Anti-Inflammatory Activities of Isogosferol, a Furanocoumarin Isolated from Citrus junos Seed Shells through Bioactivity-Guided Fractionation

Abstract

<i>Citrus junos</i> Tanaka is a traditional medicine for treating coughs, dyspepsia, diabetes, asthma, neuralgia, and inflammatory disorders, and is distributed in Asia, especially in Korea, Japan, and China. This study aimed to use bioactivity-guided fractionation to find therapeutic phytochemicals from <i>C. junos</i> seeds, which can attenuate inflammatory responses. Nine coumarins (<b>1</b>-<b>9</b>) were isolated from the methanolic extract of <i>C. junos</i> seed shells and the inhibitory effects against inflammatory mediators were investigated using murine macrophages. Among the coumarins, compound <b>3</b>, isogosferol (ISO), more potently attenuated the production of nitric oxide (NO) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. ISO also inhibited the expression of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. Additionally, the phosphorylation of extracellular-regulated kinases (pERK)1/2 was reduced by ISO. We confirmed that ISO attenuated the release of interleukin-1 beta (IL-1β), which is a central mediator of the inflammatory response. These results demonstrate that ISO from <i>C. junos</i> seed shells may be a potent therapeutic candidate for the treatment of inflammatory diseases.