Study On The Protection Of Ergothioneine Against Radiation Gastroenteritis

Radiation gastroenteritis represents a group of clinically prevalent and hazardous complications of abdominal and pelvic radiotherapy due to its unspecific killing mechanism and the rapid proliferation rate of gastrointestinal tissues.Radiation gastroenteritis not only seriously reduces patients’ quality of life,but also limits radiotherapy dose,causes interruption of radiotherapy,and impairs tumor control rate.However,the current clinical management of radiation gastroenteritis is limited to symptomatic treatments to alleviate its severity,which is often ineffective and highly toxic.Hence,there is an urgent need to develop efficient and safe gastrointestinal radioprotectors for protecting against radiation gastroenteritis.Amifostine,as the only free radical scavenging-based radioprotective agent on the market,is very limited in the protection of radiation gastroenteritis due to its poor chemical stability,ineffective oral administration and narrow therapeutic window.In contrast,another thiol compound,ergothioneine(EGT)exhibits promising potential in radioprotection,especially for gastrointestinal tissues by virtue of its excellent chemical stability,free radical scavenging ability,and gastrointestinal highly-expressed specific transporter.However,EGT,as a water-soluble small molecule faces the challenge of rapid gastrointestinal clearance when taken orally as an aqueous solution.To this end,hyaluronic sodium hydrogel(HA)with good biocompatibility,adhesiveness and versatile bioactivity is introduced to prolong EGT’s gastrointestinal residence and improve radioprotective efficacy.This project provided a primary study on the radioprotective efficacy and mechanisms of EGT and developed a facile and effective bioadhesive gastrointestinal radioprotector(EGT@HA).To begin with,In vitro stability experiments showed that EGT had good chemical stability at 37℃ and in buffer solutions simulating gastrointestinal pH.A series of free radical scavenging tests demonstrated that EGT efficiently scavenges a variety of strong free radicals including hydroxyl radicals,but not for weak superoxide anions.In addition,EGT presented good cell safety and radioprotection performance regarding cell viability and proliferation ability in the rat small intestinal crypt cell model.Mechanism studies suggested that EGT can effectively scavenge radiation-induced intracellular free radicals,relieve DNA damage and inhibit the activation of endogenous mitochondrial apoptosis pathways.Subsequently,1%HA hydrogel was screened by in vivo fluorescence imaging and proved to possess good gastrointestinal adhesive behavior.H&E pathological results attested that oral EGT@HA gel was effective in alleviating the histological disorders caused by acute and subacute radiation gastroenteritis.Mechanism studies indicated that EGT@HA gel could yield commendable gastrointestinal radioprotection by mitigating apoptosis,inflammatory infiltration,and gut flora disorder.This study investigated the protective/therapeutic potential and mechanism of EGT-based gastrointestinal radioprotector.Owing to the good chemical stability,free radical scavenging capability,and prolonged residence time in gastrointestinal tissue,EGT@HA gel could accumulate in the gastrointestinal tract with unimpaired bioactivity to effectively protect against radiation gastroenteritis by mitigating apoptosis,inflammation,and gut flora dysbiosis.This study not only provides a facile and effective gastrointestinal radioprotector but also contributes a valuable synergistic strategy for gastrointestinal radioprotection via systemically modulating oxidative stress,inflammation,and gut flora disorder,which is expected to hasten the development of novel therapeutics for radiation gastroenteritis.