基于Keap1/Nrf2/ARE信号通路探讨芍药汤抗氧化应激抑制肠“炎-癌”转化进展的作用机制

目的:选取氧化偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)诱导的慢性肠炎癌变小鼠模型,动态探究具有清热燥湿、调气和血功效的芍药汤调控抗氧化应激信号通路Keap1/Nrf2/ARE发挥抗氧化作用对肠"炎-癌"转化进展的保护机制。方法:病理学评价AOM/DSS诱导的肠炎癌变情况;定量RT-PCR检测结直肠组织中抗氧化信号通路核因子E-2-相关因子2(Nrf2)关键指标的表达;免疫组化检测结直肠组织炎症和肿瘤形成指标核因子κB(NF-κB)、Ki-67抗原(Ki-67)、Nrf2的表达;ELISA法检测结直肠组织炎性细胞因子肿瘤坏死因子-α(TNF-α)和白细胞介素1β(IL-1β)以及氧化应激蛋白超氧化物歧化酶(SOD)和丙二醛(MDA)的表达。结果:与AOM模型组比较,芍药汤各组小鼠体质量减轻较少、均能明显抑制结肠缩短、显著减少肿瘤数量(P<0.01)。与AOM组比较,芍药汤高剂量组各时间点谷胱甘肽还原酶(GR)、硫氧还蛋白还原酶(TR)、血红素氧合酶-1(HO-1)、苷二磷酸葡萄糖醛酸基转移酶1A1(UGT1A1)的mRNA表达水平,第63、98天时,醌NADH脱氢酶1(NQO-1)mRNA及第28、63天时尿苷二磷酸葡萄糖醛酸基转移酶1A10(UGT1A10)、γ-谷氨酰半胱氨酸合成酶c(γ-GCSc)mRNA表达水平均显著升高(P<0.05,P<0.01);芍药汤各剂量组第98天NF-κB、Ki-67表达水平显著降低(P<0.01),第63、98天TNF-α及IL-1β表达水平显著降低(P<0.05,P<0.01);芍药汤高、中剂量组各时间点SOD活性增强(P<0.05,P<0.01),芍药汤各剂量组各时间点MDA含量减少(P<0.01)。结论:芍药汤对AOM/DSS诱导的肿瘤发生具有一定程度的预防作用,能够抑制氧化应激诱导的炎性损伤,通过调控抗氧化应激信号通路Keap1/Nrf2/ARE发挥抗氧化和抗炎作用。

Inflammatory bowel disease-and Barrett’s esophagus-associated neoplasia:the old,the new,and the persistent struggles

Early diagnosis of and adequate therapy for premalignant lesions in patients with inflammatory bowel disease(IBD)and Barrett’s esophagus(BE)has been shown to decrease mortality.Endoscopic examination with histologic evaluation of random and targeted biopsies remains the gold standard for early detection and adequate treatment of neoplasia in both these diseases.Although eventual patient management(including surveillance and treatment)depends upon a precise histologic assessment of the initial biopsy,accurately diagnosing and grading IBD-and BE-associated dysplasia is still considered challenging by many general as well as subspecialized pathologists.Additionally,there are continuing updates in the literature regarding the diagnosis,surveillance,and treatment of these disease entities.This comprehensive review discusses the cancer risk,detailed histopathological features,diagnostic challenges,and updates as well as the latest surveillance and treatment recommendations in IBD-and BE-associated dysplasia.