Alleviation of LPS-induced oxidative stress and inflammation by lesbicoumestan (7) via the increase of Nrf2 expression in mouse Kupffer cells

Lesbicoumestans are a class of bioactive compounds isolated from the roots of Lespedeza bicolor (L. bicolor). These compounds have been reported to exhibit anticancer and antiproliferative activities. In this study, our primary focus was to examine the antioxidant capabilities of lesbicoumestan (7) (LC-7), a newly isolated coumestan from roots of L. bicolor, using lipopolysaccharide (LPS)-stimulated immortalized mouse Kupffer cells (ImKCs) as the experimental model. The investigation revealed that LC-7 played a pivotal role in inhibiting the production of reactive oxygen species (ROS). Additionally, LC-7 effectively restored the imbalanced glutathione(GSH)/glutathione disulfide ratio and enhanced the activity of glutathione peroxidase (GPx) following cellular exposure to LPS. Moreover, our investigation revealed that LC-7 exhibited the capacity to enhance the expression of heme oxygenase-1 (HO-1), leading to inhibition of nitric oxide (NO) and proinflammatory cytokines production induced by LPS. Notably, LC-7 did not significantly impact the nuclear factor kappa B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Intriguingly, LC-7 modulated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway by direct interaction with Kelch-like-ECH-associated protein 1 (Keap1). These findings suggest that LC-7 possesses antioxidant and anti-inflammatory properties in LPS-stimulated ImKCs by upregulating Nrf2 expression.