Flavonoids from Lophatherum gracile Brongn. Ameliorate Liver Damages in High-Fat Diet and Streptozotocin-Induced Diabetic Mice by Regulating PI3K/AKT and NF-Kappa B Pathways

Inflammation and metabolic disorders are crucial factors that induce type 2 diabetes mellitus (T2DM). Lophatherum gracile Brongn. (L. gracile) has been popularly consumed as folk medicine and dietary supplement for the treatment of fever and inflammatory-associated diseases. Flavonoids are the major constituents of L. gracile with various pharmacological effects. However, the protective effects of flavonoids from leaves of L. gracile against T2DM, as well as the potential mechanisms, were not yet elucidated. In the present study, the total flavonoid content of L. gracile (LGBF) with higher flavonoid content and pancreas lipase inhibitory activity was extracted and screened from the leaves of L. gracile. Twelve flavonoid compounds were identified in LGBF by liquid LC-MS analysis. Network pharmacology identified seven potential flavonoid compounds and 10 core targets associated with T2DM. GO and KEGG pathway enrichment analysis indicated that PI3K/AKT and inflammation-related pathways might occupy core status. Molecular docking results showed that the active constituents of LGBF had a good binding activity with key targets. Furthermore, high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice were developed and treated with LGBF for experimental validation. The data showed that LGBF intervention potently improved the lipid profiles and insulin sensitivity of HFD and STZ-induced mice. Hepatic inflammation and lipid accumulation were also partially reversed by LGBF intervention. Further assays confirmed that LGBF administration significantly increased PI3K and AKT phosphorylation, while reducing IL-1β expression and NF-κB P65 phosphorylation in the liver of mice. In conclusion, LGBF administration could relieve liver damage in diabetic mice via regulating PI3K/AKT and NF-κB pathways.