基于TLR4/NF-κB通路及Th17/Treg细胞平衡探讨熊果酸改善 1型糖尿病大鼠胰岛β细胞损伤的实验研究
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河南中医药大学医学院

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河南省科技攻关项目(212102311081),河南中医药大学研究生科研创新基金(2022KYCX082)


Experimental study of ursolic acid to ameliorate pancreatic β-cell injury in type 1 diabetic rats based on the TLR4/NF-κB pathway and Th17/Treg cell balance
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Medical College of Henan University of Traditional Chinese Medicine

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    摘要:

    【摘要】目的 探究熊果酸(ursolic acid,UA)对1型糖尿病(type 1 diabetes,T1DM)大鼠TLR4/NF-κB信号通路及Th17/Treg细胞的影响。方法 腹腔注射链脲佐菌素制备T1DM大鼠模型,随机分为空白组(Control组)组、模型组(Model组)、二甲双胍组(MET组)和UA组。记录大鼠体重、血糖等一般情况,灌胃六周后采集大鼠外周血、胰腺组织评估胰岛素干预情况。免疫组化观察胰腺组织病理变化;鲎试剂检测血清LPS含量变化;qRT-PCR法检测胰腺TLR4、MyD88、IκBα、NF-κB p65 mRNA的表达,以及转录因子RORγt、Foxp3 mRNA的表达;Western blot法检测胰腺TLR4、MyD88、IκBα、NF-κB p65蛋白的表达,以及转录因子RORγt、Foxp3蛋白的表达;流式细胞术检测外周血Th17、Treg细胞比例变化;ELISA法检测血清TNF-α、IL-6、IL-1β含量变化。结果 经STZ诱导的糖尿病大鼠经6周灌胃处理,与Model组相比,MET组大鼠和UA组大鼠空腹血糖(fasting blood glucose (FBG))均明显下降,体重均明升高;胰岛β细胞炎性浸润减少;TLR4、MyD88、IκBα、NF-κB p65、RORγt mRNA和蛋白的表达明显降低;LPS含量明显下降;IκBα、Foxp3 mRNA和蛋白表达明显升高;Th17/Treg比值明显下降;TNF-α、IL-6、IL-1β含量明显下降。结论 UA可通过减少LPS移位,抑制TLR4/NF-κB通路,下调RORγt并上调Foxp3的表达纠正T1DM大鼠Th17/Treg细胞比例失衡来改善大鼠症状。

    Abstract:

    [abstracts] Objective To investigate the effects of ursolic acid (UA) on TLR4/NF-κB signaling pathway and Th17/Treg cells in type 1 diabetes (T1DM) rats. Mmthods The T1DM rat model was prepared by intraperitoneal injection of streptozotocin, and randomly divided into blank (Control group) group, model group (Model group), metformin group (MET group) and UA group. General conditions such as body weight and blood glucose were recorded, and peripheral blood and pancreatic tissues were collected after six weeks of gavage to assess insulin intervention. Immunohistochemistry was used to observe the pathological changes in pancreatic tissues; horseshoe crab reagent was used to detect the changes in serum LPS content; qRT-PCR was used to detect the expression of pancreatic TLR4, MyD88, IκBα, and NF-κB p65 mRNAs, as well as the expression of the transcription factors RORγt and Foxp3 mRNAs; and Western blot was used to detect the expression of pancreatic TLR4, MyD88, IκBα , NF-κB p65 protein expression, and transcription factors RORγt, Foxp3 protein expression; flow cytometry to detect changes in the ratio of peripheral blood Th17, Treg cells; ELISA to detect changes in serum TNF-α, IL-6, IL-1β levels. Results After STZ-induced diabetic rats were treated by gavage for 6 weeks, compared with the Model group, fasting blood glucose (FBG) decreased significantly in both the MET and UA groups, and body weights increased; inflammatory infiltration of pancreatic β-cells was reduced; and the expression of TLR4, MyD88, IκBα, NF-κB p65, RORγt mRNA and protein expression was significantly decreased; LPS content was significantly decreased; IκBα, Foxp3 mRNA and protein expression was significantly increased; Th17/Treg ratio was significantly decreased; and TNF-α, IL-6, and IL-1β content was significantly decreased. Conclusion UA can improve the symptoms of rats by reducing LPS shift, inhibiting TLR4/NF-κB pathway, down-regulating RORγt and up-regulating Foxp3 expression to correct the imbalance of Th17/Treg cell ratio in T1DM rats.

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  • 收稿日期:2023-09-07
  • 最后修改日期:2023-11-09
  • 录用日期:2024-03-12
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