Anti-inflammatory effects of Juglanin H，a diarylheptanoid from Juglans regia in macrophages

Abstract

Inflammation is a complex biological response of body to endogenous and exogenous stimuli such as damaged cells, pathogens, or irradiation. Regulated inflammatory response plays an essential role in adjusting body functions and maintaining homeostasis. However, uncontrolled inflammatory response can be a principal factor of causing tissue damage or chronic inflammatory diseases, such as cardiovascular diseases, obesity, inflammatory bowel disease and cancer. Therefore, the regulation of uncontrolled inflammation responses is a strategy for prevention and therapeutic approach for inflammation associated diseases. Macrophages are innate immune cells that initiate inflammation and immune responses. When exposed to various proinflammatory factors, monocytes are recruited to extravascular tissues and differentiate into macrophages under the pathogenesis of inflammation. Once activated, macrophages are able to produce proinflammation mediated cellular signaling molecules. Diarylheptanoids are complex phenolic compounds with two phenyl rings at C-1 and C-7 positions. Juglanin H, a novel diarylheptanoid, was isolated from green walnut husk Juglans regia which is a traditional Chinese medicine used for the treatment of cancer and inflammation. However, the bioactivity and underlying mechanisms remain to be elucidated. In the present study, the anti-inflammatory activities of Juglanin H were investigated. Juglanin H significantly suppressed the production of nitric oxide and the expression of pro-inflammatory mediators including inducible nitric oxide synthase (iNOS) and interleukin-1β (IL-1β) in both protein and mRNA levels in RAW 264.7 cells. Juglanin H also inhibited the translocation of NF-κB from the cytoplasm to the nucleus and modulated the activation of signaling molecules in MAPK and PI3K/Akt pathways. In addition, Juglanin H exhibited a significant suppression of interleukin-6 (IL-6) and Interferon-β (IFN-β) at mRNA level and inhibited NF-κB translocation into nucleus in THP-1 differentiated macrophages. Juglanin H was found to be able to decrease lipopolysaccharide (LPS)-stimulated reactive oxygen species (ROS) generation by activating Nrf2 leading to the initiation of hemeoxygenase-1 (HO-1), an anti-oxidant and cytoprotective enzyme. These findings suggest that Juglanin H is a potential anti-inflammatory agent derived from natural products.