Li Angqing, Zhang Junyi, Chen Ke, Wang Jian, Xu Aman, Wang Zhengguang
Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China.
Vascular Surgery Department, Drum Tower Hospital affiliated to Nanjing University Medical College, Nanjing, China.
Pathol Int. 2023 Nov;73(11):549-559. doi: 10.1111/pin.13380. Epub 2023 Oct 13.
This article focuses on the specific effects and mechanisms of donepezil (DNPZ) hydrochloride on inflammation and apoptosis in ulcerative colitis (UC). In vivo and in vitro models of UC were established using dextran sodium sulfate (DSS)-induced mice and NCM460 cells, respectively. Following oral administration of DNPZ, body weight, disease activity index (DAI) scores and colon lengths of mice were recorded. Histopathological damage was detected employing hematoxylin and eosin (H&E) staining. Inflammatory factors were tested using enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction, respectively. Apoptosis was estimated utilizing terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot. Low-density lipoprotein receptor-related protein 1 (LRP1)/AMP activated protein kinase (AMPK)/nuclear factor-κB (NF- κB) signaling proteins were detected utilizing western blot. NCM460 cell viability was assessed by cell counting kit (CCK)-8. We found that DNPZ partially restored body weight, reduced DAI scores and attenuated intestinal pathological damage in DSS-induced mice. Additionally, inflammatory factors decreased significantly after DNPZ treatment, accompanied by reduced apoptosis level. Phosphorylation (p)-AMPK increased and p-p65 decreased after DNPZ treatment, whereas LRP1 knockdown showed the opposite effect. Moreover, DNPZ treatment greatly restored NCM460 cell viability after DSS stimulation. DNPZ attenuated DSS-induced inflammation and apoptosis in NCM460 cells, which was reversed by LRP1 knockdown. In summary, DNPZ hydrochloride attenuates inflammation and apoptosis in UC via LRP1/AMPK/NF-κB signaling.
本文聚焦于盐酸多奈哌齐（DNPZ）对溃疡性结肠炎（UC）炎症和细胞凋亡的具体作用及机制。分别使用葡聚糖硫酸钠（DSS）诱导的小鼠和NCM460细胞建立UC的体内和体外模型。口服DNPZ后，记录小鼠的体重、疾病活动指数（DAI）评分和结肠长度。采用苏木精-伊红（H&E）染色检测组织病理学损伤。分别使用酶联免疫吸附测定和定量逆转录聚合酶链反应检测炎症因子。利用末端脱氧核苷酸转移酶dUTP缺口末端标记和蛋白质免疫印迹法评估细胞凋亡。采用蛋白质免疫印迹法检测低密度脂蛋白受体相关蛋白1（LRP1）/AMP激活蛋白激酶（AMPK）/核因子-κB（NF-κB）信号蛋白。通过细胞计数试剂盒（CCK）-8评估NCM460细胞活力。我们发现，DNPZ可部分恢复DSS诱导小鼠的体重，降低DAI评分并减轻肠道病理损伤。此外，DNPZ治疗后炎症因子显著降低，同时细胞凋亡水平降低。DNPZ治疗后磷酸化（p）-AMPK增加，p-p65降低，而敲低LRP1则显示相反的效果。此外，DNPZ治疗可在很大程度上恢复DSS刺激后NCM460细胞的活力。DNPZ减轻了DSS诱导的NCM460细胞炎症和细胞凋亡，而敲低LRP1可逆转这种作用。总之，盐酸多奈哌齐通过LRP1/AMPK/NF-κB信号通路减轻UC的炎症和细胞凋亡。
