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α-硫辛酸对小鼠TNBS诱导的实验性结肠炎治疗作用的机制探讨

Mechanism of alpha-lipoic acid in treating TNBS-induced colitis in mice

摘要:

目的 探讨α-硫辛酸(ALA)通过哺乳动物雷帕霉素靶蛋白(mTOR)信号通路介导细胞自噬调节结肠炎进展的机制.方法 采用三硝基苯磺酸(TNBS)诱导建立实验性结肠炎小鼠模型,将雄性Balb/c小鼠(22~25 g)共分为4组:对照组、ALA组、结肠炎组以及ALA治疗组,每组10只.ALA以80 mg/kg剂量每天1次灌胃,共7d.计算各组大鼠结肠质量指数、疾病活动指数(DAI)以及结肠组织HE病理学评分(HDS),反转录(RT)-PCR检测各组小鼠结肠组织自噬基因Beclin-1表达,Western印迹检测mTOR、磷酸化mTOR(p-mTOR)蛋白表达情况以及Beclin-1蛋白水平变化.结果 与对照组比较,结肠质量指数在ALA组中无明显变化[(9.21±0.57)比(8.91±0.91) g/kg,P>0.05],但在结肠炎组中显著升高[(12.65±1.33) g/kg,P<0.05],在ALA治疗组中降低[(10.04±1.02) g/kg,P<0.05];DAI及HDS在ALA组中无明显变化(均P>0.05),但在结肠炎组中显著升高,在ALA治疗组中降低(均P<0.05).Beclin-1 mRNA及蛋白水平在对照组及ALA组差异无统计学意义(1.00±0.12比1.05±0.05,1.00±0.11比1.00±0.06),在结肠炎组小鼠结肠组织中表达显著降低(0.51±0.07,0.52±0.07),而经ALA干预后显著上调(1.75 ±0.09,1.82 ±0.14),差异有统计学意义(均P<0.05);mTOR总蛋白水平在各组小鼠中无明显变化,但p-mTOR在结肠炎组显著升高(3.07±0.20比1.00±0.07),而在ALA干预后受到抑制(1.49 ±0.11比3.07±0.20)(均P<0.05).结论 ALA可能通过抑制mTOR磷酸化水平促进细胞自噬而改善TNBS诱导的小鼠结肠炎症.

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abstracts:

Objective To investigate whether α-lipoic acid (ALA) regulates autophagy in the pathogenesis of colitis through the mammalian target of rapamycin (mTOR) signaling pathway.Methods Balb/c mouse colitis model was induced with 2,4,6-trinitrobenzenesulfonic acid (TNBS).Male Balb/c mice (22-25 g) were divided into four groups:control group,ALA group,colitis group,and ALA treatment group,with 10 mice in each group.ALA was administered at a dose of 80 mg/kg once a day for 7 days.The colon weight index,the disease activity index (DAI) and the histologic degeneration score (HDS) of colon tissue in each group were calculated.The autophagy gene Beclin-1 mRNA level was detected by RT-PCR.The levels of mTOR,phosphorylated mTOR (p-mTOR),and Beclin-1 proteins were detected by Western blot.Results Compared with the control group,there was no statistically significant difference in colon weight index in the ALA group [(9.21 ± 0.57) vs (8.91 ± 0.91) g/kg,P > 0.05],but increased in the colitis group [(12.65 ± 1.33)g/kg,P <0.05] and decreased in the ALA treatment group [(10.04 ± 1.02) g/kg,P < 0.05];there were no significant differences in DAI or HDS in the ALA group,but significantly increased in the colitis group,and decreased in the ALA treatment group (all P < 0.05).The Beclin-1 mRNA and protein levels showed no significant differences between the control and the ALA groups (1.00 ±0.12 vs 1.05 ±0.05,1.00 ±0.11 vs 1.00 ±0.06).However,the expression of Beclin-1 was significantly decreased in the colitis group compared to the control group (0.51 ±0.07 vs 1.00 ±0.12,0.52 ± 0.07 vs 1.00 ± 0.11,both P < 0.05),but significantly increased in the ALA treatment group compared to the colitis group (1.75 ±0.09 vs 0.51 ±0.07,1.82 ±0.14 vs 0.52 ±0.07,both P <0.05).The mTOR total protein levels were not significantly different among the four groups,but the p-mTOR level was significantly higher in the colitis group than in the control group (3.07 ± 0.20 vs 1.00 ± 0.07),and reduced in the ALA treatment group than in the colitis group (1.49 ± 0.11 vs 3.07 ± 0.20) (all P < 0.05).Conclusion ALA may improve the TNBS-induced colitis in mice by inhibiting the phosphorylation of mTOR to promote autophagy.

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作者: 孙菁 [1] 孙明军 [1]
期刊: 《中华医学杂志》2016年96卷40期 3246-3250页 MEDLINEISTICPKUCSCD
栏目名称: 基础研究
DOI: 10.3760/cma.j.issn.0376-2491.2016.40.011
发布时间: 2016-11-23
基金项目:
辽宁省科技厅科技攻关项目(2013020198-202)Key Technologies Research and Development Program of Liaoning Province
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