi

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.

2022-10-13

https://doi.org/10.1016/j.biopha.2022.113874