未经证实:嗜酸性粒细胞食管炎(EoE)是一种慢性疾病,其特征是食道嗜酸性粒细胞炎症,导致食道功能障碍,常见症状包括呕吐,喂养困难,吞咽困难,腹痛。EoE的当前主要治疗选择包括饮食消除和吞咽类固醇。饮食消除方法可能导致确定触发食物,但它通常需要在全身麻醉的情况下反复进行上消化道内窥镜检查,并可能对儿童和个体的营养摄入和生长质量产生负面影响。虽然吞咽类固醇治疗有效,停止治疗后EoE将普遍复发。消化茶配方(DTF)已被中医(TCM)实践用于改善EoE患者的胃肠道症状,包括腹痛,GE回流,排便异常.以前,黄酮类小分子化合物7,4二羟基黄酮(DHF)从甘草DTF抑制eotaxin,体外和体内Th2细胞因子和IgE产生。
UNASSIGNED:本研究使用计算模型全面评估DHF改善EoE相关症状的潜在治疗和免疫机制,包括目标采矿,基因本体论富集,途径分析,蛋白质-蛋白质相互作用分析,计算机分子对接和动态模拟,然后使用培养的人食管活检标本进行qRT-PCR,并使用EoE患者伴或不伴DHF的体外靶标验证。
未经评估:计算分析在EoE上定义了DHF的29个常见目标,其中TNF-α,IL-6,IL1β,MAPK1、MAPK3和AKT1最为重要。对接分析和动态模拟表明,DHF以-7.7kcal/mol的自由结合能直接结合TNF-α,具有更大的稳定性和灵活性。随后,在人类食道活检培养系统中,TNF-α水平显着降低,在用DHF培养的活检样品的上清液中发现IL-6、IL-8和IL1-β。此外,基因表达谱显示TNF-α水平显着降低,IL1-β,用DHF培养的食管活检样品中的IL-6、CCND和MAPK1。
未经批准:一起,本研究为我们深入了解DHF在EoE治疗中多靶向获益的分子机制,并为促进更有效的EoE治疗铺平了道路.
Eosinophilic Esophagitis (EoE) is a chronic condition characterized by eosinophilic inflammation of the esophagus which leads to esophageal dysfunction with common symptoms including vomiting, feeding difficulty, dysphagia, abdominal pain. Current main treatment options of EoE include dietary elimination and swallowed steroids. Diet elimination approach could lead to identifying the trigger food(s), but it often requires repeated upper endoscopy with general anesthesia and potentially could negatively affect nutrition intake and growth of the child and individuals\' quality of life. Although the swallowed steroid treatment of effective, the EoE will universally recur after discontinuation of the treatment. Digestive Tea formula (DTF) has been used by the Traditional Chinese Medicine (TCM) practice to improve GI symptoms in EoE patients, including abdominal pain, GE reflux, and abnormal bowel movement. Previously, a flavonoid small molecule compound 7, 4 dihydroxy flavone (DHF) from Glycyrrhiza uralensis in DTF inhibited eotaxin, Th2 cytokine and IgE production in vitro and in vivo.
This study comprehensively evaluates the potential therapeutic and immunological mechanisms underlying DHF improvement of symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analyses, in silico molecular docking and dynamic simulation followed by ex-vivo target validation by qRT-PCR using cultured human esophagus biopsy specimen with or without DHF from patients with EoE.
Computational analyses defined 29 common targets of DHF on EoE, among which TNF-α, IL-6, IL1β, MAPK1, MAPK3 and AKT1 were most important. Docking analysis and dynamic simulation revealed that DHF directly binds TNF-α with a free binding energy of -7.7 kcal/mol with greater stability and flexibility. Subsequently, in the human esophagus biopsy culture system, significant reduction in levels of TNF-α, IL-6, IL-8 and IL1-β was found in the supernatant of biopsy sample cultured with DHF. Furthermore, the gene expression profile showed significant reduction in levels of TNF-α, IL1-β, IL-6, CCND and MAPK1 in the esophagus biopsy sample cultured with DHF.
Taken together, the current study provides us an insight into the molecular mechanisms underlying multi-targeted benefits of DHF in the treatment of EoE and paves the way for facilitating more effective EoE therapies.