二氢丹参酮Ⅰ治疗胃癌前病变的药效及作用机制  

Efficacy and mechanism of dihydrotanshinoneⅠin the treatment of precancerous lesions of gastric cancer

作　　者：孟祥梅 褚福浩 郑浩呈 陈洁娜 林洁 李涛 丁霞 MENG Xiangmei;CHU Fuhao;ZHENG Haocheng;CHEN Jiena;LIN Jie;LI Tao;DING Xia(School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102401,China;Xiyuan Hospital of China Academy of Chinese Medical Sciences,Beijing 100091,China;Institute of Regulatory Science for Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 102401,China;Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine,Beijing 100007,China;National Institute of Constitution and Preventive Treatment of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]北京中医药大学中医学院,北京102401 [2]中国中医科学院西苑医院,北京100091 [3]北京中医药大学中药监管科学研究院,北京102401 [4]北京中医药大学东直门医院,北京100007 [5]北京中医药大学国家中医体质与治未病研究院,北京100029

出　　处：《药学研究》2025年第4期320-327,共8页Journal of Pharmaceutical Research

基　　金：国家自然科学基金面上项目(No.81903792);国家自然科学基金青年科学基金项目(No.82305179、82204894);国家博士后科学基金资助项目(No.2019M650600)。

摘　　要：目的探究二氢丹参酮Ⅰ(DHT)对胃癌前病变(PLGC)的药效及作用机制。方法使用20μmol·L^(-1)的N-甲基-N′-硝基-N-亚硝基胍(MNNG)诱导正常胃上皮细胞GES-124 h构建胃癌前病变细胞,随后采用不同浓度的二氢丹参酮Ⅰ进行干预。通过CCK-8和细胞集落实验检测细胞增殖能力,细胞划痕实验检测细胞迁移能力,流式细胞术检测细胞凋亡情况。此外,通过Western blotting检测N-cadherin、E-cadherin、Bcl2、Bax的表达变化。转录组测序技术、分子对接、分子动力学和等温滴定量热法用于探索二氢丹参酮Ⅰ干预后的MC细胞中关键通路和蛋白的变化。结果成功构建胃癌前病变细胞模型MC。二氢丹参酮Ⅰ抑制了MC细胞的增殖和迁移能力,并促进了细胞的凋亡。转录组测序结果显示,二氢丹参酮Ⅰ干预后差异基因主要聚焦p53信号通路、细胞凋亡、肌醇磷酸盐代谢通路、EGFR信号通路等。此外,二氢丹参酮Ⅰ的干预能够促进MC细胞中p53的表达,降低鼠双微体2(MDM2)的表达,进而干扰MC中的p53/MDM2反馈回路。同时,二氢丹参酮Ⅰ与MDM2-p53肽复合物之间具有较高的亲和力。结论二氢丹参酮Ⅰ可能作为一种有效的MDM2抑制剂,通过靶向p53-MDM2信号通路在PLGC的治疗中发挥作用。Objective To explore the efficacy and mechanism of action of dihydroartemisininⅠon the precancerous lesions of gastric cancer.Methods Normal gastric epithelial cells GES-1 were induced with 20μmol·L-1 MNNG for 24 hours to construct precancerous cells,followed by intervention with different doses of dihydroartemisininⅠ.Cell proliferation capacity was evaluated using CCK-8 and colony formation assays,cell migration ability was assessed using the scratch assay,and apoptosis was detected using flow cytometry.Additionally,changes in the expression of N-cadherin,E-cadherin,Bcl2,and Bax were examined using Western blotting.Transcriptome sequencing,molecular docking,molecular dynamics,and isothermal titration calorimetry were employed to explore the key pathways and protein changes in MC cells after dihydroartemisininⅠintervention.Results The precancerous cell model MC was successfully established.DihydroartemisininⅠsignificantly inhibited the proliferation and migration abilities of MC cells and promoted cell apoptosis.Transcriptome sequencing results revealed that differentially expressed genes after dihydroartemisininⅠintervention primarily focused on the p53 signaling pathway,cell apoptosis,inositol phosphate metabolism pathway,and EGFR signaling pathway.Furthermore,dihydroartemisininⅠintervention promoted the expression of p53 in MC cells,reduced the expression of MDM2,thereby interfering with the p53/MDM2 feedback loop in MC.Additionally,dihydroartemisininⅠexhibited high affinity with the MDM2-p53 peptide complex.Conclusion DihydroartemisininⅠmay serve as an effective MDM2 inhibitor,exerting its effects in the treatment of PLGC by targeting the p53-MDM2 signaling pathway.

关 键 词：二氢丹参酮Ⅰ 胃癌前病变 P53 鼠双微体2 

分 类 号：R285.5[医药卫生—中药学]