尿素C通过激活Nrf2信号通路缓解1型糖尿病胰腺β细胞功能障碍。

IF 4.6 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Cheng Luo, Can Hou, Danyi Yang, Tingting Tan, Chen Chao
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引用次数: 0

摘要

目的:1型糖尿病(T1D)是一种自身免疫性疾病,破坏产生胰岛素的胰腺β细胞。保留胰腺β细胞功能对治疗T1D至关重要。我们的研究旨在探讨尿素C (UC)介导的β细胞功能调节的机制。方法:给予非肥胖型糖尿病(NOD)小鼠UC,评价UC对T1D的保护作用。苏木精和伊红染色检查胰岛的炎症情况。采用葡萄糖刺激胰岛素分泌(GSIS)试验和口服糖耐量试验评估T1D的进展。在UC存在的情况下,用TNF-α、IL-1β和IFN-γ处理MIN6细胞。CCK-8检测细胞活力。Annexin V-FITC染色、PI染色、EdU掺入和彗星染色检测细胞凋亡、增殖和DNA断裂。western blot检测Keap1、Nrf2、HO-1和NQO1。免疫荧光染色检测Nrf2和胰岛素。结果:UC给药可显著降低NOD小鼠的糖尿病发病率,减轻胰岛素炎,升高胰岛素水平和GSIS,降低血糖和AUC。细胞因子处理抑制了MIN6细胞的活力和增殖,但增加了细胞凋亡和DNA损伤,UC处理减轻了这些不利影响。UC可抑制NOD小鼠Keap1表达,促进Nrf2、HO-1和NQO1的表达。据报道,Nrf2信号传导与预防糖尿病发病有关,HO-1和NQO1是受Nrf2信号传导调节的II期抗氧化酶。细胞因子处理可上调MIN6细胞的Keap1,下调Nrf2、HO-1和NQO1,但UC可逆转。细胞因子处理可阻止Nrf2的核易位,而UC可促进其核易位。uc介导的Nrf2、HO-1和NQO1的上调、细胞凋亡的减少、增殖和胰岛素分泌的增加通过Nrf2的沉默被消除。结论:UC通过激活Nrf2信号改善胰腺β细胞功能,从而缓解T1D进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Urolithin C alleviates pancreatic β-cell dysfunction in type 1 diabetes by activating Nrf2 signaling.

Urolithin C alleviates pancreatic β-cell dysfunction in type 1 diabetes by activating Nrf2 signaling.

Aims: Type 1 diabetes (T1D) is an autoimmune disorder that destroys insulin-generating pancreatic β-cells. Preserving pancreatic β-cell function is important for treating T1D. Our study aims to explore the mechanism underlying urolithin C (UC)-mediated regulation of β-cell function.

Methods: Non-obese diabetic (NOD) mice were administrated with UC to evaluate UC-mediated protection of T1D. The inflammation of the pancreas islets was examined by hematoxylin and eosin staining. Glucose-stimulated insulin secretion (GSIS) assay and oral glucose tolerance test were applied to evaluate the progression of T1D. MIN6 cells were treated with TNF-α, IL-1β and IFN-γ in the presence of UC. Cell viability was analyzed by CCK-8. Cell apoptosis, proliferation and DNA fragmentation were examined by Annexin V-FITC and PI staining, EdU incorporation and comet assays. Keap1, Nrf2, HO-1 and NQO1 were examined by western blot. Immunofluorescence staining was applied to detect Nrf2 and insulin.

Results: UC administration significantly reduced diabetes incidence, attenuated insulitis, elevated insulin levels and GSIS and reduced blood glucose and AUC in NOD mice. Cytokine treatment suppressed MIN6 cell viability and proliferation but enhanced apoptosis and DNA damage, and these detrimental effects were relieved by UC treatment. Furthermore, UC administration inhibited Keap1 expression and promoted the expression of Nrf2, HO-1 and NQO1 in NOD mice. Nrf2 signaling has been reported to be implicated in preventing the onset of diabetes, and HO-1 and NQO1 are phase II antioxidant enzymes that are regulated by Nrf2 signaling. Cytokine treatment upregulated Keap1 and downregulated Nrf2, HO-1 and NQO1 in MIN6 cells, but it was reversed by UC. The nuclear translocation of Nrf2 was prevented by cytokine treatment, but UC promoted its nuclear translocation. UC-mediated upregulation of Nrf2, HO-1 and NQO1, decreased cell apoptosis and increased proliferation and insulin secretion were abolished by silencing of Nrf2.

Conclusion: UC improves pancreatic β-cell function by activating Nrf2 signaling, thereby alleviating T1D progression.

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来源期刊
Nutrition & Diabetes
Nutrition & Diabetes ENDOCRINOLOGY & METABOLISM-NUTRITION & DIETETICS
CiteScore
9.20
自引率
0.00%
发文量
50
审稿时长
>12 weeks
期刊介绍: Nutrition & Diabetes is a peer-reviewed, online, open access journal bringing to the fore outstanding research in the areas of nutrition and chronic disease, including diabetes, from the molecular to the population level.
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