红豆杉能通过激活 Nrf2 信号轴防止糖尿病诱导的肝铁细胞沉积。

IF 5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
BioFactors Pub Date : 2024-02-01 DOI:10.1002/biof.2042
Nevena Savic, Milica Markelic, Ana Stancic, Ksenija Velickovic, Ilijana Grigorov, Milica Vucetic, Vesna Martinovic, Andjelija Gudelj, Vesna Otasevic
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引用次数: 0

摘要

最近,我们研究了糖尿病小鼠肝脏的嗜铁表型,发现核因子(红细胞衍生-2)相关因子 2(Nrf2)失活是肝损伤不可或缺的一部分。在此,我们旨在研究作为 Nrf2 激活剂和抗氧化剂的莱菔硫烷是否能预防糖尿病诱导的肝铁沉着病及其机制。雄性 C57BL/6 小鼠分为四组:对照组(车辆处理)、糖尿病组(链脲佐菌素诱导;40 毫克/千克,从第 1 天到第 5 天)、糖尿病舒乐安定处理组(2.5 毫克/千克,从第 1 天到第 42 天)和非糖尿病舒乐安定处理组(2.5 毫克/千克,从第 1 天到第 42 天)。结果显示,糖尿病诱导的 Nrf2 失活,其下游对抗氧化防御(过氧化氢酶、超氧化物歧化酶、硫氧还原酶)、铁代谢(铁蛋白重链 (FTH1)、铁蛋白 1)、谷胱甘肽 (GSH)谷胱甘肽(GSH)合成(胱氨酸-谷氨酸反转运体系统、胱硫醚酶、谷氨酸-半胱氨酸连接酶催化亚基、谷氨酸-半胱氨酸连接酶修饰亚基、谷胱甘肽合成酶)和 GSH 循环--谷胱甘肽还原酶(GR)在红霉素处理后发生逆转/增加。此外,我们还发现糖尿病肝脏中的铁嗜性表型与铁蛋白吞噬作用增强和 FTH1 免疫阳性率降低有关。通过提高 GSH 水平、减少易溶铁和脂质过氧化物(4-羟基-2-壬烯醛、脂褐质)的积累、减少嗜铁细胞和肝损伤(减少纤维化、丙氨酸氨基转移酶和天冬氨酸氨基转移酶),进一步证明了红景天的抗铁锈色素沉着作用。最后,由糖尿病引起的血清葡萄糖和甘油三酯水平的升高也因莱菔硫烷而明显降低。尽管这项研究受限于使用一种实验诱导的糖尿病模型,但研究结果首次证明,红豆杉叶素可通过激活 Nrf2 信号通路,防止糖尿病诱导的体内肝脏铁蛋白沉积。这表明红景天是一种很有前景的植物药,可用于预防/缓解糖尿病相关病症中的铁沉着病。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis

Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis

Sulforaphane prevents diabetes-induced hepatic ferroptosis by activating Nrf2 signaling axis

Recently, we characterized the ferroptotic phenotype in the liver of diabetic mice and revealed nuclear factor (erythroid-derived-2)-related factor 2 (Nrf2) inactivation as an integral part of hepatic injury. Here, we aim to investigate whether sulforaphane, an Nrf2 activator and antioxidant, prevents diabetes-induced hepatic ferroptosis and the mechanisms involved. Male C57BL/6 mice were divided into four groups: control (vehicle-treated), diabetic (streptozotocin-induced; 40 mg/kg, from Days 1 to 5), diabetic sulforaphane-treated (2.5 mg/kg from Days 1 to 42) and non-diabetic sulforaphane-treated group (2.5 mg/kg from Days 1 to 42). Results showed that diabetes-induced inactivation of Nrf2 and decreased expression of its downstream antiferroptotic molecules critical for antioxidative defense (catalase, superoxide dismutases, thioredoxin reductase), iron metabolism (ferritin heavy chain (FTH1), ferroportin 1), glutathione (GSH) synthesis (cystine-glutamate antiporter system, cystathionase, glutamate-cysteine ligase catalitic subunit, glutamate-cysteine ligase modifier subunit, glutathione synthetase), and GSH recycling - glutathione reductase (GR) were reversed/increased by sulforaphane treatment. In addition, we found that the ferroptotic phenotype in diabetic liver is associated with increased ferritinophagy and decreased FTH1 immunopositivity. The antiferroptotic effect of sulforaphane was further evidenced through the increased level of GSH, decreased accumulation of labile iron and lipid peroxides (4-hydroxy-2-nonenal, lipofuscin), decreased ferritinophagy and liver damage (decreased fibrosis, alanine aminotransferase, and aspartate aminotransferase). Finally, diabetes-induced increase in serum glucose and triglyceride level was significantly reduced by sulforaphane. Regardless of the fact that this study is limited by the use of one model of experimentally induced diabetes, the results obtained demonstrate for the first time that sulforaphane prevents diabetes-induced hepatic ferroptosis in vivo through the activation of Nrf2 signaling pathways. This nominates sulforaphane as a promising phytopharmaceutical for the prevention/alleviation of ferroptosis in diabetes-related pathologies.

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来源期刊
BioFactors
BioFactors 生物-内分泌学与代谢
CiteScore
11.50
自引率
3.30%
发文量
96
审稿时长
6-12 weeks
期刊介绍: BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.
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