核因子相关因子2/抗氧化反应元件通路对2型糖尿病大鼠胰岛β细胞功能的影响及其与胰岛素受体底物-2表达的关系

目的探讨核因子相关因子2(Nrf2)/抗氧化反应元件(ARE)通路对T2DM大鼠胰岛β细胞功能的影响及其与胰岛素受体底物-2(IRS-2)表达的关系。方法雄性Wistar大鼠随机分为正常对照组(NC)、糖尿病模型组(DM)及叔丁基对苯二酚干预组(DM+tBHQ)。连续干预8周,评测胰岛β细胞功能及相关检测。结果 DM+tBHQ组胰岛β细胞功能、总超氧化物歧化酶(T-SOD)浓度、Nrf2、IRS-2蛋白表达及IRS-2磷酸化程度较DM组升高;丙二醛(MDA)、TNF-α浓度较DM组降低(P=0.000)。结论激活Nrf2/ARE通路可通过上调Nrf2下游靶基因在胰岛β细胞中的表达,以减轻氧化应激和慢性炎症反应对IRS-2的进一步损伤,从而延缓胰岛β细胞功能衰退。     

Nrf2/ARE/HO-1通路:阿尔茨海默病神经保护的潜在靶点

<正>近年研究表明,调节Nrf2/ARE/HO-1通路在各种神经系统疾病中具有神经保护作用。通过遗传学或药理学手段上调Nrf2或HO-1的表达,在动物模型和细胞体系中具有神经保护作用。因此有必要就Nrf2/ARE/HO-1在阿尔茨海默病(AD)中作用的研究进行梳理。本文对Nrf2/ARE/HO-1在AD中作用的研究历史进行了梳理。调节Nrf2/ARE/HO-1通路的激活     

Nrf2/ARE通路在炎症性肠病中的研究进展

Nrf2(nuclear factor-erythroid 2-related factor-2)能激活细胞抗氧化机制并抑制炎症反应,在机体抗氧化应激中起关键作用。Nrf2/ARE通路能够缓解包括炎症性肠病(inflammatory bowel disease,IBD)在内的多种炎症相关疾病。IBD是目前临床治疗的难点之一,其发病机制尚未阐明,多项研究表明氧化损伤在IBD的发生、发展过程中起重要作用。本文就Nrf2/ARE通路在IBD中的研究进展作一概述。     

Keap1-Nrf2-ARE通路在肺部疾病中的研究进展

核因子E2相关因子2(Nrf2)是细胞调节抗氧化应激反应的重要转录因子,通过与其胞浆伴侣蛋白Keap1和抗氧化反应元件(ARE)相互作用,启动编码抗氧化蛋白和Ⅱ相解毒酶的基因表达,在细胞防御保护中发挥作用.Nrf2缺失或激活障碍,将加重氧化应激源的细胞毒性,导致细胞功能障碍、凋亡甚至死亡.Keap1-Nrf2-ARE通路在炎症、肿瘤、衰老、凋亡、神经损伤、呼吸系统疾病、心血管疾病和自身免疫病等疾病中发挥广泛的细胞保护功能.本文对Keap1-Nrf2-ARE通路在肺部疾病中的最新研究进展进行了综述.     

自然杀伤细胞与2型糖尿病

近年来,免疫-代谢的相互关系已成为目前新的研究热点之一.自然杀伤细胞(NK细胞)作为固有免疫的主要成员,与2型糖尿病有着密切的联系:一方面,2型糖尿病患者外周血中NK细胞的数量出现异常以及功能出现紊乱,肥胖、胰岛素抵抗和氧化应激均可能参与2型糖尿病患者NK细胞的损伤机制.另一方面,NK细胞不仅可作为联系内脏脂肪炎性反应和脂肪应激的桥梁,参与内脏脂肪胰岛素抵抗,还可作为炎性细胞,促进2型糖尿病患者动脉粥样硬化的形成和进展,从而加剧糖尿病血管损伤.     

老年2型糖尿病患者氧化应激状态与β细胞功能的研究

糖尿病相关的氧化应激是自由基产生过多和机体抗氧化能力下降长期作用的后果.氧化应激可直接损伤胰岛β细胞,还可通过影响胰岛素合成和分泌的信号转导通路间接损伤β细胞功能[1].本文旨在研究2型糖尿病(T2DM)氧化应激状况,分析其与β细胞功能的关系及相关影响因素,为预防和治疗糖尿病提供依据.     

Nrf2/HO-1信号通路在慢性肝病中的研究

核因子相关因子2(Nrf2)是调控细胞氧化损伤的关键转录因子,可与抗氧化物元件(antioxidant response element,ARE)结合调控抗氧化物的表达。在氧化应激作用下Nrf2被激活,诱导其下游血红素加氧酶-1(HO-1)等抗氧化酶的表达,通过抗炎、抗氧化和调控细胞凋亡等机制,在肝损伤、脂肪肝、肝纤维化及肝癌等慢性肝病方面具有保护作用。本文通过总结近年来有关Nrf2/HO-1信号通路在慢性肝病中的研究进展,为探索肝病慢性化的发病机制、寻找新的靶点治疗方法提供理论依据。     

高胰岛素血症对平滑肌细胞基因异常甲基化的作用研究进展

调查发现70％的2型糖尿病患者合并动脉粥样硬化,进一步实验证实胰岛素导致血管平滑肌细胞表型转化是导致动脉粥样硬化发生的重要原因之一.平滑肌细胞表型转化已被证实与基因异常甲基化有关,最近发现高胰岛素可以导致平滑肌细胞基因异常甲基化,由此提出假设,血液中高浓度胰岛素可导致血管平滑肌细胞表型转化,最终导致动脉粥样硬化的发生.     

2型糖尿病胰岛细胞胰岛素抵抗的机制

胰岛素抵抗是2型糖尿病(T2DM)主要病理生理机制之一.肝脏、肌肉和脂肪组织存在胰岛素抵抗.近年来研究显示,胰岛α细胞与β细胞也存在胰岛素抵抗.高糖、高游离脂肪酸(FFA)、氧化应激、炎性反应均可导致胰岛素抵抗:高糖作用可下调胰岛α、β细胞磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(PKB)途径;高FFA抑制胰岛素受体底物(IRS)及PI3K活性;氧化应激使胰岛α、β细胞的IRS表达下降;炎性因子可干扰IRS/PI3K信号通路.     

高血糖毒性作用的分子机制

糖尿病的主要危害在于其慢性并发症 ,可广泛累及心、脑、肾、眼、神经系统及皮肤等器官组织。无论是 1型还是 2型糖尿病 ,血管并发症的主要致病因素目前已公认为高血糖的糖毒性作用。对于 2型糖尿病 ,除糖毒性作用外高脂血症及高胰岛素血症也是血管并发症 ,尤其是动脉粥样硬化的协同致病因素 ,在此仅介绍高血糖对血管细胞的毒性作用。高血糖导致血管并发症的分子致病机制目前主要有四种假说 :(1)多元醇通路增多假说 ;(2 )ＤＡＧ ＰＡＣ活化假说 ;(3)非酶促蛋白糖基化假说 ;(4 )氧化还原势能失衡及氧化应激假说。其中多元醇通路增多假说最早…     

Nuclear Factor (Erythroid-Derived 2)-Like-2 Factor (Nrf2), a Key Regulator of the Antioxidant Response to Protect Against Atherosclerosis and Nonalcoholic Steatohepatitis

Tissue oxidative stress is a common hallmark of atherosclerosis and non-alcoholic steatohepatitis (NASH), 2 conditions linked epidemiologically and pathophysiologically. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of inducible antioxidant responses, that can attenuate cellular injury from oxidative stress induced by obesity and other redox insults. Nrf2 expression and activation is reduced in mouse and human vessels that harbor accelerated atherosclerosis and in livers with histologic criteria of NASH. Systemic antioxidants have thus been attractive therapeutic targets, but clinical trials have been largely unsuccessful in improving cardiovascular health. Macrophage-selective Nrf2 activation may, however, provide an approach to reduce vascular and hepatocyte injury without the complications of systemic antioxidants, since macrophages play key roles in the development and progression of both atherosclerosis and NASH. In this article, we review the common mechanisms of oxidative stress and inflammation in atherosclerosis and NASH, and discuss the role of Nrf2 in vascular and hepatocyte protection.     

Mitochondrial Reactive Oxygen Species and Risk of Atherosclerosis

High levels of reactive oxygen species (ROS) are observed in chronic human diseases such as obesity, type 2 diabetes, atherosclerosis, and cardiovascular diseases. In addition to the presence of oxidative stress, these diseases are also characterized by deregulated inflammatory responses. Our first aim is to discuss distinct molecular pathways that determine the rate of mitochondrial ROS (mtROS) production and identify agents and enzymes that disrupt the balance between ROS generation and ROS elimination. Recent studies exploring the mechanisms linking ROS and inflammation found that ROS derived from mitochondria act as signal-transducing molecules that provoke endothelial dysfunction associated with uncoupling of nitric oxide synthase, induce the infiltration and activation of inflammatory cells, and increase apoptosis of endothelial and vascular smooth muscle cells. Therefore, our second aim is to give a comprehensive overview of the role of mtROS in all these processes contributing to atherosclerotic lesion progression and causing plaque erosion and rupture. Our third aim is to emphasize the role of the inflammatory toll-like receptor 2/NF-κB signaling pathway in the induction of pro-inflammatory cytokines and mtROS production in relation to insulin resistance, type 2 diabetes, and atherosclerosis. Because mtROS play an active role in several pathogenic mechanisms there is need for mitochondria-targeted antioxidants. Preliminary experiments in cell and animal models of cardiovascular diseases showed that some mitochondria-targeted antioxidants indeed reduce ROS production. However, wide-spread use in humans requires the development of specific and sensitive assays to evaluate mitochondrial oxidative stress and the development of orally active compounds.     

Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging

Recent studies demonstrate that age-related dysfunction of NF-E2-related factor-2 (Nrf2)-driven pathways impairs cellular redox homeostasis, exacerbating age-related cellular oxidative stress and increasing sensitivity of aged vessels to oxidative stress-induced cellular damage. Circulating levels of insulin-like growth factor (IGF)-1 decline during aging, which significantly increases the risk for cardiovascular diseases in humans. To test the hypothesis that adult-onset IGF-1 deficiency impairs Nrf2-driven pathways in the vasculature, we utilized a novel mouse model with a liver-specific adeno-associated viral knockdown of the Igf1 gene using Cre-lox technology (Igf1(f/f) + MUP-iCre-AAV8), which exhibits a significant decrease in circulating IGF-1 levels (~50%). In the aortas of IGF-1-deficient mice, there was a trend for decreased expression of Nrf2 and the Nrf2 target genes GCLC, NQO1 and HMOX1. In cultured aorta segments of IGF-1-deficient mice treated with oxidative stressors (high glucose, oxidized low-density lipoprotein, and H(2)O(2)), induction of Nrf2-driven genes was significantly attenuated as compared with control vessels, which was associated with an exacerbation of endothelial dysfunction, increased oxidative stress, and apoptosis, mimicking the aging phenotype. In conclusion, endocrine IGF-1 deficiency is associated with dysregulation of Nrf2-dependent antioxidant responses in the vasculature, which likely promotes an adverse vascular phenotype under pathophysiological conditions associated with oxidative stress (eg, diabetes mellitus, hypertension) and results in accelerated vascular impairments in aging.