Euxanthone inhibits lipopolysaccharide-induced injury, inflammatory response, and MUC5AC hypersecretion in human airway epithelial cells by the TLR4/MyD88 pathway.

Abstract

Asthma progression is involved in airway epithelial dysfunction, airway inflammatory response, and mucus hypersecretion. Euxanthone has been found to exhibit cytotoxic activity on several human diseases, such as neurological disorders and cancers. Our study aimed to explore the influence of euxanthone on lipopolysaccharide (LPS)-induced injury, inflammatory response, and mucin 5AC (MUC5AC) hypersecretion in human airway epithelial cells (AECs). Network pharmacology analysis was carried out to analyze the drug targets and key pathways of euxanthone against asthma. Cell injury was evaluated by CCK-8, Lactate dehydrogenase (LDH) release assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The production of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and MUC5AC was measured using enzyme-linked immunosorbent assay (ELISA). MUC5AC mRNA expression was detected by qRT-PCR. Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) protein expression was examined by western blot analysis. Venn diagram showed 14 overlapping targets between euxanthone and asthma. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, we focused on TLR signaling pathway. LPS exposure evoked viability reduction, increased LDH release and apoptosis, and induced production of inflammatory cytokines (IL-6, IL-8, and MCP-1) and MUC5AC hypersecretion in human AECs, which were alleviated by euxanthone. Mechanistically, we validated that euxanthone attenuated LPS-induced activation of TLR4/MyD88 pathway in AECs. Moreover, inhibition of the TLR4/MyD88 pathway enhanced the inhibitory effect of euxanthone on LPS-induced cell injury, inflammatory response and MUC5AC expression. In conclusion, euxanthone attenuated LPS-induced cell injury, inflammatory response, and MUC5AC expression in AECs by inhibiting the activation of TLR4/MyD88 pathway.

• Authors: Wen Shen, Yuyao Yin, Tiantian Li, Gang Cao
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) Vol. 42 Issue 4 Pg. 671-682 (04 2022) ISSN: 1099-1263 [Electronic] England
• PMID: 34655103 (Publication Type: Journal Article)
• Copyright: © 2021 John Wiley & Sons, Ltd.

Chemical References

• Interleukin-8
• Lipopolysaccharides
• MUC5AC protein, human
• Mucin 5AC
• Myeloid Differentiation Factor 88
• TLR4 protein, human
• Toll-Like Receptor 4
• Xanthones
• euxanthone

Topics

• Asthma (metabolism)
• Epithelial Cells
• Humans
• Interleukin-8 (metabolism)
• Lipopolysaccharides (toxicity)
• Mucin 5AC (genetics, metabolism, pharmacology)
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)
• Xanthones