Isoliquiritigenin attenuates high-fat diet-induced intestinal damage by suppressing inflammation and oxidative stress and through activating Nrf2

The protective effect of ISL against HFD-induced intestinal damage. High-fat diet (HFD) feeding promotes overproduction of reactive oxygen species (ROS) in the duodena of rats by increasing the accumulation of triglycerides (TGs) and cholesterol (CHOL). These ROS scavenge antioxidants include glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). In addition, ROS stimulates the activities of NF-κB p65, which stimulates the synthesis of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). In addition, HFD suppresses the levels and activities of the Nrf2 through upregulating keap-1, which degrades Nrf2. This leads to further oxidative stress and inflammation by decreasing antioxidant levels and further activating Nrf2. On the other hand, ISL attenuates this by direct upregulation and activation of Nrf2. [Display omitted] •ISL attenuates HFD-induced intestinal damage by activating Nrf2.•ISL improved the duodenal damage and reduced the intestinal accumulation of TGs and CHOL.•ISL reduced neutrophils accumulation and levels of MDA, TNF-α, IL-6, and MCP-1.•ISL lowered circulatory levels of LPS and increased levels of tight junction proteins. This study examined if isoliquiritigenin (ISL) attenuates high-fat diet (HFD)-induced intestinal damage and if this involves modulating Nrf2. Rats included 5 groups (n = 8/group): control (vehicle), ISL, HFD, HFD + ISL, and HFD + ISL + brusatol (an inhibitor of Nrf2). Treatments with the vehicle and ISL (30 mg/kg) were given orally. With no effect on intestinal lipids, ISL improved the duodenal structure in HFD rats and reduced the duodenal levels of malondialdehyde, tumor necrosis factor-α, interleukin-6, macrophage chemoattractant protein-1, and nuclear levels of NF-κB p65. Also, ISL increased the intestinal levels of superoxide dismutase, catalase, glutathione, and the cytoplasmic and nuclear levels of Nrf2. Furthermore, ISL lowered circulatory levels of lipopolysaccharides, deactivated the myosin light chain kinase (MLCK), and increased mRNA claudin-1, occluding, and zonula occludens‑1. All these effects were prevented by co-treatment of brusatol. In conclusion, ISL is a potent activator of Nrf2 intestinal inflammatory disorders.