LAUSR

ABSTRACT Prenylated flavonoids are a unique class of naturally occurring flavonoids that have various pharmacological activities. In the present study, we investigated the anti‐inflammatory effect in murine macrophages of a prenylated flavonoid, 10‐oxomornigrol F (OMF), which was isolated from the twigs of Morus alba (Moraceae). OMF inhibited the lipopolysaccharide (LPS)‐induced production of nitric oxide (NO), tumor necrosis factor‐&agr; (TNF‐&agr;), interleukin (IL)‐1&bgr;, and IL‐6 in RAW264.7 cells, as well as in mouse bone marrow‐derived macrophages (BMMs). OMF also rescued LPS‐induced septic mortality in ICR mice. LPS‐induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), TNF‐&agr; and IL‐6 was also significantly suppressed by OMF treatment in RAW264.7 cells. Treatment of RAW264.7 cells with OMF induced heme oxygenase (HO)‐1 mRNA and protein expression and increased the nuclear translocation of the nuclear factor‐E2‐related factor 2 (Nrf2) as well as the expression of Nrf2 target genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1). Treatment of RAW264.7 cells with OMF increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation levels of p38 mitogen‐activated protein kinase (MAPK); co‐treatment with the antioxidant N‐acetyl‐cysteine (NAC) blocked this OMF‐induced p38 MAPK phosphorylation. Moreover, NAC, or SB203580 (a p38 MAPK inhibitor), blocked the OMF‐induced nuclear translocation of Nrf2 and HO‐1 expression, suggesting that OMF induces HO‐1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO‐1 pathway has anti‐inflammatory properties, inhibiting HO‐1 significantly abrogated the anti‐inflammatory effects of OMF in LPS‐stimulated RAW264.7 cells. Taken together, these findings suggest that OMF exerts its anti‐inflammatory effect by activating the Nrf2/HO‐1 pathway, and may be a potential Nrf2 activator to prevent or treat inflammatory diseases. HighlightsThe anti‐inflammatory effect of 10‐oxomornigrol F, a prenylated flavonoid from Morus alba, is demonstrated.The Nrf2/HO‐1 pathway is attributable to the anti‐inflammatory properties of 10‐oxomornigrol F.10‐Oxomornigrol F activates the Nrf2/HO pathway via the p38 MAPK pathway.The mechanism explains the anti‐inflammatory effect of 10‐oxomornigrol F.