Platycodon grandiflorus polysaccharides combined with hesperidin exerted the synergistic effect of relieving ulcerative colitis in mice by modulating PI3K/AKT and JAK2/STAT3 signaling pathways

Ulcerative colitis (UC) is a persistent inflammatory disorder with refractory etiology, accompanied by intestinal inflammation and intestinal barrier dysfunction. Platycodon grandiflorus polysaccharides (PGP) is the main component of Platycodon grandiflorus (Jacq.) A. DC. (PG), and hesperidin (Hesp) is prominent active components in Citrus aurantium L. (CAL), both of which have demonstrated anti-inflammatory properties. This study attempts to elucidate the underlying mechanism of the synergistic effect of PGP combined with Hesp on UC, focusing on the coordinated interaction between the PI3K/AKT and JAK2/STAT3 signaling pathways. A mouse model of UC induced by dextran sulfate sodium (DSS) and a cell model using lipopolysaccharide (LPS)-induced RAW264.7/IEC6 cells were employed to investigate the in vitro and in vivo anti-inflammatory effects of PGP combined with Hesp on UC and its potential mechanism of action. The results showed that compared with the effects of two drugs alone, the combination of PGP and Hesp could significantly modulate the levels of inflammatory factors, inhibit the occurrence of oxidative stress, regulate the colonic mucosal immunity, inhibit apoptosis, and restore the intestinal barrier function in vitro and in vivo. Further in vitro studies showed that PGP significantly inhibited the PI3K/AKT signaling pathway, and Hesp significantly inhibited the JAK2/STAT3 signaling pathway. The utilization of inhibitors and activators targeting both pathways validated the synergistic effects of PGP combined with Hesp on the PI3K/AKT and JAK2/STAT3 signaling pathways. Therefore, PGP combined with Hesp exhibits a synergistic effect on DSS-induced colitis, which may be related to the PTEN/PI3K/ AKT and IL-6/JAK2/STAT3 signaling pathway.