A Flavonoid Compound 7, 4 Dihydroxy Flavone as a Potential Therapeutic for the Treatment and Management of EoE

Abstract

Eosinophilic Esophagitis (EoE) is a chronic condition characterized by esophageal dysfunction including dysphagia, abdominal pain and eosinophilic inflammation (>15/HPF) of the esophagus. At present, the most commonly used treatment for the management of EoE are steroids, both systemic as well as tropical, and dietary elimination. The advantage of the systemic steroids include ease of administration, rapid response, and very high response rate. However, poor solubility and the adverse effect related to prolonged steroid use are well documented. Moreover, there is a high relapse rate of EoE after the treatment is discontinued which limit the use of oral steroids as a maintenance therapy. Similarly, Ranitidine (Zantac), histamin‐2 blocker, used to treat gastrointestinal reflux and heart burns, has been recently withdrawn from the market by FDA due to increased risk of cancer. Digestive Tea has been used at the Traditional Chinese Medicine (TCM) practice to improve gastrointestinal (GI) symptoms such as stomach pain, constipation and abnormal bowel movement. Different versions of Digestion Teas are further developed to address specific clinical GI symptoms. Compound 7, 4 Dihydroxy flavone (DHF) is a flavonoid purified from Glycyrrhiza uralensis from Digestive Tea. Previously our group has shown inhibition of Eotaxin, Th2 cytokines and IgE in‐vitrousing DHF. The objective of this study is to reveal potential mechanisms underlying DHF improving symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein‐protein interaction analyses, and in silico molecular docking. Based on the pathway analyses, the most important targets identified were TNF‐ α, IL‐6, IL1β, MAPK1, MAPK3, AKT1, CASP3 and CCND in AGE‐RAGE pathway. We further validated the targets of our computational modeling in human esophagus biopsy sample by ELISA and qRT‐PCR. We found significant reduction in levels of TNF‐α (p<0.001), IL‐6 (p<0.001), IL‐8 (p<0.001) and IL1‐β (p<0.05) in the supernatant of biopsy sample cultured with DHF. Moreover, gene expression profile showed significant reduction in level of TNF‐ α (p<0.01), IL1‐β (p<0.05), IL‐6 (p<0.01) and CCND (p<0.05) in the biopsy sample cultured with DHF. Furthermore, our molecular docking analysis revealed that DHF can directly bind TNF‐ α with free binding energies of ‐7.7 kcal/mol. Taken together, the current study may lead to development of DHF as an active therapeutic candidate in treatment of EoE.