BACKGROUND & AIMS: :The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy.

背景与目标： ：Nrf2（核因子红系2 [NF-E2]-相关因子2 [Nrf2]）-Keap1（与Kelch样红系细胞衍生的蛋白具有CNC同源性[ECH]相关蛋白1）信号通路是最重要的信号途径之一重要的细胞防御和生存途径。 Nrf2可以通过增加许多细胞保护性基因的表达来保护细胞和组织免受多种毒物和致癌物的侵害。结果，目前正在临床试验中将几种Nrf2激活剂作为化学预防化合物进行测试。正如Nrf2保护正常细胞一样，研究表明Nrf2也可以保护癌细胞免受化学治疗剂的侵害并促进癌症的进展。 Nrf2在许多类型的癌症中异常积累，其表达与患者预后不良有关。另外，在耐药过程中诱导了Nrf2表达。总体而言，这些研究表明Nrf2有助于内在和获得性化学抗性。这项发现开辟了广泛的研究，旨在更好地了解Nrf2在癌症中的作用。这篇综述概述了（1）Nrf2-Keap1信号传导途径，（2）Nrf2在癌症中的双重作用，（3）Nrf2在癌细胞中激活的分子基础，以及（4）肝癌发展中的挑战基于Nrf2的化学预防和化学治疗药物。

BACKGROUND & AIMS: :The up-regulation of phase II detoxifying and stress-responsive genes is believed to play an important role in cancer prevention, and many natural compounds have been shown to be potent inducers of these genes. Previous studies showed that the antioxidant responsive element (ARE), found in these genes, can be bound by the transcription factor Nrf2, and is responsive to the activation by chemopreventive compounds and by oxidative stress. In the present study, we investigated the roles of extracellular signal-regulated kinase (ERK) and c-Jun-NH(2)-kinase (JNK) in the regulation of phenethyl isothiocyanate (PEITC)-induced and Nrf2-dependent ARE activity and ARE-driven heme oxygenase-1 (HO-1) gene expression in PC-3 cells. ARE activity and HO-1 expression were strongly increased after treatment with PEITC. PEITC also increased the phosphorylation of ERK1/2 and JNK1/2 and caused release of Nrf2 from sequestration by Keap1, and its subsequent translocation into the nucleus. Importantly, Nrf2 was also translocated into the nucleus after transfection with ERK or JNK and that these activated ERK and JNK colocalized with Nrf2 in the nucleus. Activation of ERK and JNK signaling also resulted in the elevation of ARE activity and HO-1 expression. Importantly, PEITC-induced ARE activity was attenuated by inhibition of ERK and JNK signaling. In vitro kinase assays showed that both ERK2 and JNK1 could directly phosphorylate glutathione S-transferase-Nrf2 protein. Taken together, these results strongly suggest a model in which PEITC treatment of PC-3 cells activates ERK and JNK, which, in turn, phosphorylate Nrf2 and induce its translocation to the nucleus. Nuclear Nrf2 activates ARE elements and induces expression of stress-responsive genes, including HO-1.

背景与目标： ：II期排毒和应激反应基因的上调被认为在癌症预防中起着重要作用，许多天然化合物已被证明是这些基因的有效诱导剂。先前的研究表明，在这些基因中发现的抗氧化剂响应元件（ARE）可以与转录因子Nrf2结合，并且对化学预防化合物和氧化应激的激活具有响应性。在本研究中，我们调查了细胞外信号调节激酶（ERK）和c-Jun-NH（2）激酶（JNK）在苯硫异氰酸酯（PEITC）诱导的和Nrf2依赖性ARE活性的调节中的作用，以及ARE驱动的血红素加氧酶-1（HO-1）基因在PC-3细胞中的表达。用PEITC处理后，ARE活性和HO-1表达大大增加。 PEITC还增加了ERK1 / 2和JNK1 / 2的磷酸化作用，并导致从Keap1隔离中释放Nrf2，并随后将其转位入核中。重要的是，Nrf2在用ERK或JNK转染后也转移到核中，并且这些活化的ERK和JNK与Nrf2在核中共定位。 ERK和JNK信号的激活也导致ARE活性和HO-1表达的升高。重要的是，PEITC诱导的ARE活性通过抑制ERK和JNK信号传导而减弱。体外激酶测定表明，ERK2和JNK1均可直接磷酸化谷胱甘肽S-转移酶-Nrf2蛋白。综上所述，这些结果有力地提出了一种模型，其中PEITC处理PC-3细胞会激活ERK和JNK，进而使Nrf2磷酸化并诱导其向核的转运。核Nrf2激活ARE元件并诱导应激反应基因（包括HO-1）的表达。

BACKGROUND & AIMS: :Oxidative stress has been associated with the etipathogenesis of Diabetic retinopathy (DR). Studies have shown that DJ-1 plays an important role in regulating the reactive oxygen species (ROS) production and resistance to oxidative stress-induced apoptosis. This study aimed to investigate whether DJ-1 upregulates oxidative stress and prevents damage to retinal capillary pericytes by increasing antioxidant capacity through the Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Nrf2 is a redox-sensitive transcription factor that encode antioxidant enzymes and phase II metabolic enzymes, activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many tissues. Our results showed after DJ-1 overexpression, apoptosis of rat retinal pericytes (RRPs) decreased, the ratio of B-cell lymphoma-2 (Bcl-2) to BCL2-Associated X Protein (BAX) increased, the production of ROS decreased, and the protein expression and activity of manganese superoxide dismutase (MnSOD, also called SOD2) and catalase (CAT) increased. DJ-1 overexpression activated Nrf2 expression, however, after Nrf2 silencing, apoptosis of RRPs increased, the ratio of Bcl-2 to BAX decreased, the production of ROS increased, the protein expression of MnSOD and CAT decreased, and the expression of heme oxygenase-1 (HO-1), NADP(H) quinone oxidoreductase (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) decreased. These data suggest that enhancement of the Nrf2 pathway is a potential protective strategy for the treatment of DR. Therefore, DJ-1 may prevent high glucose-induced oxidative stress and RRPs apoptosis through the Nrf2 signaling pathway, thereby preventing the early onset and progression of DR.

背景与目标： 氧化应激与糖尿病性视网膜病（DR）的病因相关。研究表明，DJ-1在调节活性氧（ROS）的产生以及抵抗氧化应激诱导的细胞凋亡中起着重要作用。这项研究旨在调查DJ-1是否通过核因子红系2相关因子2（Nrf2）信号通路增加抗氧化能力，从而上调氧化应激并防止损害视网膜毛细血管周细胞。 Nrf2是氧化还原敏感的转录因子，编码抗氧化酶和II期代谢酶，Nrf2功能的激活是抵抗许多组织中氧化应激的关键防御机制之一。我们的结果显示，DJ-1过表达后，大鼠视网膜周细胞（RRP）的凋亡减少，B细胞淋巴瘤2（Bcl-2）与BCL2相关X蛋白（BAX）的比率增加，ROS的产生减少，锰超氧化物歧化酶（MnSOD，也称为SOD2）和过氧化氢酶（CAT）的蛋白质表达和活性增加。 DJ-1过表达激活了Nrf2的表达，但是，Nrf2沉默后，RRP的凋亡增加，Bcl-2与BAX的比例降低，ROS的产生增加，MnSOD和CAT的蛋白质表达降低，血红素加氧酶的表达-1（HO-1），NADP（H）醌氧化还原酶（NQO1），谷氨酸-半胱氨酸连接酶催化亚基（GCLC）和修饰子亚基（GCLM）降低。这些数据表明，Nrf2途径的增强是治疗DR的潜在保护策略。因此，DJ-1可能通过Nrf2信号传导途径阻止高葡萄糖诱导的氧化应激和RRPs凋亡，从而防止DR的早期发作和发展。

BACKGROUND & AIMS: :NF-E2-related factor 2 (NRF2) is a master transcriptional regulator that integrates cellular stress responses and is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) at the post-translational level. In human cancers, aberrantly stabilized NRF2, by the mutation of either NRF2 or KEAP1 or by the potential inhibition of autophagy, plays a vital role in tumor growth and chemoresistance through the activation of target genes. MicroRNAs (miRNA) are endogenous small noncoding RNAs that can negatively regulate gene expression by interfering with translation and/or stability of target transcripts. However, miRNA-mediated regulation of the NRF2-KEAP1 pathway under physiological conditions is poorly understood. Here, miR-432-3p positively regulates NRF2 activity through the downregulation of KEAP1 by a direct-binding mechanism to the coding region of KEAP1. Overexpression of miR-432-3p resulted in a decreased sensitivity of esophageal squamous cell carcinoma (ESCC) cells to chemotherapy drugs including cisplatin (CDDP). Conversely, the inhibition of miR-432-3p expression by the CRISPR/Cas9 system resulted in an increased sensitivity of ESCC cells to CDDP. Furthermore, miR-432-3p was overexpressed in primary ESCC tumors (55 of 84, 65.5%) and a negative correlation between the expression level of KEAP1 and miR-432-3p in primary ESCC tumors was observed.Implications: These findings provide novel insights into the mechanism of NRF2 stabilization in human cancers. Mol Cancer Res; 15(11); 1570-8. ©2017 AACR.

背景与目标： ：NF-E2相关因子2（NRF2）是整合细胞应激反应的主要转录调节因子，在翻译后水平受Kelch样ECH相关蛋白1（KEAP1）负调节。在人类癌症中，通过NRF2或KEAP1的突变或潜在的自噬抑制，异常稳定的NRF2通过激活靶基因在肿瘤生长和化学抗性中起着至关重要的作用。微小RNA（miRNA）是内源性小非编码RNA，可通过干扰目标转录本的翻译和/或稳定性来负面调节基因表达。然而，在生理条件下，miRNA介导的NRF2-KEAP1途径的调控知之甚少。在这里，miR-432-3p通过与KEAP1编码区的直接结合机制，通过下调KEAP1来正向调节NRF2活性。 miR-432-3p的过表达导致食管鳞状细胞癌（ESCC）细胞对化疗药物（包括顺铂（CDDP））的敏感性降低。相反，CRISPR / Cas9系统对miR-432-3p表达的抑制导致ESCC细胞对CDDP的敏感性增加。此外，miR-432-3p在原发性ESCC肿瘤中过表达（55 of 84，65.5％），并且在原发性ESCC肿瘤中观察到KEAP1和miR-432-3p的表达水平呈负相关。对人类癌症中NRF2稳定机制的见解。分子癌症研究； 15（11）; 1570-8。 ©2017 AACR。

BACKGROUND & AIMS: BACKGROUND:SC-E1 is a novel herbal formula consisting of five oriental medicinal herbs used frequently in traditional herbal medicine for the treatment of inflammatory diseases in Korea. This study examined the effects of SC-E1 on lipopolysaccharide (LPS)-stimulated macrophages and the molecular mechanism involved. METHODS:The cytotoxic effect of the SC-E1 extract was evaluated in RAW 264.7 cells by MTT assay. The effects of SC-E1 on the free radical scavenging and generation of intracellular reactive oxygen species were measured using DPPH and DCFH-DA, respectively. The effects of SC-E1 on the production of pro-inflammatory cytokines, inflammatory mediators, and related products were determined by ELISA and western blotting. The molecular mechanism and the nuclear translocation of nuclear factor-kappa B (NF-κB) and NF-E2-related factor 2 (Nrf2) were examined by western blot analysis and immunocytochemistry. RESULTS:SC-E1 exhibited strong anti-oxidant activity and inhibited LPS-induced NO secretion as well as iNOS expression and the production of pro-inflammatory cytokines, without affecting the cell viability. SC-E1 also suppressed the LPS-induced NF-κB activation and the mitogen-activated protein kinase (MAPK) pathway. Moreover, SC-E1 induced heme oxygenase-1 (HO-1) expression via the nuclear translocation of Nrf2. The inhibitory effects of SC-E1 on the production of pro-inflammatory cytokines were abrogated by treatment with SnPP, an HO-1 inhibitor. CONCLUSION:These results suggest that SC-E1 exerts its anti-oxidant and anti-inflammatory effects through the inhibition of NF-κB and MAPK as well as Nrf2-mediated HO-1 induction in macrophages. These findings provide evidences for SC-E1 to be considered as a new prescription for treating inflammatory diseases.

背景与目标： 背景：SC-E1是一种新颖的草药配方，由五种东方草药组成，这些草药在韩国用于治疗炎症的传统草药中经常使用。这项研究检查了SC-E1对脂多糖（LPS）刺激的巨噬细胞的作用及其涉及的分子机制。
方法：采用MTT法检测SC-E1提取物在RAW 264.7细胞中的细胞毒性作用。使用DPPH和DCFH-DA分别测量了SC-E1对自由基清除和细胞内活性氧种类生成的影响。通过ELISA和Western印迹法确定SC-E1对促炎细胞因子，炎性介质和相关产物产生的影响。通过蛋白质印迹分析和免疫细胞化学检查了核因子-κB（NF-κB）和NF-E2相关因子2（Nrf2）的分子机制和核易位。
结果：SC-E1具有很强的抗氧化活性，并能抑制LPS诱导的NO分泌，iNOS的表达和促炎细胞因子的产生，而不会影响细胞的活力。 SC-E1还抑制LPS诱导的NF-κB激活和丝裂原激活的蛋白激酶（MAPK）途径。此外，SC-E1通过Nrf2的核转位诱导血红素加氧酶-1（HO-1）表达。通过用HO-1抑制剂SnPP处理，可以消除SC-E1对促炎性细胞因子产生的抑制作用。
结论：这些结果表明，SC-E1通过抑制巨噬细胞中的NF-κB和MAPK以及Nrf2介导的HO-1诱导而发挥其抗氧化和抗炎作用。这些发现为将SC-E1视为治疗炎性疾病的新处方提供了证据。

BACKGROUND & AIMS: :High glucose (HG)-induced oxidative damage of retinal ganglion cells (RGCs) contributes to the pathogenesis of diabetic retinopathy, a severe complication of diabetes mellitus. Brahma-related gene 1 (Brg1) has currently emerged as a cytoprotective protein that alleviates oxidative damage induced by various stress. However, whether Brg1 is involved in the regulation of HG-induced oxidative damage of RGCs remains unknown. In this study, we aimed to investigate the potential role and underlying mechanism of Brg1 in regulating HG-induced damage of RGCs. We found that Brg1 expression was significantly downregulated in RGCs in response to HG treatment. Functional experiments showed that Brg1 knockdown enhanced HG-induced apoptosis and production of reactive oxygen species, while Brg1 overexpression suppressed HG-induced apoptosis and reactive oxygen species production, showing a protective effect. Moreover, Brg1 overexpression resulted in an increase in nuclear expression of nuclear factor-erythroid-2-related factor-2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in RGCs. Notably, inhibition of Nrf2 or HO-1 significantly blocked Brg1-mediated protection against HG-induced damage. Overall, these findings demonstrate that Brg1 protects RGCs from HG-induced oxidative damage through promotion of Nrf2/HO-1 signaling, indicating a potential role of Brg1 in the pathogenesis of diabetic retinopathy.

背景与目标： ：高葡萄糖（HG）诱导的视网膜神经节细胞（RGCs）氧化损伤导致糖尿病性视网膜病（糖尿病的一种严重并发症）的发病机理。梵天相关基因1（Brg1）目前已作为一种细胞保护蛋白出现，减轻了各种压力引起的氧化损伤。然而，Brg1是否参与HG诱导的RGC氧化损伤的调控尚不清楚。在这项研究中，我们旨在研究Brg1在调节HG诱导的RGC损伤中的潜在作用及其潜在机制。我们发现响应HG治疗，RGC中Brg1表达显着下调。功能实验表明，Brg1敲低增强了HG诱导的细胞凋亡和活性氧的产生，而Brg1过表达抑制了HG诱导的细胞凋亡和活性氧的产生，显示出保护作用。此外，Brg1的过表达导致RGCs中核因子-类胡萝卜素-2相关因子2（Nrf2）的核表达和血红素加氧酶-1（HO-1）的表达增加。值得注意的是，Nrf2或HO-1的抑制作用显着阻断了Brg1介导的针对HG诱导的损伤的保护作用。总体而言，这些发现表明Brg1通过促进Nrf2 / HO-1信号传导保护RGC免受HG诱导的氧化损伤，表明Brg1在糖尿病性视网膜病的发病机理中具有潜在的作用。

BACKGROUND & AIMS: :Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2-mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria-targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2-mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial-specific interventions as a key aspect of antioxidant and antiaging therapies.

背景与目标： ：有证据表明，慢性氧化应激是衰老过程的关键驱动因素。唐氏综合症（DS）的特征在于复杂的表型，包括早期衰老。 DS细胞显示出更高水平的活性氧（ROS）以及线粒体结构和代谢功能障碍，这由持续的Nrf2介导的细胞抗氧化剂反应元件（ARE）的转录所抵消。在这里，我们表明，DS和Dp16（DS的小鼠模型）细胞中Nrf2途径的胱天蛋白酶3 /PKCδ依赖性激活对于防止慢性氧化损伤和保持细胞功能是必需的。线粒体靶向过氧化氢酶（mCAT）显着降低了氧化应激，恢复了线粒体的结构和功能，恢复了正常的复制和伤口愈合能力，并使Nrf2介导的抗氧化剂反应变得可有可无。这些结果突显了Nrf2 / ARE在维持DS细胞稳态中的关键作用，并验证了线粒体特异性干预作为抗氧化剂和抗衰老疗法的关键方面。

BACKGROUND & AIMS: BACKGROUND:It is well established that airway remodeling and inflammation are characteristics for chronic obstructive pulmonary disease (COPD). Moreover, cigarette smoke extract (CSE) promots inflammation, apoptosis and oxidative stress in COPD. And, there is evidence suggested that alantolactone (ALT), a sesquiterpene lactone isolated from Inula helenium, plays an adverse role in inflammation, apoptosis and oxidative stress. However, few studies have investigated the function and mechanism of ALT treatment on the COPD pathological process. METHODS:The levels of IL-1 β, TNF-α, IL-6 and IFN-γ were examined by ELISA. Cells' apoptosis and caspase-3 activity were detected by Cell Death Detection PLUS enzyme-linked immunosorbent assay and caspase-Glo 3/7 Assay, respectively. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using MDA and SOD assay kits. Reactive oxygen species (ROS) generation was measured by DCFH-DA assay. Protein expression was assayed by Western blot. RESULTS:In the present study, we aimed to observe the protective effects of ALT against inflammation, apoptosis and oxidative stress in human bronchial epithelial Beas-2B and NHBE cells. Our results showed that different doses of CSE exposure induced Beas-2B and NHBE cell inflammatory cytokines IL-1 β, TNF-α, IL-6 and IFN-γ expression, cell apoptosis, caspase-3 activity and mediated oxidative stress markers MDA, ROS and SOD levels, while ALT treatment counteracted the effects of CSE. Further studies suggested that ALT attenuated NF-κB pathway activation. ALT also activated the Nrf2/HO-1 signal pathway through promoting Nrf2 nuclear aggregation and downstream HO-1 protein expression. HO-1 inhibitor tin protoporphyrin IX (SnPP IX) reversed the effects of ALT on Beas-2B and NHBE cell inflammation, apoptosis and oxidative stress. CONCLUSIONS:The above results collectively suggested that ALT suppressed CSE-induced inflammation, apoptosis and oxidative stress by modulating the NF-ĸB and Nrf2/ HO-1 axis.

背景与目标： 背景：众所周知，气道重塑和炎症是慢性阻塞性肺疾病（COPD）的特征。此外，香烟烟雾提取物（CSE）促进了COPD的炎症，细胞凋亡和氧化应激。并且，有证据表明，从菊粉中分离出的倍半萜内酯丙内酯（ALT）在炎症，细胞凋亡和氧化应激中起着不利的作用。但是，很少有研究调查ALT治疗对COPD病理过程的功能和机制。
方法：采用ELISA法检测IL-1β，TNF-α，IL-6和IFN-γ的水平。通过细胞死亡检测PLUS酶联免疫吸附测定法和caspase-Glo 3/7测定法分别检测细胞的凋亡和caspase-3活性。使用MDA和SOD分析试剂盒测定丙二醛（MDA）和超氧化物歧化酶（SOD）的含量。通过DCFH-DA测定法测量活性氧（ROS）的产生。通过蛋白质印迹法测定蛋白质表达。
结果：在本研究中，我们旨在观察ALT对人支气管上皮Beas-2B和NHBE细胞炎症，凋亡和氧化应激的保护作用。我们的结果表明，不同剂量的CSE暴露诱导Beas-2B和NHBE细胞炎性细胞因子IL-1β，TNF-α，IL-6和IFN-γ的表达，细胞凋亡，caspase-3活性和介导的氧化应激标记MDA， ROS和SOD水平，而ALT治疗则抵消了CSE的影响。进一步的研究表明，ALT减弱了NF-κB途径的激活。 ALT还通过促进Nrf2核聚集和下游HO-1蛋白表达来激活Nrf2 / HO-1信号途径。 HO-1抑制剂锡原卟啉IX（SnPP IX）逆转了ALT对Beas-2B和NHBE细胞炎症，细胞凋亡和氧化应激的影响。
结论：以上结果共同提示，ALT通过调节NF-ĸB和Nrf2 / HO-1轴来抑制CSE诱导的炎症，细胞凋亡和氧化应激。

BACKGROUND & AIMS: :Transcription factor Nrf2 is considered a master regulator of antioxidant defense in mammals. However, it is unclear whether this concept is applicable to nonmammalian vertebrates, because no animal model other than Nrf2 knockout mice has been generated to examine the effects of Nrf2 deficiency. Here, we characterized a recessive loss-of-function mutant of Nrf2 (nrf2(fh318)) in a lower vertebrate, the zebrafish (Danio rerio). In keeping with the findings in the mouse model, nrf2(fh318) mutants exhibited reduced induction of the Nrf2 target genes in response to oxidative stress and electrophiles but were viable and fertile, and their embryos developed normally. The nrf2(fh318) larvae displayed enhanced sensitivity to oxidative stress and electrophiles, especially peroxides, and pretreatment with an Nrf2-activating compound, sulforaphane, decreased peroxide-induced lethality in the wild type but not nrf2(fh318) mutants, indicating that resistance to oxidative stress is highly dependent on Nrf2 functions. These results reveal an evolutionarily conserved role of vertebrate Nrf2 in protection against oxidative stress. Interestingly, there were no significant differences between wild-type and nrf2(fh318) larvae with regard to their sensitivity to superoxide and singlet oxygen generators, suggesting that the importance of Nrf2 in oxidative stress protection varies based on the type of reactive oxygen species (ROS).

背景与目标： ：转录因子Nrf2被认为是哺乳动物抗氧化防御的主要调节剂。但是，尚不清楚该概念是否适用于非哺乳动物的脊椎动物，因为除Nrf2基因敲除小鼠以外，没有其他动物模型可以用来研究Nrf2缺乏症的影响。在这里，我们表征了低等脊椎动物斑马鱼（Danio rerio）中Nrf2（nrf2（fh318））的隐性功能丧失突变体。与小鼠模型中的发现一致，nrf2（fh318）突变体表现出对Nrf2靶基因的诱导减少，以响应氧化应激和亲电试剂，但它们具有活力和繁殖力，并且它们的胚胎正常发育。 nrf2（fh318）幼虫显示出对氧化应激和亲电子试剂（特别是过氧化物）的敏感性增强，并且在野生型中用Nrf2活化化合物萝卜硫烷进行预处理可降低过氧化物诱导的致死性，但不会降低nrf2（fh318）突变体，表明对氧化应激高度依赖于Nrf2功能。这些结果揭示了脊椎动物Nrf2在保护抗氧化应激方面的进化保守作用。有趣的是，野生型和nrf2（fh318）幼虫对超氧化物和单线态氧产生剂的敏感性之间没有显着差异，这表明Nrf2在氧化应激保护中的重要性根据活性氧种类（ROS）的不同而不同。 ）。

BACKGROUND & AIMS: :Mycosporine-like amino acids (MAAs) are UVR-absorbing metabolites typically produced by cyanobacteria and marine algae, but their properties are not limited to direct sun screening protection. Herein, we examine the antioxidant activities of porphyra-334 and shinorine and demonstrate that these MAAs are prospective activators of the cytoprotective Keap1-Nrf2 pathway. The ability of porphyra-334 and shinorine to bind with Keap1 was determined using fluorescence polarization (FP) and thermal shift assays to detect Keap1 receptor antagonism. Concomitantly, the ability of porphyra-334 and shinorine to dissociate Nrf2 from Keap1 was confirmed also by measurement of increased mRNA expression of Nrf2 targeted genes encoding oxidative stress defense proteins in primary skin fibroblasts prior and post UVR exposure. Surprisingly, enhanced transcriptional regulation was only promoted by MAAs in cells after exposure to UVR-induced oxidative stress. Furthermore, the in-vitro antioxidant activities of porphyra-334 and shinorine determined by the DPPH free-radical quenching assay were low in comparison to ascorbic acid. However, their antioxidant capacity determined by the ORAC assay to quench free radicals via hydrogen atom transfer is substantial. Hence, the dual nature of MAAs to provide antioxidant protection may offer a prospective chemotherapeutic strategy to prevent or retard the progression of multiple degenerative disorders of ageing.

背景与目标： ：霉菌素样氨基酸（MAAs）是通常由蓝细菌和海藻产生的吸收UVR的代谢产物，但它们的性质不仅限于直接防晒。在这里，我们检查了卟啉334和shinorine的抗氧化活性，并证明这些MAA是细胞保护性Keap1-Nrf2途径的前瞻性激活剂。使用荧光偏振（FP）和热位移分析法检测Keap1受体拮抗作用，从而确定了卟啉334和shinorine与Keap1结合的能力。同时，通过测量UVR暴露前后初级皮肤成纤维细胞中编码氧化应激防御蛋白的Nrf2靶向基因的mRNA表达增加，也证实了卟啉334和shinorine从Keap1分离Nrf2的能力。令人惊讶地，增强的转录调控仅在暴露于UVR诱导的氧化应激后由细胞中的MAA促进。此外，与抗坏血酸相比，通过DPPH自由基猝灭测定法测定的卟啉334和紫碱碱的体外抗氧化活性较低。然而，由ORAC测定法测定的其通过氢原子转移淬灭自由基的抗氧化能力是实质性的。因此，MAA提供抗氧化保护的双重性质可以提供一种预防或阻止多种衰老退行性疾病发展的前瞻性化学治疗策略。

BACKGROUND & AIMS: :Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.

背景与目标： ：核因子红系2相关因子2（NRF2）是基因的主要转录调节因子，其产物捍卫我们的细胞免受毒性和氧化性侵害。尽管NRF2激活可以通过抑制氧化应激和促进肿瘤的炎症来降低患癌症的风险，但是由于突变破坏了NRF2活性的负控制或其他因素，许多癌症都表现出较高的NRF2活性。重要的是，NRF2激活与不良预后有关，而NRF2已证明是癌症支持的合成代谢代谢的关键激活剂。在这篇综述中，我们总结了NRF2在癌症中扮演的各种角色，重点是代谢重编程和肿瘤促进炎症。

BACKGROUND & AIMS: :Mastitis is one of three bovine diseases recognized as a cause of substantial economic losses every year throughout the world. Niacin is an important feed additive that is used extensively for dairy cow nutrition. However, the mechanism by which niacin acts on mastitis is not clear. The aim of this study is to investigate the mechanism of niacin in alleviating the inflammatory response of mammary epithelial cells and in anti-mastitis. Mammary glands, milk, and blood samples were collected from mastitis cows not treated with niacin (n = 3) and treated with niacin (30 g/d, n = 3) and healthy cows (n = 3). The expression of GPR109A, IL-6, IL-1β, and TNF-α in the mammary glands of the dairy cows with mastitis was significantly higher than it was in the glands of the healthy dairy cows. We also conducted animal experiments in vivo by feeding rumen-bypassed niacin. Compared with those in the untreated mastitis group, the somatic cell counts (SCCs) and the expression of IL-6, IL-1β, and TNF-α in the blood and milk were lower. In vitro, we isolated the primary bovine mammary epithelial cells (BMECs) from the mammary glands of the healthy cows. The mRNA levels of IL-6, IL-1β, TNF-α, and autophagy-related genes were detected after adding niacin, shRNA, compound C, trans retinoic acid, 3-methyladenine to BMECs. Then GPR109A, AMPK, NRF-2, and autophagy-related proteins were detected by Western blot. We found that niacin can activate GPR109A and phosphorylate AMPK, and promote NRF-2 nuclear import and autophagy to alleviate LPS-induced inflammatory response in BMECs. In summary, we found that niacin can reduce the inflammatory response of BMECs through GPR109A/AMPK/NRF-2/autophagy. We also preliminarily explored the alleviative effect of niacin on mastitis in dairy cows.

背景与目标： ：乳腺炎是被公认为全世界每年造成重大经济损失的三种牛病之一。烟酸是一种重要的饲料添加剂，已广泛用于奶牛营养。但是，烟酸对乳腺炎起作用的机制尚不清楚。这项研究的目的是研究烟酸减轻乳腺上皮细胞和抗乳腺炎的炎症反应的机制。从未使用烟酸（n = 3），未使用烟酸（30 g / d，n = 3）和健康的母牛（n = 3）处理的乳腺炎奶牛中收集乳腺，牛奶和血液样本。 GPR109A，IL-6，IL-1β和TNF-α在患有乳腺炎的奶牛的乳腺中的表达明显高于在健康奶牛的乳腺中的表达。我们还通过饲喂瘤胃绕过的烟酸进行了体内动物实验。与未治疗的乳腺炎组相比，血液和牛奶中的体细胞计数（SCC）以及IL-6，IL-1β和TNF-α的表达较低。在体外，我们从健康母牛的乳腺中分离出了原代的牛乳腺上皮细胞（BMEC）。向BMECs中添加烟酸，shRNA，化合物C，反式维甲酸，3-甲基腺嘌呤后，检测IL-6，IL-1β，TNF-α和自噬相关基因的mRNA水平。然后通过蛋白质印迹检测GPR109A，AMPK，NRF-2和自噬相关蛋白。我们发现烟酸可以激活GPR109A并磷酸化AMPK，并促进NRF-2核的导入和自噬，从而减轻LPEC诱导的BMEC炎症反应。总之，我们发现烟酸可以通过GPR109A / AMPK / NRF-2 /自噬减少BMEC的炎症反应。我们还初步探讨了烟酸对奶牛乳腺炎的缓解作用。

BACKGROUND & AIMS: :In this study, protective effects of insoluble-bound polyphenol extracts from adlay seed against H2O2-induced oxidative stress in HepG2 cells were investigated. Each fraction of insoluble-bound polyphenol extracts from adlay seed was obtained by separating with Sephadex LH-20 column and semi-preparative HPLC. Ferulic acid was found being the main active component of insoluble-bound polyphenol in adlay seed. The cytoprotective effects of ferulic acid against oxidative challenge were determined by cell viability, intracellular reactive oxygen stress change in HepG2 cells, western blot and apoptosis by flow cytometry. Ferulic acid had a positive correlation with cell viability and a negative correlation with apoptosis. Ferulic acid treatment increased the activity of GSH-PX, CAT, γ-GCS. Moreover, the nuclear factor E2 related factor (Nrf2) protein expression in the ferulic acid group positively correlated with the HO-1, GCLC and NQO1 protein levels. Thus the results demonstrated that ferulic acid, the main active component of insoluble-bound polyphenol in adlay seed could ameliorate H2O2-induced oxidative stress in HepG2 cells via Nrf2 signalling. The research can provide a reference for the in-depth study of its regulatory mechanism and the development of antioxidant related functional food and health products.

背景与目标： ：在这项研究中，研究了来自ad仁种子的不溶结合多酚提取物对H2O2诱导的HepG2细胞氧化应激的保护作用。通过用Sephadex LH-20色谱柱和半制备型HPLC分离，可从ad杂种子中提取不溶性结合的多酚提取物的各个馏分。发现阿魏酸是ad仁种子中不溶性结合的多酚的主要活性成分。通过细胞活力，HepG2细胞内细胞内活性氧应激变化，Western印迹和流式细胞仪确定阿魏酸对氧化挑战的细胞保护作用。阿魏酸与细胞活力呈正相关，与细胞凋亡呈负相关。阿魏酸处理增加了GSH-PX，CAT，γ-GCS的活性。此外，阿魏酸组中核因子E2相关因子（Nrf2）蛋白的表达与HO-1，GCLC和NQO1蛋白水平呈正相关。因此结果表明，阿魏酸是，仁种子中不溶性结合多酚的主要活性成分，可以通过Nrf2信号减轻H2O2诱导的HepG2细胞氧化应激。该研究可为深入研究其调控机制以及抗氧化剂相关功能食品和保健品的开发提供参考。

BACKGROUND & AIMS: :Glutathione (GSH) and GSH-associated metabolism provide the major line of defense for the protection of cells from various forms of toxic stress. GSH also plays a key role in regulating the intracellular redox environment. Thus, maintenance of GSH levels is developing into an important therapeutic objective for the treatment of a variety of diseases. Among the transcription factors that play critical roles in GSH metabolism are NF-E2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4). Thus, compounds that can upregulate these transcription factors may be particularly useful as treatment options through their effects on GSH metabolism. We previously showed that the flavonoid fisetin not only increases basal levels of GSH but also maintains GSH levels under oxidative stress conditions. However, the mechanisms underlying these effects have remained unknown until now. Here we show that fisetin rapidly increases the levels of both Nrf2 and ATF4 as well as Nrf2- and ATF4-dependent gene transcription via distinct mechanisms. Although fisetin greatly increases the stability of both Nrf2 and ATF4, only the effect on ATF4 is dependent on protein kinase activity. Using siRNA we found that ATF4, but not Nrf2, is important for fisetin's ability to increase GSH levels under basal conditions whereas both ATF4 and Nrf2 appear to cooperate to increase GSH levels under oxidative stress conditions. Based upon these results, we hypothesize that compounds able to increase GSH levels via multiple mechanisms, such as fisetin, will be particularly effective for maintaining GSH levels under a variety of different stresses.

背景与目标： ：谷胱甘肽（GSH）和GSH相关的代谢为保护细胞免受各种形式的毒性应激提供了主要的防御力。 GSH在调节细胞内氧化还原环境中也起着关键作用。因此，维持谷胱甘肽水平正在发展为治疗多种疾病的重要治疗目标。在GSH代谢中起关键作用的转录因子包括NF-E2相关因子2（Nrf2）和激活转录因子4（ATF4）。因此，可以上调这些转录因子的化合物通过其对GSH代谢的作用，可能特别有用作为治疗选择。我们以前的研究表明，类黄酮非瑟酮不仅可以增加基础谷胱甘肽的含量，而且在氧化应激条件下仍可以维持谷胱甘肽的含量。但是，到目前为止，这些作用的潜在机制仍然未知。在这里，我们显示非瑟酮通过不同的机制迅速增加Nrf2和ATF4以及Nrf2和ATF4依赖基因转录的水平。尽管非瑟酮极大地增加了Nrf2和ATF4的稳定性，但仅对ATF4的作用取决于蛋白激酶的活性。使用siRNA，我们发现ATF4（而非Nrf2）对菲塞汀在基础条件下增加GSH水平的能力很重要，而ATF4和Nrf2似乎在氧化应激条件下均能协同增加GSH水平。基于这些结果，我们假设能够通过多种机制增加GSH水平的化合物（例如非瑟定）在维持各种不同压力下对保持GSH水平特别有效。

BACKGROUND & AIMS: :The transcription factor Nrf2 controls inducible expression of multiple antioxidant/detoxification genes. We previously found that Nrf2-/- mice have increased sensitivity to in vivo mitochondrial stress and ischemia. Although Nrf2 regulated these forms of neuronal toxicity, it was unclear which injury-triggered signal(s) led to Nrf2 activation in vivo. In this study, we use primary cultures to test the hypothesis that excessive dopamine release can act as an endogenous Nrf2-inducing signal. We cultured two cell types that show increased Nrf2 activity during ischemia in vivo, astrocytes and meningeal cells. Cultures were infected with an adenovirus reporter of Nrf2 transcriptional activity. Dopamine-induced Nrf2 activity in both cell types by generating oxidative stressors, H2O2 and dopamine-quinones. Nrf2 activation in meningeal cells was significantly higher than astrocytes. The effect of dopamine was blocked by antioxidants, and by over-expression of either dominant-negative Nrf2 or Keap1. Nrf2 induction was specific to oxidative stress caused by catecholaminergic neurotransmitters as epinephrine also induced Nrf2, but the monoamine serotonin had no significant effect. These in vitro results suggest Nrf2 activity in astrocytes and meningeal cells link the neurotoxic actions of dopamine to neuroprotective pathways that may potentially modulate ischemic injury and neurodegeneration.

背景与目标： 转录因子Nrf2控制多种抗氧化剂/解毒基因的诱导表达。我们先前发现Nrf2-/-小鼠对体内线粒体应激和局部缺血的敏感性增加。尽管Nrf2调节了这些形式的神经元毒性，但尚不清楚哪种损伤触发信号在体内导致Nrf2激活。在这项研究中，我们使用原代培养来检验多巴胺释放过多可以作为内源性Nrf2诱导信号的假设。我们培养了两种在体内缺血过程中显示出增加的Nrf2活性的细胞类型：星形胶质细胞和脑膜细胞。用Nrf2转录活性的腺病毒报道基因感染培养物。多巴胺通过产生氧化应激因子，H2O2和多巴胺醌而在两种细胞类型中诱导Nrf2活性。脑膜细胞中Nrf2的激活明显高于星形胶质细胞。多巴胺的作用被抗氧化剂和显性负性Nrf2或Keap1的过表达所阻断。 Nrf2诱导特异于儿茶酚胺能神经递质引起的氧化应激，因为肾上腺素也诱导Nrf2，但单胺5-羟色胺没有明显作用。这些体外结果表明，星形胶质细胞和脑膜细胞中的Nrf2活性将多巴胺的神经毒性作用与可能潜在地调节缺血性损伤和神经变性的神经保护途径联系起来。