CODONOPSIS RADIX Oligosaccharides Improve Gastric Mucosal Injury in Rats with Precancerous Lesions of Gastric Cancer by Inhibiting PI3K/AKT/HIF-1α Pathway
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 prolifera-tion activity,apoptosis-related proteins(BAX,BCL-2,and Caspase-3)and phosphatidylinositol 3 kinase/protein kinase B/Hypoxiainducible-factor 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(0.6 g/kg),model control group,vitamin enzyme treatment group(0.27 g/kg),and CODONOPSIS RADIX oligosaccharides groups(0.15 and 0.6 g/kg).The PLGC 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-1α pathway in PLGC 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 PL-GC rats.Results:The cell experiment showed that compared with the normal control group,the relative survival rate of GES-1 cells in the hy-poxia control group was significantly decreased(P＜0.01).The BCL-2/BAX ratio,PI3K,and p-AKT protein levels were significantly down-regulated,while the levels of Caspase-3 and HIF-1α were 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-1α were signifi-cantly 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 and 1.25 mg/mL)at 48 h was significant-ly increased(P＜0.01).The BCL-2/BAX ratio and the protein expressions of PI3K and p-AKT were significantly up-regulated,while the Caspase-3 and HIF-1α levels were significantly down-regulated(P＜0.05).The relative survival rate of AGS cells was significantly decreased(P＜0.01).The BCL-2/BAX ratio and the protein expressions of PI3K,p-AKT,and HIF-1α were significantly down-regulated,while the Caspase-3 level was significantly up-regulated(P＜0.05 orP＜0.01).Animal experiments showed that compared with the normal control group,gastric mucosa atrophy,intestinal metaplasia,and atypical hyperplasia were observed in the model control group,and the ratio of serum pepsinogen Ⅰ/pepsinogen Ⅱ(PGⅠ/PGⅡ)and the level of gastrin-17(G-17)were significantly decreased(P＜0.01).The levels of in-terleukin-1β(IL-1β),interleukin-6(IL-6),and tumor necrosis factor(TNF-α)were significantly increased(P＜0.01),while the activities of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)were significantly decreased.The MDA level was significantly in-creased(P＜0.01).The ratio of BCL-2/BAX and the protein expressions of PI3K,p-AKT,and HIF-1α in gastric mucosa were significantly up-regulated,while the level of Caspase-3 was significantly down-regulated(P＜0.01).The serum levels of glycerol phosphocholine,2-ketogl-utaric acid,lactic acid,fumaric acid,and taurogodeoxycholate were significantly increased,while the levels of histidine,betaine,citrulline,argi-nine,proline,pantothenic acid,taurocholic acid,citric acid,and 1-palmitoylglycerol phosphocholine were significantly decreased(P＜0.05 or P＜0.01).Compared with the model control group,the gastric mucosa atrophy,intestinal metaplasia,and atypical hyperplasia were alleviated significantly in the CODONOPSIS RADIX oligosaccharide groups(0.15 and 0.6 g/kg).In the CODONOPSIS RADIX oligosaccharide group(0.6 g/kg),the ratio of serum PG Ⅰ/PG Ⅱ and G-17 level was significantly increased(P＜0.05),and the levels of IL-1β,IL-6,and TNF-αwere significantly decreased(P＜0.01).The activities of SOD and GSH-Px were significantly increased,while the level of MDA was signifi-cantly decreased(P＜0.05).The ratio of BCL-2/BAX and the protein expressions of PI3K,p-AKT,and HIF-1α in gastric mucosa were sig-nificantly down-regulated,and the protein expression of Caspase-3 was significantly up-regulated(P＜0.01).The levels of 14 serum metabo-lites were significantly back to normal levels(P＜0.05 or P＜0.01),mainly involved in the tricarboxylic acid cycle,arginine and proline me-tabolism,glycerophospholipid metabolism,glycolysis,and taurine and taurine metabolism.Conclusion:CODONOPSIS RADIX oligosaccha-rides can improve the hypoxic injury of normal gastric mucosa cells and inhibit the proliferation of gastric cancer cells,and it can improve gas-tric mucosa injury in PLGC rats by inhibiting inflammation,antioxidation,promoting apoptosis,and regulating metabolic disorders.The mecha-nism of action is related to the inhibition of the overactivation of the PI3K/AKT/HIF-1α pathway.
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