Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway

Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(-/-)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.     

Emerging functional cross-talk between the Keap1-Nrf2 system and mitochondria

Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) was originally identified as a positive regulator of drug detoxifying enzyme gene expression during exposure to environmental electrophiles. Currently, Nrf2 is known to regulate the expression of hundreds of cytoprotective genes to counteract endogenously or exogenously generated oxidative stress. Furthermore, when activated in human tumors by somatic mutations, Nrf2 confers growth advantages and chemoresistance by regulating genes involved in various processes such as the pentose phosphate pathway and nucleotide synthesis in addition to antioxidant proteins. Interestingly, increasing evidence shows that Nrf2 is associated with mitochondrial biogenesis during environmental stresses in certain tissues such as the heart. Furthermore, SKN-1, a functional homolog of Nrf2 in C. elegans, is activated by mitochondrial reactive oxygen species and extends life span by promoting mitochondrial homeostasis (i.e., mitohormesis). Similarly, Nrf2 activation was recently observed in the heart of surfeit locus protein 1 (Surf1) -/- mice in which cellular respiration was decreased due to cytochrome c oxidase defects. In this review, we critically examine the relationship between Nrf2 and mitochondria and argue that the Nrf2 stress pathway intimately communicates with mitochondria to maintain cellular homeostasis during oxidative stress.     

转录因子核因子E2相关因子2对长期中波紫外线照射诱导皮肤肿瘤的影响

背景：紫外线照射是引起皮肤肿瘤的重要环境因素,与其诱导氧化应激反应有关。核因子E2相关因子2是调节细胞内抗氧化应激反应的重要转录因子,胞浆蛋白Kelch样环氧氯丙烷相关蛋白1为其特异性受体,目前核因子E2相关因子2-胞浆蛋白Kelch样环氧氯丙烷相关蛋白1抗氧化系统与皮肤紫外线损伤的关系受到密切关注。目的：观察中波紫外线照射所致皮肤DNA氧化损伤及光致癌作用,研究转录因子核因子E2相关因子2对长期中波紫外线照射诱导小鼠皮肤肿瘤形成的影响。方法：取8周龄雌性核因子E2相关因子2基因敲除（Nrf2-/-）BALB/c小鼠和野生型（Nrf2＋/＋）BALB/c小鼠,以100mJ/cm2剂量的中波紫外线照射小鼠背部4h。另取Nrf2-/-小鼠和Nrf2＋/＋小鼠以300mJ/cm2剂量的中波紫外线对小鼠背部进行长期照射,每周3次,连续36周。结果与结论：Nrf2-/-小鼠表皮内8-羟基脱氧鸟嘌呤核苷阳性细胞数量显著高于Nrf2＋/＋小鼠（P〈0.05）,Nrf2-/-和Nrf2＋/＋小鼠中波紫外线长期照射诱导皮肤肿瘤数目和发生率接近（P〉0.05）,且皮肤肿瘤组织病理学改变相似,提示核因子E2相关因子2对急性中波紫外线照射所致的DNA损伤具有抗氧化防护作用,在长期中波紫外线照射致癌过程中,转录因子核因子E2相关因子2的活性可能受到多种因素的调节,其具体机制有待于进一步研究。     

Platelet-activating factor: a possible mediator of the dual response to allergen?

Certain allergic asthmatic patients exhibit a dual response in the lung following bronchial challenge with the appropriate allergen. Often this is paralleled by a cutaneous dual response when the antigen is injected intradermally. The mechanisms underlying such phenomena are not established, but some evidence suggests that the late response is a consequence of the early response. Since platelet activation has been observed following antigen challenge in asthmatic subjects, we have studied the ability of platelet activating factor (PAF-acether, AGEPC) to induce cutaneous inflammatory responses in man. In a time course study over 24 hr, PAF-acether produced a biphasic response: an immediate weal and flare reaction, which resolved within 1-2 hr and was followed some 3-6 hr later by a delayed reaction in which erythema associated with hyperalgesia was evident. These observations suggest that PAF-acether should be considered in the context of allergic asthma as a possible mediator of the dual response to allergen.     

1,25二羟维生素D3对哮喘小鼠的Rac1-IL33-ILC2通路的作用

目的观察1,25二羟维生素D31,25-(OH)2-D3对哮喘小鼠Ras相关的C3肉毒素底物1(Ras-related C3 botulinum toxin substrate 1,Rac1)、白细胞介素-33(IL-33)和2型固有淋巴细胞(type 2 innate lymphocytes,ILC2)的影响。方法将30只7周龄BALB/c雌性小鼠随机分为对照组、哮喘组、干预组,每组各10只小鼠,卵清蛋白混合液致敏并雾化吸入建立哮喘小鼠模型,干预组每次激发前腹腔注射1,25(OH)2-D3混合液0.08 ml,对照组和哮喘组以生理盐水代替。末次激发24 h后对小鼠肺组织中IL-33、Rac1、ILC2进行检测并比较。结果与对照组比较,哮喘组Rac1下降,IL-33水平增高,ILC2数目升高。且Rac1与IL-33、ILC2呈明显的负相关性(r=-0.954、r=-0.957,P<0.05)。干预组IL-33及ILC2数目较哮喘组显著下降,Rac1较哮喘组显著上升,差异有统计学意义(P<0.05)。结论哮喘小鼠存在Rac1下降,IL-33水平增高,ILC2数目升高的免疫变化;1,25-(OH)2-D3可能通过上调哮喘小鼠Rac1的表达,导致IL-33等细胞因子水平产生减少,进而抑制ILC2的活化、减轻哮喘的免疫炎症。     

Nrf2及其信号通路在脓毒症相关脏器损伤中的研究进展

脓毒症(sepsis)是重症监护病房(ICU)患者死亡的常见病因,治疗难度大,且预后较差,给全球医疗卫生系统造成巨大经济负担。然而针对脓毒症的治疗仍缺乏有效的防治手段。核转录因子-E2相关因子2(Nrf2)是抗氧化应激体系中的关键转录因子,它通过调节抗氧化反应原(ARE)介导的抗氧化酶和Ⅱ相解毒酶等的表达,在脓毒症治疗中发挥关键作用。本文总结了Nrf2相关信号通路及其在脓毒症器官损伤中的最新研究进展,以期为临床治疗脓毒症提供新的治疗策略。