党参低聚糖通过抑制PI3K/AKT/HIF-1α通路改善胃癌前病变大鼠胃粘膜损伤  

CODONOPSIS RADIX Oligosaccharides Improve Gastric Mucosal Injury in Rats with Precancerous Lesions of Gastric Cancer by Inhibiting PI3K/AKT/HIF-1αPathway

作　　者：闫巧 崔方[1,2] 李文 王子夏[1,2] 邵亚洲 王燕萍 郭艺娜 余华侨[1,2] 胡芳弟 YAN Qi;CUI Fang;LI Wen;WANG Zixia;HAO Yazhou;WANG Yanping;GUO Yina;YU Huaqiao;HU Fang(School of Pharmacy,State Key Laboratory of Applied Organic Chemistry Lanzhou University,Lanzhou730000;Codonopsis Radix Industrial Technology Engineering Research Center of Gansu Province,Lanzhou 730000)

机构地区：[1]兰州大学药学院,功能有机分子化学国家重点实验室,兰州730000 [2]甘肃省党参产业技术工程研究中心,兰州730000

出　　处：《中药药理与临床》2024年第3期49-59,共11页Pharmacology and Clinics of Chinese Materia Medica

基　　金：甘肃省重大项目(编号:21ZD4FA013)(甘科计[2021]16号);国家重点研发计划项目(编号:2018YFC1706300、2018YFC17063003);甘肃省技术创新引导计划-民生专项(编号:20CX4FK014);兰州市人才创新创业项目(2020-RC-41);泰山产业领军人才(编号:TSCY20180234)。

摘　　要：目的:研究党参低聚糖对胃癌前病变(PLGC)大鼠胃黏膜损伤的改善作用及机制。方法:分析党参低聚糖对缺氧条件下胃黏膜上皮细胞(GES-1)和胃癌细胞(AGS)增殖活性,及对凋亡相关蛋白(BAX、BCL-2、Caspase-3)和磷酯酰肌醇3激酶/蛋白激酶B/缺氧诱导因子1α信号通路(PI3K/AKT/HIF-1α)的影响。70只大鼠随机分为正常对照组、正常动物给予党参低聚糖0.6 g/kg组、模型对照组、维酶素0.27 g/kg组、党参低聚糖0.15、0.6 g/kg组。采用灌胃N-甲基-N’-硝基-N-亚硝基胍(MNNG)和40%乙醇并结合饥饱饮食的方法构建PLGC模型。分析党参低聚糖对PLGC大鼠胃组织病理变化、血清生化指标、凋亡相关蛋白(BAX、BCL-2、Caspase-3)和PI3K/AKT/HIF-1α通路的影响。同时通过LC/MS/MS代谢组学技术研究影响党参低聚糖改善PLGC的潜在生物标志物和代谢通路。结果:细胞实验显示,与空白对照组比较,缺氧对照组GES-1细胞的相对存活率显著降低(P<0.01),BCL-2/BAX比值、PI3K及p-AKT蛋白表达显著下调,Caspase-3和HIF-1α蛋白表达明显上调(P<0.05或P<0.01);AGS细胞的相对存活率显著增加(P<0.01),BCL-2/BAX比值、PI3K、p-AKT及HIF-1α蛋白表达均显著上调,Caspase-3蛋白表达显著下调(P<0.01);与缺氧对照组比较,党参低聚糖1、1.25 mg/mL组在48 h时使GES-1细胞的相对存活率显著增加(P<0.01),BCL-2/BAX比值、PI3K及p-AKT蛋白表达均显著上调,Caspase-3和HIF-1α蛋白表达明显下调(P<0.05);使AGS细胞的相对存活率显著降低(P<0.01),BCL-2/BAX比值、PI3K、p-AKT及HIF-1α蛋白表达均明显下调,Caspase-3蛋白表达明显上调(P<0.05或P<0.01)。动物实验显示,与正常对照组比较,模型对照组大鼠胃黏膜发生萎缩,肠上皮化生和不典型增生,血清胃蛋白酶原Ⅰ/胃蛋白酶原Ⅱ(PGⅠ/PGⅡ)比值和胃泌素-17(G-17)含量显著降低(P<0.01),白细胞介素-1β(IL-1β)、IL-6及肿瘤坏死因子(TNF-α)含量显著增加(P<0.01),超氧化物歧化�Objective:To investigate the improvement effect and mechanism of CODONOPSIS RADIX oligosaccharides on gastric mucosal injury in rats with precancerous lesions of gastric cancer(PLGC).Methods:The effects of CODONOPSIS RADIX oligosaccharides on the proliferation activity,apoptosis-related proteins(BAX,BCL-2,and Caspase-3)and phosphatidylinositol 3 kinase/protein kinase B/Hypoxiainduciblefactor 1α(PI3K/AKT/HIF-1α)pathway of hypoxic-cultured gastric epithelial cells(GES-1)and gastric cancer cells(AGS)were analyzed.70 rats were randomly divided into the normal control group,CODONOPSIS RADIX oligosaccharides group(O.6 g/kg),model control group,vitamin enzyme treatment group(0.27 g/kg),and CODONOPSIS RADIX oligosaccharides groups(O.15 and 0.6 g/kg).The PLCC model was established by gavage of 1-methyl-3-nitro-1-nitrosoguanidine(MNNG)and 40%ethanol combined with an irregular diet.The effects of CODONOPSIS RADIX oligosaccharides on gastric histopathology,serum biochemical indexes,apoptosis-related proteins(BAX,BCL-2,and Caspase-3),and PI3K/AKT/HIF-1αpathway in PLCC rats were analyzed.Moreover,LC/MS/MS metabonomics technology was performed to investigate the potential biomarkers and metabolic pathways affecting the ameliorative effect of CODONOPSIS RADIX oligosaccharides on PLGC rats.Results:The cell experiment showed that compared with the normal control group,the relative survival rate of GES-1 cells in the hypoxia control group was significantly decreased(P<0.01).The BCL-2/BAX ratio,PI3K,and p-AKT protein levels were significantly downregulated,while the levels of Caspase-3 and HIF-1αwere significantly up-regulated(P<0.05 or P<0.01).The relative survival rate of AGS cells was significantly up-regulated(P<0.01).The BCL-2/BAX ratio and the protein expressions of PI3K,p-AKT,and HIF-1αwere significantly up-regulated,while the expression level of Caspase-3 was significantly down-regulated(P<0.01).Compared with the hypoxia control group,the relative survival rate of GES-1 cells in CODONOPSIS RADIX oligosaccharide groups(1

关 键 词：党参低聚糖 胃癌前病变 炎症 氧化应激 细胞凋亡 磷酯酰肌醇3激酶/蛋白激酶B/缺氧诱导因子1α信号通路 代谢组学 

分 类 号：R285.5[医药卫生—中药学]