木犀草素通过调节Wnt/β-catenin信号通路对糖尿病大鼠的胰腺保护作用
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摘要
目的:研究木犀草素对链脲佐菌素(STZ)诱导的2型糖尿病(T2DM)大鼠胰腺Wnt/β-catenin信号通路表达的影响,探讨木犀草素对DM大鼠胰腺的保护作用及可能机制。方法:将40只雄性SD大鼠随机分为正常对照组(NC)、正常对照+木犀草素组(NC+L)、糖尿病组(DM)和木犀草素治疗组(DM+L),每组10只。采用高脂饮食联合腹腔注射STZ制备T2DM大鼠模型。NC+L组和DM+L组给予木犀草素[100mg/(kg·d)]灌胃,NC组和DM组给予等量生理盐水灌胃。干预6周后,检测体重(W)、空腹血糖(FPG)、餐后血糖(2hPBG)、血清胰岛素(INS)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)水平;HE染色光镜下观察胰腺病理改变;Western Blot检测胰腺组织中wnt3a、β-catenin、cyclin D1、c-myc蛋白表达。结果:与NC组相比,DM组FPG、2hPBG、INS、TC、TG、LDL水平均明显升高(P<0.05),胰岛形态不规则,胰岛内细胞数量减少且排列紊乱,胰腺组织wnt3a、β-catenin、cyclin D1、c-myc蛋白水平明显降低(P<0.05);与DM组相比,DM+L组FPG、2hPBG、INS、TC、TG、LDL水平明显降低(P<0.05),胰腺组织病理结构损害减轻,胰腺组织wnt3a、β-catenin、cyclin D1、c-myc蛋白水平明显升高(P<0.05)。结论:木犀草素改善DM大鼠糖脂代谢,减轻胰腺组织的病理损伤,其机制与调节Wnt/β-catenin信号通路有关。
Objective:To investigate the protective effect and mechanism of luteolin on pancreas of diabetic rats.Methods:SD rats were randomly divided into four groups(n=10 per group)as follows:normal group(NC),normal group treated with luteolin group(NC+L),diabetic mellitus group(DM),diabetic mellitus treated with luteolin group(DM+L).Luteolin was administered by gavage to the rats of NC+L group and DM+L group at a dose of 100 mg/(kg·d)for 6 weeks.The rats in NC group and DM group were treated with equal volume of normal saline.The animals were sacrificed after 6 weeks of treatment with luteolin.The weight(W),fasting plasma glucose(FPG),2 hours postprandial blood glucose(2 hPBG),insulin(INS),total cholesterol(TC),triglyceride(TG),low-density lipoprotein(LDL),high-density lipoprotein(HDL)were determined.HE staining was used to observe the pathological changes of pancreatic tissues.Western Blot was used to detect the protein expression of wnt3 a,β-catenin,cyclin D1,c-myc.Results:As compared with NC group,DM group had significantly increased FPG,2 hPBG,INS,TC,TG and LDL(P<0.05).In DM group,the shapes of islets were irregular and the boundaries between exocrine glands and islets were blurring.Furthermore,the number of islet cells with disorderly arrangment was decreased.The protein expression of wnt3 a,β-catenin,cyclin D1,c-myc were decreased in pancreatic tissues in DM group(P<0.05).Luteolin treatment had a positivity influence in the pancreatic function and pancreatic histopathological changes,decreased the levels of FPG,2 hPBG,INS,TC,TG and LDL(P<0.05).The protein expression of wnt3 a,β-catenin,cyclin D1,and c-myc were also up-regulated in pancreatic tissues of rats treated with luteolin(P<0.05).Conclusion:Luteolin relieves pancreatic injury in diabetic rats via improving the Wnt/β-catenin signaling pathway.
Objective:To investigate the protective effect and mechanism of luteolin on pancreas of diabetic rats.Methods:SD rats were randomly divided into four groups(n=10 per group)as follows:normal group(NC),normal group treated with luteolin group(NC+L),diabetic mellitus group(DM),diabetic mellitus treated with luteolin group(DM+L).Luteolin was administered by gavage to the rats of NC+L group and DM+L group at a dose of 100 mg/(kg·d)for 6 weeks.The rats in NC group and DM group were treated with equal volume of normal saline.The animals were sacrificed after 6 weeks of treatment with luteolin.The weight(W),fasting plasma glucose(FPG),2 hours postprandial blood glucose(2 hPBG),insulin(INS),total cholesterol(TC),triglyceride(TG),low-density lipoprotein(LDL),high-density lipoprotein(HDL)were determined.HE staining was used to observe the pathological changes of pancreatic tissues.Western Blot was used to detect the protein expression of wnt3 a,β-catenin,cyclin D1,c-myc.Results:As compared with NC group,DM group had significantly increased FPG,2 hPBG,INS,TC,TG and LDL(P<0.05).In DM group,the shapes of islets were irregular and the boundaries between exocrine glands and islets were blurring.Furthermore,the number of islet cells with disorderly arrangment was decreased.The protein expression of wnt3 a,β-catenin,cyclin D1,c-myc were decreased in pancreatic tissues in DM group(P<0.05).Luteolin treatment had a positivity influence in the pancreatic function and pancreatic histopathological changes,decreased the levels of FPG,2 hPBG,INS,TC,TG and LDL(P<0.05).The protein expression of wnt3 a,β-catenin,cyclin D1,and c-myc were also up-regulated in pancreatic tissues of rats treated with luteolin(P<0.05).Conclusion:Luteolin relieves pancreatic injury in diabetic rats via improving the Wnt/β-catenin signaling pathway.
引文
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[10]刘振平.糖脂毒性与胰岛β细胞功能衰竭[J].中华老年多器官疾病杂志,2010,9(4):377-380.Liu ZP.Glucolipotoxicity withislet beta-cell failure[J].Chinese Journal of Multiple Organ Diseases in the Elderly,2010,9(4):377-380.
[11]Liu JF,Ma Y,Wang Y,et al.Reduction of lipid accumulation in HepG2cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress[J].Phytotherapy Research,2011,25(4):588-596.
[12]Xi XH,Wang FW,Yan W,et al.Alteration of Wnt/β-catenin signaling pathway in early diabetic rat myocardium[J].Chinese Pharmacological Bulletin,2015,31(3):363-366.
[13]Hsu YC,Lee PH,Lei CC,et al.Nitric oxide donors rescue diabetic nephropathy through oxidative-stressand nitrosative-stress-mediated Wnt signaling pathways[J].Journal of Diabetes Investigation,2015,6(1):24-34.
[14]Gaudio A,Privitera F,Battaglia K,et al.Sclerostin levels associated with inhibition of the Wnt/β-catenin signaling and reduced bone turnover in type 2diabetes mellitus[J].J Clin Endocrinol Metab,2012,97(10):3 744-3 750.
[2]Xie F,Lang Q,Zhou M,et al.The dietary flavonoid luteolin inhibits Aurora B kinase activity and blocks proliferation of cancer cells[J].European Journal of Pharmaceutical Sciences,2012,46(5):388-396.
[3]Li J,Li X,Xu W,et al.Antifibrotic effects of luteolin on hepatic stellate cells and liver fibrosis by targeting AKT/mTOR/p70S6K and TGFβ/Smad signalling pathways[J].Liver International,2015,35(4):1 222-1 233.
[4]Zang Y,Igarashi K,Li Y.Anti-diabetic effects of luteolin and luteolin-7-O-glucoside on KK-Ay mice[J].Biosci Biotechnol Biochem,2016,80(8):1 580-1 586.
[5]Figeac F,Uzan B,Faro M,et al.Neonatal growth and regeneration ofbeta-cells are regulated by the Wnt/betacatenin signaling in normal and diabetic rats[J].American Journal of Physiology Endocrinology&Metabolism,2010,298(2):E245.
[6]Wang X,Lei X G,Wang J.Malondialdehyde regulates glucose-stimulated insulin secretion in murine islets via TCF7L2-dependent Wnt signaling pathway[J].Molecular&Cellular Endocrinology,2014,382(1):8-16.
[7]Kaneto H.Pancreaticβ-cell glucose toxicity in type2diabetes mellitus[J].Current Diabetes Reviews,2015,11(1):2.
[8]Ding L,Jin DZ,Chen XL.Luteolin enhances insulin sensitivity via activation of PPARγtranscriptional activity in adipocytes[J].Journal of Nutritional Biochemistry,2010,21(10):941-947.
[9]Lu HE,Chen Y,Sun XB,et al.Effects of luteolin on retinal oxidative stress and inflammation in diabetes[J].Rsc Advances,2014,5(7):4 898-4 904.
[10]刘振平.糖脂毒性与胰岛β细胞功能衰竭[J].中华老年多器官疾病杂志,2010,9(4):377-380.Liu ZP.Glucolipotoxicity withislet beta-cell failure[J].Chinese Journal of Multiple Organ Diseases in the Elderly,2010,9(4):377-380.
[11]Liu JF,Ma Y,Wang Y,et al.Reduction of lipid accumulation in HepG2cells by luteolin is associated with activation of AMPK and mitigation of oxidative stress[J].Phytotherapy Research,2011,25(4):588-596.
[12]Xi XH,Wang FW,Yan W,et al.Alteration of Wnt/β-catenin signaling pathway in early diabetic rat myocardium[J].Chinese Pharmacological Bulletin,2015,31(3):363-366.
[13]Hsu YC,Lee PH,Lei CC,et al.Nitric oxide donors rescue diabetic nephropathy through oxidative-stressand nitrosative-stress-mediated Wnt signaling pathways[J].Journal of Diabetes Investigation,2015,6(1):24-34.
[14]Gaudio A,Privitera F,Battaglia K,et al.Sclerostin levels associated with inhibition of the Wnt/β-catenin signaling and reduced bone turnover in type 2diabetes mellitus[J].J Clin Endocrinol Metab,2012,97(10):3 744-3 750.