p-Synephrine suppresses inflammatory responses in lipopolysaccharide-stimulated RAW264.7 cells and alleviates systemic inflammatory response syndrome in mice.

p-Synephrine is the primary protoalkaloid found in Citrus species such as Citrus aurantium (bitter orange) and is widely used as a dietary supplement. Although studies have shown the anti-inflammatory effect of p-synephrine, the cells targeted and detailed mechanism(s) of action are not established. Therefore, we investigated the anti-inflammatory effects of p-synephrine and elucidated its underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, peritoneal macrophages, and an LPS-induced systemic inflammatory response syndrome (SIRS) mouse model. We found that p-synephrine inhibits the production of proinflammatory cytokines and nitric oxide in LPS-stimulated RAW264.7 cells, and proinflammatory cytokines in primary peritoneal macrophages. This effect of p-synephrine is due to downregulation of the p38 MAPK and NF-κB signaling pathway and is mediated by ß-adrenergic receptors. Oral administration of p-synephrine to SIRS mice inhibited the serum levels of proinflammatory cytokines and improved their survival rate. Thus, our findings show that p-synephrine alleviates the hyperinflammatory response in macrophages and a SIRS mouse model.

Anti-inflammatory effect of aqueous extract from Kawachi-bankan (Citrus maxima) peel in vitro and in vivo.

Kawachi-bankan (Citrus maxima) is one of the citruses produced in Ehime, Japan. Although health functions of flavonoids and carotenoids in citrus peel have been studied very well, those of water-soluble substances in the peel have not been focused. We herein indicated the anti-inflammatory effect of Kawachi-bankan peel aqueous extract (KPE) in vitro and in vivo. KPE significantly inhibited the production of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α by LPS-stimulated RAW264.7 cells without cytotoxicity. KPE also significantly inhibited the mRNA expression levels of IL-6 and TNF-α in the cells, suggesting that KPE inhibits the production of inflammatory cytokines by suppressing the gene expression levels. Immunoblot analysis revealed that KPE shows an anti-inflammatory effect on macrophages through the suppression of the phosphorylation of p38 and the translocation of NF-κB into nucleus. The oral administration of KPE inhibited the serum levels of inflammatory cytokines and improved the survival rate in systemic inflammatory response syndrome (SIRS) model mice. Our experiments using a cell line suggested that KPE inhibits the production of inflammatory cytokines by macrophages in hyperinflammatory state. In addition, experiments in vivo showed that the oral administration of KPE inhibited the serum levels of inflammatory cytokines and improved the survival rate in SIRS model mice. Our findings indicated that KPE contributes to alleviating of a hyperinflammatory response.