Nrf2/ARE信号通路与肝脏疾病的研究进展

对近几年关于Nrf2在各种肝脏疾病中作用的文献进行分析、归纳、总结,发现Nrf2/ARE信号通路的激活在防治病毒性肝炎、酒精性和非酒精性肝炎、胆汁淤积型肝损伤、肝纤维化、肝癌等肝脏疾病中起着重要作用。Nrf2/ARE通路在肝脏病理生理学过程中发挥重要作用,可能为防治肝脏疾病提供新的治疗靶点。     

Nrf2/Keap1/ARE信号通路与难治性呼吸系统疾病研究进展

Nrf2/Keap1/ARE是重要的抗氧化信号通路,对维持体内抗氧化物与过氧化物平衡有重要作用。氧化应激发生时,Nrf2/Keap1/ARE信号通路被激活,调控下游抗氧化蛋白表达,减轻氧化应激对机体的损伤并减弱氧化应激的程度。近年来的研究发现,Nrf2/Keap1/ARE信号通路与肺纤维化、肺癌、慢性阻塞性肺病等难治性呼吸系统疾病的发生发展有密切联系,该通路可能作为治疗这类疾病的潜在靶点。该文就Nrf2/Keap1/ARE信号通路在难治性呼吸系统疾病中的作用进行综述,进一步了解其在难治性呼吸系统疾病中的作用机制,为这类疾病发病机制和治疗方案的研究提供可靠的参考。     

Nrf2-ARE信号通路功能与临床疾病及相关药物的研究新进展

Nrf2（NF-E2-related factor 2）核因子E2相关因子是一种机体抵抗内界和外界氧化或化学等刺激的中枢调节者。Nrf2-ARE则是近年来新发现的细胞氧化应激反应的关键传导通路,当其在体内被有毒有害物质激活后转位进入细胞核能与抗氧化反应元件（antioxidant response element,ARE）结合形成Nrf2-ARE信号通路,从而调控下游抗氧化蛋白、氧化酶和Ⅱ相解毒酶等。研究发现该通路在抗衰老、抗肿瘤、抗炎症、神经损伤、眼科等多方面均有重要作用。以Nrf2为靶点的药物有望用于肿瘤、糖尿病、神经退行性疾病等。本文综述了Nrf2-ARE信号通路功能及以其为靶点的药物研究的进展。     

Nrf2在神经退行性疾病中的作用及激活剂的研究进展

氧化应激被认为是多种神经退行性疾病的发病机制之一,在疾病的发生发展过程中起重要作用。核转录因子E2相关因子2(nuclear factor erythroid 2 related factor 2,Nrf2)是内源性抗氧化防御系统的关键调节蛋白,在氧化应激条件下核转录因子Nrf2发生核转位,与抗氧反应元件(antioxidant response element,ARE)结合,启动下游大量的抗氧化酶基因的转录,发挥抗氧化的保护作用。Nrf2诱导剂在多种神经退行性疾病模型中能减缓氧化应激,表现出良好的神经保护作用。如何有效地激活Nrf2-ARE通路已经越来越受到研究者的重视。本文概述了Nrf2-ARE通路的作用机制并具体阐述了激活Nrf2在不同的神经退行性疾病中所发挥的保护作用,同时统计了目前研究中的Nrf2激活剂。     

Nrf2-ARE信号通路参与肝脏疾病病理机制研究进展

核因子NF-E2相关因子2(Nrf2)是细胞抵御氧化应激的一个重要转录因子,它能够在活性氧或亲电试剂的刺激下,转位进入细胞核,并与抗氧化反应元件(ARE)相互作用,从而诱导下游保护性Ⅱ相解毒酶和抗氧化酶的表达,达到细胞保护的作用。氧化应激是诸多肝脏疾病共同的发病机制,而Nrf2-ARE是体内一条极为重要的抗氧化应激信号通路,该通路在肝脏疾病的发生、发展及预防过程中起着非常重要的作用,Nrf2或将成为肝脏疾病治疗的新靶点。该文综述了Nrf2-ARE信号通路参与肝脏疾病病理机制的最新研究进展,以期为日后相关研究提供参考。     

表没食子儿茶素没食子酸酯作为Nrf2/ARE信号通路激活剂的研究进展

表没食子儿茶素没食子酸酯(EGCG)是绿茶含量最多、活性最强的有效成分,是绿茶生物学功效的主要研究对象。大量研究表明,EGCG具有抗氧化、清除自由基、抗癌等生物学活性,并参与多条信号通路的调控。核转录因子红细胞系-2p45相关因子2/抗氧化反应元件(Nrf2/ARE)信号通路调节Ⅱ相解毒酶、抗氧化酶和抗炎蛋白等物质转录,直接影响细胞氧化应激水平,是调控氧化还原水平的核心通路。研究表明,EGCG对Nrf2/ARE信号通路具有激活作用,在泌尿、呼吸、心脑血管和消化等众多系统中发挥作用。本文总结了EGCG作为Nrf2/ARE信号通路激活剂的研究进展,为EGCG开发利用提供参考。     

以Nrf2为靶点防治肾脏疾病的研究进展

核因子Nrf2是调控机体内源性抗氧化信号通路的核心转录因子,其调控一系列抗氧化酶、Ⅱ相解毒酶和Ⅲ相转运体的表达,维持机体氧化还原平衡。而且,Nrf2还能调控炎症反应。近年来,研究证实Nrf2在肾脏疾病的防治中具有重要生理学作用,激活Nrf2能提高细胞或组织的抗氧化应激和抗炎能力,减轻机体损伤。因此,该文综述了Nrf2对各种肾脏疾病的保护作用,探讨以Nrf2为靶点防治肾脏疾病的可能性。     

Keap1-Nrf2-ARE信号通路及其激活剂的研究进展

Keap1-Nrf2-ARE信号通路是细胞防御氧化应激损伤的最重要机制之一。许多具有解毒、抗氧化防御功能的蛋白质,其转录调控都依赖于Nrf2信号通路的激活。研究表明,Nrf2信号通路已成为氧化应激相关疾病(神经退行性疾病、癌症、心血管系统疾病、代谢和炎症等疾病)预防和治疗的靶点。因此,Nrf2信号通路的激活剂在多种氧化应激诱发的疾病方面都表现出良好的预防及治疗作用,发现及研究Nrf2信号通路的激活剂已越来越受到研究者们的重视。该文概述了Keap1-Nrf2-ARE通路的作用机制,并阐述了Keap1-Nrf2-ARE信号通路小分子激活剂的研究进展。     

虾青素调控Nrf2通路发挥心血管保护作用的研究进展

氧化应激在多种心血管疾病的发病机制中起着重要作用。核因子E2相关因子2(Nrf2)是机体调节氧化应激的关键转录因子，也是氧化应激相关疾病的新兴治疗靶点。虾青素是类胡萝卜素的一种，具有极强的抗炎、抗氧化作用，被认为在心血管疾病中发挥良好的保护作用。多项研究表明虾青素能通过激活Nrf2通路改善血脂、血糖异常，抑制血管钙化，延缓动脉粥样硬化的发展，减轻心肌损伤并改善心力衰竭，在防治心血管疾病方面具有广阔前景。     

Nrf2信号通路在防治肝、肾损伤中的研究进展

核因子E2相关因子2(nuclear factor E2 related factor 2, Nrf2)是诸多细胞信号通路中最重要的一种,是一种基础转录调节因子,主要编码表达多种重要的细胞保护因子,包括解毒酶、抗氧化蛋白、外排型转运体、抗凋亡蛋白、抗炎因子以及其他的应激反应因子。在肝脏或肾脏因外界条件造成损伤时,Nrf2通过调节细胞对毒物的代谢排泄、细胞凋亡以及在应激状态下细胞的抗炎抗氧化进程而发挥作用。对Nrf2在肝脏、肾脏损伤中的保护作用及其分子机制做一综述,以期为新药研发提供理论依据。     

Cellular adaptive response to glutathione depletion modulates endothelial dysfunction triggered by TNF-α

Several interrelated cellular signaling molecules are involved in modulating adaptive compensatory changes elicited by low exposures to toxins and other stressors. The most prominent example of signaling pathway typically involved in this adaptive stress response, is represented by the activation of a redox-sensitive gene regulatory network mediated by the NF-E2-related factor-2 (Nrf2) which is intimately involved in mediating the Antioxidant Responsive Element (ARE)-driven response to oxidative stress and xenobiotics.We investigated if Nrf2 pathway activation following intracellular glutathione depletion through buthionine sulfoximine (BSO) exposure, might be able to alter the response to TNF-α, a proinflammatory cytokine, in cultured human umbilical vein endothelial cells. Herein, we revealed that such a change in the cellular redox status is able to reduce TNF-α induced endothelial activation (as shown by a decreased gene expression of adhesion molecules) by activating an adaptive response mediated by an increased Nrf2 nuclear translocation and overexpression of the ARE genes HO-1 and NQO-1. Furthermore, we have demonstrated the involvement of ERK1/2 kinases in Nrf2 nuclear translocation activated by BSO-induced glutathione depletion. The coordinate induction of endogenous cytoprotective proteins through adaptive activation of Nrf2 pathway is a field of great interest for potential application in prevention and therapy of inflammatory diseases such as atherosclerosis.     

经Nrf2／ARE通路发挥化学防癌作用的天然化合物

消除各种内外源性致癌物对机体细胞和组织的侵害，是对癌症进行化学预防的有效方法，该过程与Ⅱ相代谢酶的作用有关，并主要受Nrf2／ARE通路调控。研究表明，某些天然化合物能通过Nrf2／ARE途径，诱导Ⅱ相代谢酶而发挥化学防癌作用。本文综述经上述途径发挥化学防癌作用的各种天然化合物。     

Hesperetin induces glyoxalase 1 enhancement in SH-SY5Y cells cultured with high glucose via Nrf2/ARE activation

OBJECTIVE To investigate the neuroprotective effects of hesperetin on central neurons under chronic high glucose, and the relationship to glyoxalase 1(Glo-1), a cytoprotective enzyme. METHODS The human neuroblastoma SH-SY5 Y cells were divided into 5 groups: normal glucose, high glucose(HG), HG plus low, middle, or high concentration of hesperetin(1, 5, 25 μmol·L~(-1)). After treatment for 72 h, neuron damages, Glo-1 expressions and functions, as well as Nrf2/ARE pathway and its regulating mechanisms were examined. RESULTS Hesperetin increased cell viability and decreased lactate dehydrogenase release, which was accompanied by the elevated activity, protein, and mRNA levels of Glo-1 as well as the enhanced Glo-1 functions in SH-SY5 Y cells cultured with HG. Moreover, hesperetin activated Nrf2/ARE pathway as evidenced by the raised Nrf2 and p-Nrf2 levels in nucleus and up-regulation of γ-glutamycysteine synthase(γ-GCS), a well-known target gene of Nrf2/ARE pathway. Nevertheless, pretreatment with a PKC inhibitor(Go6983) or an Akt inhibitor(MK-2206 2 HCl, reflecting GSK-3β activation) abolished the effect of hesperetin on protein expressions of Glo-1 and γ-GCS. CONCLUSION Hesperetin exerted the neuroprotection by promoting Glo-1 function in central neurons in long-term HG condition, which was mediated by activation of Nrf2/ARE pathway; moreover, the increased Nrf2 phosphorylation and nuclear translocation mediated by PKC activation and/or GSK-3β inhibition were involved in the activation of Nrf2/ARE pathway by hesperetin.     

Eriodictyol-7-O-glucoside activates Nrf2 and protects against cerebral ischemic injury

Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke.