In vitro and in vivo anti-inflammatory effects of 5-hydroxyconiferaldehyde via NF-κB, MAPK/AP-1, and Nrf2 modulation

We previously reported that 5-hydroxyconiferaldehyde (5-HCA), a phenolic compound isolated from the Campanula takesimana, potently inhibits prostaglandin E₂ (PGE₂) production triggered by lipopolysaccharide (LPS) in macrophages. As the precise molecular mechanisms underlying the anti-inflammatory effects of 5-HCA remain unclear, we further examined these mechanisms in LPS-stimulated RAW 264.7 macrophages and carrageenan-induced paw edema rats. The results revealed that 5-HCA considerably impeded nitric oxide (NO) and PGE₂ production as well as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β expression by suppressing the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in LPS-induced RAW 264.7 macrophages. Furthermore, 5-HCA suppressed the generation of reactive oxygen species (ROS) triggered by LPS by enhancing heme oxygenase-1 (HO-1) expression via nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). In rats with carrageenan-induced paw edema, administration of 5-HCA (10 or 30 mg/kg, i.p.) resulted in a significant reduction in the inflammatory response (paw volume and thickness) and inflammatory hyperalgesia by suppressing pro-inflammatory mediators through NF-κB, MAPK/AP-1, and Nrf2 regulation. These findings highlight the anti-inflammatory properties of 5-HCA in the acute inflammation model and suggest its potential for further investigation of broader inflammatory disorders.