Li Yang, Deng Wenzhen, Wu Jinlin, He Qirui, Yang Gangyi, Luo Xie, Jia Yanjun, Duan Yaqian, Zhou Liping, Liu Dongfang
Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Department of Endocrinology, Qianjiang Central Hospital of Chongqing, Chongqing, China.
Antioxid Redox Signal. 2023 Mar;38(7-9):480-495. doi: 10.1089/ars.2021.0224.
Thioredoxin-interacting protein (TXNIP) is a crucial molecular promoter of oxidative stress and has been identified to be associated with cellular senescence. It is an important mediator of β cell insulin secretion and has effects on β cell mass. However, its role in β cell senescence is unclear. The present study was designed to investigate the effects and mechanisms of TXNIP on the senescence and aging- and diet-related dysfunction of β cells. Human pancreatic paraffin tissues and serum samples from different ages were collected to detect TXNIP expression. TXNIP and C57BL/6J mice were fed either a normal chow diet (NCD) or a high-fat diet (HFD) until 5, 11, 14, or 20 months. The recapitulation experiment was conducted with TXNIP protein injection. MIN6 cells were transfected with LV-TXNIP and LV-siTXNIP. The biochemical indexes, ageing-related markers, cell cycle proteins, and pathways were examined both and . TXNIP expression showed an age-related increase in β cells and serum samples from humans. TXNIP significantly impaired glucose metabolism and insulin secretion in an age-dependent manner. TXNIP aggravated age-related and obesity-induced structural failure, oxidative stress, decreased proliferation, increased apoptosis in β cells, and induced the cell cycle arrest. TXNIP interacted with p38 mitogen-activated protein kinase (p38MAPK) and modulated the p16/p21-CDK-Rb axis to accelerate β cell senescence. The present study demonstrated that TXNIP may exacerbate pancreatic β cell senescence and age-related dysfunction by inducing cell cycle arrest through the p38-p16/p21-CDK-Rb pathway, in natural and pathological states. . 38, 480-495.
硫氧还蛋白相互作用蛋白（TXNIP）是氧化应激的关键分子促进因子，已被确定与细胞衰老相关。它是β细胞胰岛素分泌的重要调节因子，对β细胞数量有影响。然而，其在β细胞衰老中的作用尚不清楚。本研究旨在探讨TXNIP对β细胞衰老以及与衰老和饮食相关功能障碍的影响及机制。收集不同年龄段的人胰腺石蜡组织和血清样本以检测TXNIP表达。将TXNIP基因敲除小鼠和C57BL/6J小鼠分别喂食正常饲料（NCD）或高脂饮食（HFD），持续5、11、14或20个月。通过注射TXNIP蛋白进行重复实验。用LV-TXNIP和LV-siTXNIP转染MIN6细胞。检测了生化指标、衰老相关标志物、细胞周期蛋白和信号通路。TXNIP表达在人类β细胞和血清样本中随年龄增加。TXNIP以年龄依赖性方式显著损害葡萄糖代谢和胰岛素分泌。TXNIP加剧了与年龄相关和肥胖诱导的结构破坏、氧化应激、β细胞增殖减少、凋亡增加，并诱导细胞周期停滞。TXNIP与p38丝裂原活化蛋白激酶（p38MAPK）相互作用，调节p16/p21-CDK-Rb轴以加速β细胞衰老。本研究表明，在自然和病理状态下，TXNIP可能通过p38-p16/p21-CDK-Rb途径诱导细胞周期停滞，从而加剧胰腺β细胞衰老和与年龄相关的功能障碍。（参考文献）38, 480 - 495。
