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金丝桃苷对糖尿病足溃疡大鼠炎症反应、创面愈合及AMPK_SIRT1信号通路的影响 (1).pdf
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1、天津医药 2023 年 11 月第 51 卷第 11 期金丝桃苷对糖尿病足溃疡大鼠炎症反应、创面愈合及AMPK/SIRT1信号通路的影响雷慧1,鲍亚玲1,鲍喜静2,马君2摘要:目的探究金丝桃苷对糖尿病足溃疡(DFU)大鼠炎症反应、创面愈合以及对腺苷酸活化蛋白激酶(AMPK)/沉默信息调节因子1(SIRT1)信号通路的影响。方法构建DFU大鼠模型,并将建模成功的48只大鼠随机分为模型组,金丝桃苷低(100 mg/kg)、高(200 mg/kg)剂量组,二甲双胍(200 mg/kg)组,每组12只;另取12只大鼠作为对照组。各组大鼠给予相应药物干预,每日1次,连续4周。采用血糖仪分别检测大鼠给药前
2、后空腹血糖(FBG)水平;酶联免疫吸附试验检测大鼠血清中白细胞介素6(IL-6)、肿瘤坏死因子(TNF-)水平;计算大鼠创面愈合率;苏木素-伊红(HE)染色观察大鼠创面肉芽组织病理学变化;荧光定量PCR检测创面肉芽组织中AMPK、SIRT1 mRNA表达水平;蛋白免疫印迹法检测AMPK、SIRT1蛋白表达水平。结果对照组大鼠创面肉芽组织细胞结构完整,排列整齐,少量炎性细胞浸润;与对照组相比,模型组大鼠创面肉芽组织成纤维细胞及毛细血管坏死严重,伴随大量炎性细胞浸润,FBG、血清TNF-、IL-6水平升高(P0.05),创面愈合率、AMPK、SIRT1 mRNA和蛋白表达水平降低(P0.05);与
3、模型组相比,金丝桃苷低、高剂量组创面肉芽组织病变程度依次减轻,FBG、血清中TNF-、IL-6水平依次降低(P0.05),创面愈合率、AMPK、SIRT1 mRNA和蛋白表达水平依次升高(P0.05);二甲双胍组和金丝桃苷高剂量组肉芽组织病理学变化及各项指标比较差异无统计学意义(P0.05)。结论金丝桃苷可减轻DFU大鼠炎症反应,加快创面愈合,其机制可能与激活AMPK/SIRT1信号通路有关。关键词:金丝桃苷;糖尿病足;足溃疡;炎症;腺苷酸活化蛋白激酶;沉默信息调节因子1中图分类号:R285.5,R349.6文献标志码:ADOI:10.11958/20230140基金项目:河北省医学科学研究课
4、题计划项目(20211151)作者单位:1张家口学院护理学院(邮编075000);2张家口市第一医院内分泌科作者简介:雷慧(1979),女,副教授,主要从事中药药理学方面研究。E-mail:通信作者E-mail:al.Long-chain acyl-CoA synthetase 4 participates in the formationof highly unsaturated fatty acid-containing phospholipids in murinemacrophages J.Biochim Biophys Acta Mol Cell Biol Lipids,2019,1
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11、rneol on corticalneuronsagainstoxygen-glucosedeprivation/reperfusion:involvementofanti-oxidationandanti-inflammationthroughnucleartranscriptionfactorappaBsignalingpathway J.Neuroscience,2011,176:408-419.doi:10.1016/j.neuroscience.2010.11.029.24 WU H Y,TANG Y,GAO L Y,et al.The synergetic effect of ed
12、aravoneand borneol in the rat model of ischemic stroke J.Eur J Pharmacol,2014,740:522-531.doi:10.1016/j.ejphar.2014.06.035.25 HUA Y,ZHOU L M,YANG W D,et al.Y-2 reduces oxidativestress and inflammation and improves neurological function ofcollagenase-induced intracerebral hemorrhage ratsJ.Eur JPharma
13、col,2021,910:174507.doi:10.1016/j.ejphar.2021.174507.(2022-11-07收稿2023-03-13修回)(本文编辑陈丽洁)实验研究1205Tianjin Med J,November 2023,Vol.51 No.11糖尿病足溃疡(DFU)与周围神经病变、血管疾病和足部感染有关1。糖尿病性溃疡肉芽组织中血管生成异常会导致营养供应减少,延缓创面愈合2。炎症是组织损伤和感染的保护性反应,机体识别病原体后,巨噬细胞会启动早期炎症反应,从而募集免疫细胞,包括中性粒细胞和单核细胞,以产生炎性细胞因子,如白细胞介素6(IL-6)和肿瘤坏死因子(TNF-
14、)等。炎症反应可加重2型糖尿病患者伤口愈合期间的组织损伤,这种损伤的主要病理机制涉及炎性因子的相互作用和活性氧的产生3。因此,长时间的炎症会导致伤口愈合延迟。金丝桃苷是一种类黄酮,具有抗炎、抗氧化、改善糖尿病肾病(DN)以及保护血管的作用4。研究表明,金丝桃苷能下调脓毒症模型大鼠心肌细胞中的炎性因子水平,改善大鼠心肌损伤5。同时,金丝桃苷也可抑制DN大鼠肾组织炎症反应,改善糖脂代谢,从而减轻肾组织病理损伤6。腺苷酸活化蛋白激酶(AMPK)/沉默信息调节因子1(SIRT1)信号通路参与能量代谢和炎症反应过程,在糖尿病中也有调控作用7。研究发现,激活AMPK/SIRT1信号通路可抑制糖尿病心肌病小
15、鼠的炎症和心肌细胞凋亡,从而减轻糖尿病心肌病症状8。由于金丝桃苷的抗炎活性,其对DFU也具有治疗作用。本研究拟探讨金丝桃苷对DFU模型大鼠创面愈合及 AMPK/SIRT1 信号通路的影响,为DFU的治疗提供参考。1材料与方法1.1实验动物SPF级SD大鼠(雌雄不限)60只,78周龄,体质量235256 g,购自江苏瀚江生物科技有限公司,生产许可证号:SCXK(苏)2021-0004,大鼠均饲养于室温2226,相对湿度60%70%,12 h光暗交替的饲养房中。本研究经张家口学院伦理委员会批准(伦理号:伦理审核2022-078)。1.2主要药物、试剂及仪器金丝桃苷(原料药,纯度99.5%)购自商丘
16、美兰生物工程有限公司;二甲双胍片(0.25 g/片)购自深圳中联制药有限公司;高糖高脂饲料购自Effects of hyperin on inflammatory reaction,wound healing and AMPK/SIRT1 signalingpathway in diabetic foot ulcer model ratsLEI Hui1,BAO Yaling1,BAO Xijing2,MA Jun21 Nursing College of Zhangjiakou University,Zhangjiakou 075000,China;2 Department of Endoc
17、rinology,Zhangjiakou First HospitalCorresponding AuthorE-mail:Abstract:ObjectiveTo explore the effect of hyperin on inflammatory reaction,wound healing and AMP-activatedprotein kinase(AMPK)/silent information regulator 1(SIRT1)signaling pathway in diabetic foot ulcer(DFU)rats.MethodsThe DFU rat mode
18、l was established,and 48 rats with successful DFU model were randomly divided into the model group,thehyperin low dose(100 mg/kg)group,the hyperin high dose(200 mg/kg)group and the metformin(200 mg/kg)group,with 12rats in each group.Another 12 rats were taken as the control group.Rats of each group
19、were given corresponding drugintervention,once a day for 4 weeks.Fasting blood glucose(FBG)levels of rats were detected by glucose meter aftermodeling(before administration)and after administration.Serum levels of interleukin(IL-6)and tumor necrosis factor-(TNF-)were detected by enzyme linked immuno
20、sorbent assay.The wound healing rate of rats was calculated by takingpictures.Hematoxylin-eosin staining was used to observe pathological changes of wound granulation tissue.Fluorescencequantitative PCR was used to detect mRNA expression levels of AMPK and SIRT1 in wound granulation tissue of rats.W
21、estern blot assay was used to detect protein expression levels of AMPK and SIRT1 in wound granulation tissue of rats.ResultsIn the control group,the granulation tissue cells on the wound surface of rats were intact and orderly arranged,withless inflammatory cell infiltration.Compared with the contro
22、l group,the necrosis of fibroblasts and capillaries in woundgranulation tissue was severe,accompanied by a large number of inflammatory cell infiltration,and FBG,TNF-and IL-6levels in serum were significantly increased(P0.05).The wound healing rate,the mRNA and protein expression levels ofAMPK and S
23、IRT1 in wound granulation tissue were significantly decreased(P0.05).Compared with the model group,thelesion degree of wound granulation tissue was reduced in turn in the hyperin low dose group and the hyperin high dose group,and the FBG,serum levels of TNF-and IL-6 were decreased in turn as well(P0
24、.05).The wound healing rate,the mRNAand protein expression levels of AMPK and SIRT1 in wound granulation tissue were increased in turn(P0.05).There wereno significant differences in pathological changes of the wound granulation tissue and other indicators between themetformin group and the hyperin h
25、igh dose group(P0.05).ConclusionHyperin can reduce inflammatory reaction andaccelerate wound healing in DFU rats,and its mechanism may be related to the activation of AMPK/SIRT1 signal pathway.Key words:hyperin;diabetic foot;foot ulcer;inflammation;AMP-activated protein kinase;silent informationregu
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