Buckwheat Flavonoids Modulate Inflammation in RAW 264.7 Macrophages at Physiologically Relevant Concentrations via the LPS/COX-2 Pathway

Buckwheat (BW) is recognized as a functional food with antioxidant and anti-inflammatory properties. BW (poly)phenols are important bioactive compounds associated with these benefits, although their therapeutic role remains elusive. We used a multidisciplinary approach to identify the bioactive flavonoids of BW and their molecular mechanisms. Physiologically relevant concentrations of luteolin (Lute), quercetin (Quer), apigenin (Api), and kaempferol (Kaem) were effective in reducing prostaglandin (PG)E₂ and PGD₂ biosynthesis in LPS-activated macrophages by acting at distinct branch points of the LPS/COX-2 pathway. Lute, Api, and Kaem reduced COX-2 levels, whereas Quer exerted the opposite effect. Lute and Kaem inhibited Ikkβ phosphorylation, while TLR4 was identified as a flavonoid's target. PGE₂ and PGD₂ reductions were independent of COX-2 modulation and correlated with hematopoietic prostaglandin D synthase (hPGDS) inhibition (exerted by Lute and Quer). These findings offer a new perspective on the LPS/COX-2 pathway as a target of BW-derived products to address inflammation-related diseases.