葡萄籽原花青素通过Nrf2信号通路拮抗高糖高脂诱导的MIN6细胞铁死亡

doi:10.7506/spkx1002-6630-20220111-089

食品科学 ›› 2023, Vol. 44 ›› Issue (1): 140-148.doi: 10.7506/spkx1002-6630-20220111-089

葡萄籽原花青素通过Nrf2信号通路拮抗高糖高脂诱导的MIN6细胞铁死亡

张丽媛，刘丹丹，李海燕，王同玲，陆恒，杨瑞瑞，王浩，丁玉松

（1.石河子大学医学院，新疆石河子 832000；2.新疆第二医学院公共卫生学院，新疆克拉玛依 834000）

出版日期:2023-01-15 发布日期:2023-01-31
基金资助:
中国博士后科学基金项目（2017M613310XB）；石河子大学科研项目（ZZZC201704A）

Grape Seed Procyanidin Extract Inhibited High Glucose and High Fat-Induced Ferroptosis through the Nrf2 Signaling Pathway in MIN6 Cells

ZHANG Liyuan, LIU Dandan, LI Haiyan, WANG Tongling, LU Heng, YANG Ruirui, WANG Hao, DING Yusong

(1. School of Medicine, Shihezi University, Shihezi 832000, China;2. College of Public Health, Xinjiang Second Medical College, Karamay 834000, China)

Online:2023-01-15 Published:2023-01-31

摘要/Abstract

摘要： 目的：铁死亡可能是高糖高脂诱导胰岛β细胞死亡的一种主要形式，本研究探讨葡萄籽原花青素提取物（grape seed procyanidin extract，GSPE）对高糖高脂诱导胰岛β细胞铁死亡的拮抗作用机制。方法：用25 mmol/L葡萄糖和200 μmol/L棕榈酸钠干预MIN6细胞建立胰岛β细胞损伤模型，进一步用不同质量浓度10、20、30、40、50、75、100 mg/L的GSPE以及核转录因子E2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）小干扰RNA（small interfering RNA，siRNA）进行干预，用细胞计数试剂盒（cell counting kit-8 assay，CCK8）检测细胞活性，用试剂盒检测细胞内谷胱甘肽（glutathione，GSH）、丙二醛（malonaldehyde，MDA）含量以及活性氧（reactive oxygen species，ROS）水平，用Western blot检测Nrf2、血红素氧化酶1（heme oxygenase-1，HO-1）、醌氧化还原酶1（NADPH:quinone oxido-reductase-1，NQO1）、铁代谢指标转铁蛋白受体1（transferrin receptor 1，TfR1）、二价金属离子蛋白转运体（divalent metal transporter 1，DMT1）、铁蛋白（ferritin）、铁死亡的指标蛋白溶质载体家族7成员11（solute carrier family 7 member 11，SLC7A11）、谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）、酰基合成酶长链家族成员4（acyl-CoA synthetase long-chain family member 4，ACSL4）蛋白表达水平。结果：与对照组相比，高糖高脂组导致细胞内铁沉积，上调TfR1、DMT1、ferritin蛋白表达水平，增加氧化产物MDA含量、ROS、ACSL4水平，降低GSH水平，下调GPX4、SLC7A11蛋白表达水平，而GSPE干预后能够激活Nrf2/HO-1信号通路进而上调GPX4、SLC7A11蛋白表达水平，增加GSH水平从而降低MDA、ROS、ACSL4水平和铁代谢指标水平（TfR1、DMT1、ferritin蛋白表达水平），抑制高糖高脂诱导的MIN6细胞铁死亡。联合Nrf2 siRNA干预后发现，抑制Nrf2信号通路后会抑制GSPE的保护作用，造成抗氧化酶HO-1、GPX4、SLC7A11表达水平降低。结论：GSPE可能是通过激活MIN6细胞内的Nrf2信号通路，上调抗氧化酶表达，抑制高糖高脂诱导的细胞铁死亡，从而提高MIN6细胞存活率。

关键词: 铁死亡；葡萄籽原花青素提取物；核转录因子E2相关因子2；MIN6细胞

Abstract: Objective: Ferroptosis may be an important mechanism of high glucose and high fat-induced pancreatic β cell death. This study investigated the effect and mechanism of grape seed procyanidin extract (GSPE) on ferroptosis in pancreatic β cells induced by high glucose and high fat. Methods: An islet β cell injury model was established by treating MIN6 cells with 25 mmol/L glucose and 200 μmol/L sodium palmitate. Then, the cells were transfected with nuclear factor erythroid 2-related factor 2 small-interfering RNA (Nrf2 siRNA) and treated with 10, 20, 30, 40, 50, 75 and 100 mg/L GSPE. The cell activity was detected by the cell counting kit-8 (CCK8) assay, and the levels of intracellular glutathione (GSH), malonaldehyde (MDA) and reactive oxygen species (ROS) were detected by commercial kits. The protein expression of Nrf2, heme oxygenase-1 (HO-1), NADPH:quinone oxidoreductase-1 (NQO1), iron metabolism indicator transferrin receptor 1 (TfR1), divalent metal transporter 1 (DMT1), ferritin, solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were measured by Western blot. Results: Compared with the control group, high glucose and high fat caused intracellular iron deposition, up-regulated the protein expression levels of TfR1, DMT1 and ferritin, increased the levels of MDA, ROS and ACSL4, decreased the level of GSH and down-regulated the protein expression levels of GPX4 and SLC7A11. Intervention with GSPE could activate the Nrf2 signaling pathway to up-regulate GPX4 and SLC7A11 protein expression and increase the level of GSH. GSPE could also decrease the levels of MDA, ROS and ACSL4 and iron metabolism indices (TfR1, DMT1 and ferritin protein expression), thereby preventing ferroptosis in MIN6 cells induced by high glucose and high fat. After?inhibition of the Nrf2 signaling pathway?by?Nrf2-siRNA?transfection, the protective effect of GSPE was inhibited and the expression of the antioxidant enzymes HO-1, GPX4 and SLC7A11 was decreased. Conclusion: GSPE reduces ferroptosis induced by high glucose and high fat possibly by activating the Nrf2 signaling pathway and up-regulating antioxidant enzymes, consequently improving the cell viability of MIN6 cells.

Key words: ferroptosis; grape seed procyanidin extract; nuclear factor erythroid 2-related factor 2; MIN6 cells

中图分类号:

R151

张丽媛，刘丹丹，李海燕，王同玲，陆恒，杨瑞瑞，王浩，丁玉松. 葡萄籽原花青素通过Nrf2信号通路拮抗高糖高脂诱导的MIN6细胞铁死亡[J]. 食品科学, 2023, 44(1): 140-148.

ZHANG Liyuan, LIU Dandan, LI Haiyan, WANG Tongling, LU Heng, YANG Ruirui, WANG Hao, DING Yusong. Grape Seed Procyanidin Extract Inhibited High Glucose and High Fat-Induced Ferroptosis through the Nrf2 Signaling Pathway in MIN6 Cells[J]. FOOD SCIENCE, 2023, 44(1): 140-148.

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葡萄籽原花青素通过Nrf2信号通路拮抗高糖高脂诱导的MIN6细胞铁死亡

Grape Seed Procyanidin Extract Inhibited High Glucose and High Fat-Induced Ferroptosis through the Nrf2 Signaling Pathway in MIN6 Cells

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