Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR

Abstract

Severe acute pancreatitis (SAP) is a lethal gastrointestinal disorder, yet no specific and effective treatment is available. Its pathogenesis involves inflammatory cascade, oxidative stress, and autophagy dysfunction. Xanthohumol (Xn) displays various medicinal properties,including anti-inflammation, antioxidative, and enhancing autophagic flux. However, it is unclear whether Xn inhibits SAP. This study investigated the efficacy of Xn on sodium taurocholate (NaT)-induced SAP (NaT-SAP) in vitro and in vivo. First, Xn attenuated biochemical and histopathological responses in NaT-SAP mice. And Xn reduced NaT-induced necrosis, inflammation, oxidative stress, and autophagy impairment. The mTOR activator MHY1485 and the AKT activator SC79 partly reversed the treatment effect of Xn. Overall, this is an innovative study to identify that Xn improved pancreatic injury by enhancing autophagic flux via inhibition of AKT/mTOR. Xn is expected to become a novel SAP therapeutic agent.

The Pathogenesis of Pancreatitis and the Role of Autophagy

“…Xanthohumol (Xn), a natural prenylated chalcone compound isolated from hops, restored autophagy flux by inhibiting the AKT/mTOR pathway in experimental pancreatitis. This was associated with reductions in necrosis, inflammation, oxidative stress, and the severity of pancreatitis [384]. Experiments also indicated that Pancreatic Protein kinase C iota (PKCi) significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to cerulein-induced pancreatitis.…”

“…Restoration of autophagy. Reduction of pancreatitis severity [384] ER stress Activation of trypsinogen and impaired autophagy [402][403][404]407] ROS overproduction Mitophagy disruption. Activation of AKT/mTOR pathway.…”