Antioxidants Based On Quercetin And Their Prevention And Treatment For Intestinal Inflammatory Diseases

Gastrointestinal tract is one of the most important organs in our body responsible for the digestion and absorption of nutrients.Because of the large surface area of mucosa and constant facing external environments,intestines are easily suffered from inflammatory damages under the exposure of environmental,genetic,immune,or bacterial stress.The pathogenesis of intestinal inflammatory damages highly associates with the disruption of intestinal barrier functions,the dysbiosis of the gut microbiome,and the dysregulation of mucosal immune responses to gut commensal bacteria.As a typical inflammatory mediator,reactive oxygen species(ROS)is considered as the central progression of inflammation.Excessive ROS production and continuous oxidative stress in intestines can elicit local mucosal injury,accelerate mucosal ulceration,and amplify the inflammatory response.It has been reported that mucosal ROS concentrations are 10–100 times higher in patients suffering from intestinal inflammatory diseases than those in healthy people.Thereby,antioxidant therapy represents a promising approach for treating intestinal inflammatory diseases.Current clinical intervention of intestinal inflammatory diseases relies on small molecular drugs,antibiotics,and antibodies.Unfortunately,a fair number of patients cannot benefit from these therapeutic regimens due to the poor response,the severe adverse effects,and the systemic exposure of these medications.More importantly,most of these medicines depend on delivery via the bloodstream,and few are truly specific to inflamed lesions.Although a series of antioxidant nanomaterials have been developed to enhance therapeutic effect for intestinal inflammatory diseases,the clinical translation of these antioxidant nanomaterials still confronts with some crucial challenges,such as drug loading capacity,batch-to-batch reproducibility,biological compatibility,cost-effectiveness,and large-scale production.Hence,exploring antioxidant nanomedicines with targeting capability to inflamed lesions,boosted antioxidant activity for ROS scavenging,and great potential for large-scale preparation is still urgent.Oral delivery is highly welcomed for treating intestinal inflammatory diseases owing to its convenience,high patient compliance,desirable cost-effectiveness,and good safety profile.Moreover,the patchy inflammation of the intestinal mucosa always accompanies by the destruction and increased discontinuity of the mucus layer,and the in situ accumulation of positively charged proteins involving transferrin,eosinophil cationic protein,and bactericidal/permeability-increasing protein.This provides a targeting strategy for negatively charged nanomedicines to adhere to the inflamed intestinal epithelium via electrostatic interactions.However,the harsh environments of GI tract,for example,the acidic gastric fluid and the presence of the huge amount of proteases,can damage the stability and bioactivity of nanomedicines considerably.Thus,antioxidant nanomedicines should fulfill multiple tasks during their journey from oral cavity to inflamed intestine,in particular the stabilization and bioactivity retention in GI tract.Natural polyphenols,such as curcumin,resveratrol,quercetin,rosmarinic acid,bilirubin,and ellagic acid represent over 50% of U.S.Food and Drug Administration approved therapeutics owing to their economical cost,purported safety,and health benefits including antioxidant and anti-inflammatory effects.However,the intrinsic poor water solubility,low GI stability,rapid metabolism,and quick systemic elimination after oral administration have severely limited the clinical translation of natural polyphenols.Details as follows:In chapter 2,We reported to quercetin nanoparticles based on the fast three-component Mannish reaction of quercetin with lysine for radioprotection.quercetin nanoparticles show the powerful performance in the intestine,including efficient free radical scavenging ability,satisfying biosafety,good chemical stability,and good metabolism.The results show that quercetin nanoparticles can effectively remove the radiation-induced ROS so as to increase cell survival.Animal experimental results exhibit that quercetin nanoparticles significantly alleviate hemafecia,weight loss,and intestinal damage since they can efficiently protect intestinal cells and maintain the balance of redox so as to alleviate the radiation enteritis.Consequently,the quercetin nanoparticles can be used as an intestinal radioprotective drug for radiation enteritis.In chapter 3,we have constructed quercetin SNRs by using free quercetin molecules as the sole building block for preventing and treating intestinal inflammatory diseases via oral administration.The as-prepared quercetin SNRs can retain their excellent antioxidant activity in the harsh environments of GI tract without any attenuation.The microscale of quercetin SNRs ensure a relative long retention time in GI tract and an admirable metabolism in GI tract without burdening other organs.Moreover,the negatively charged zeta potential endow quercetin SNRs with a targeting capability to specifically adhere to the positively charged inflamed intestinal epithelium via electrostatic interactions.In vitro and in vivo studies verify that our quercetin SNRs possess the promising protective and therapeutic effects for radiation-induced acute enteritis and DSS-induced acute colitis.Because the super easy and fast preparation procedure and the nearly100% loading capacity of quercetin SNRs,the current work provides a supramolecular nanomedicine with great clinical translation potential against intestinal inflammatory diseasesIn summary,we proposed that polyphenols with good biocompatibility can be used as antioxidant agents to prevent and treat intestinal inflammation.Through a series of methods,the water solubility and bioavailability of plant polyphenols were improved.The test results showed that polyphenol antioxidant drugs can show excellent antioxidant capacity in the gastrointestinal tract,and have the potential to prevent and treat intestinal inflammatory diseases.