BACKGROUND & AIMS: OBJECTIVES:This study aims to determine the effects of ozone therapy on restoring impaired Nrf2 activation to ameliorate chronic tubulointerstitial injury in rats with adenine-induced CKD. MATERIALS AND METHODS:Sprague-Dawley rats were fed with 0.75% adenine-containing diet to induce CKD and chronic tubulointerstitial injury. Ozone therapy was administered by rectal insufflation. After 4 weeks, serum and kidney samples were collected and analyzed. Renal function and systemic electrolyte level were detected. Pathological changes in kidney were assessed by hematoxylin-eosin staining and Masson trichrome staining. Nrf2 activation was detected by immunohistochemistry and Western blot analyses. The levels of SOD, CAT, GSH, PCO, and MDA were detected in the kidney. Immunohistochemistry, Western blot, and real-time PCR analyses were performed to evaluate the activation of the nuclear factor kappa B (NF-κB) P65 pathway and inflammation infiltration in the tubulointerstitium of the rats. RESULTS:Ozone therapy improved severe renal insufficiency and tubulointerstitial morphology injury as well as restored Nrf2 activation and inhibited the NF-κB pathway in rats with adenine-induced CKD. Ozone therapy also up-regulated anti-oxidation enzymes (SOD, CAT, and GSH) and down-regulated oxidation products (PCO and MDA), as well as inflammatory cytokines (IL-1β, IL-6, TNF-α, and ICAM-1) in the kidney. CONCLUSION:These findings indicated that ozone therapy could attenuate tubulointerstitial injury in rats with adenine-induced CKD by mediating Nrf2 and NF-κB.

背景与目标： 目的：本研究旨在确定臭氧治疗对恢复腺嘌呤诱发的CKD大鼠慢性肾小管间质损伤的Nrf2活化受损的影响。
材料与方法：给Sprague-Dawley大鼠喂食含0.75％腺嘌呤的饮食，以诱导CKD和慢性肾小管间质损伤。臭氧通过直肠吹入法进行治疗。 4周后，收集并分析血清和肾脏样品。检测肾功能和全身电解质水平。通过苏木精-伊红染色和Masson三色染色评估肾脏的病理变化。通过免疫组织化学和蛋白质印迹分析检测到Nrf2激活。在肾脏中检测到了SOD，CAT，GSH，PCO和MDA的水平。进行了免疫组织化学，蛋白质印迹和实时PCR分析，以评估大鼠肾小管间质中核因子κB（NF-κB）P65途径的激活和炎症浸润。
结果：臭氧治疗改善了腺嘌呤诱发的CKD大鼠的严重肾功能不全和肾小管间质形态损伤，并恢复了Nrf2活化并抑制了NF-κB通路。臭氧疗法还可以上调抗氧化酶（SOD，CAT和GSH）和下调氧化产物（PCO和MDA），以及炎性细胞因子（IL-1β，IL-6，TNF-α和ICAM） -1）在肾脏。
结论：这些发现表明，臭氧治疗可以通过介导Nrf2和NF-κB减轻腺嘌呤诱发的CKD大鼠肾小管间质损伤。

BACKGROUND & AIMS: :An ovalbumin (OVA)-induced allergic rhinitis (AR) mouse model was established to investigate whether α-Lipoic acid (LA) has a protective effect against upper respiratory tract inflammation. BALB/c mice were sensitized by intraperitoneal injection and challenged by intranasal application of OVA. Mice were orally administered various doses of LA once daily (2, 10, 50 mg/kg) and dexamethasone (Dex; 2.5 mg/kg) 1 h before OVA challenge. Allergic nasal symptoms, levels of OVA-specific immunoglobulins, cytokines, and transcription factors were measured. Nasal and lung histopathology were evaluated. LA administration significantly alleviated the nasal symptoms such as rubbing and sneezing, markedly reduced both serum OVA-specific IgE and IgG1 levels. The LA treatment group showed markedly up-regulated levels of the Treg cytokine IL-10 and Treg transcription factor Foxp3. In contrast, it showed down-regulated levels of the Th17 cytokine IL-17 and the Th17 transcription factor STAT3, and RORγ. LA greatly enhanced the nuclear factor erythroid-derived 2/heme oxygenase 1 (Nrf2/HO-1) pathway signaling and inhibited the activation of NF-κB/IκB, markedly suppressed the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, IL-8 and chemokine COX-2. The histologic alterations of nasal and lung tissues of AR mice were effectively ameliorated by LA. Based on these results, we suggest that LA could be a potential therapeutic agent in OVA-induced AR by virtue of its role in controlling the Th17/Treg balance and enhancing Nrf2/HO-1 pathway signaling.

背景与目标： ：建立了卵白蛋白（OVA）诱导的变应性鼻炎（AR）小鼠模型，以研究α-硫辛酸（LA）是否对上呼吸道炎症具有保护作用。通过腹腔注射致敏BALB / c小鼠，并通过鼻内施用OVA攻击。每天向小鼠口服一次不同剂量的LA（2、10、50 mg / kg）和地塞米松（Dex; 2.5 mg / kg）于OVA攻击前1小时。测量过敏性鼻症状，OVA特异性免疫球蛋白，细胞因子和转录因子的水平。评估鼻和肺的组织病理学。 LA给药可显着缓解鼻部症状，如揉搓和打喷嚏，可显着降低血清OVA特异性IgE和IgG1水平。 LA治疗组显示Treg细胞因子IL-10和Treg转录因子Foxp3的水平明显上调。相反，它显示Th17细胞因子IL-17和Th17转录因子STAT3和RORγ的水平下调。 LA大大增强了核因子类红细胞衍生的2 /血红素加氧酶1（Nrf2 / HO-1）信号通路并抑制了NF-κB/IκB的激活，显着抑制了促炎性细胞因子TNF-α，IL-1β的水平，IL-6，IL-8和趋化因子COX-2。 LA有效改善了AR小鼠鼻和肺组织的组织学改变。基于这些结果，我们认为LA可能由于其在控制Th17 / Treg平衡和增强Nrf2 / HO-1信号通路中的作用而可能是OVA诱导的AR的潜在治疗剂。

BACKGROUND & AIMS: BACKGROUND:Diabetic retinopathy (DR) is a serious symptom associated with diabetes and could cause much suffer to patients. MiR-221, SIRT1 and Nrf2 were associated with apoptosis and proliferation and their expression were altered in DR patients. However, their roles and regulatory mechanisms in human retinal microvascular endothelial cells (hRMEC) were not clear. METHODS:Expression of mRNA was detected by qRT-PCR. Protein expression was detected by Western blot. Interaction between miR-221 and SIRT1 was predicted by bioinformatics analysis and validated by dual-luciferase reporter assay. We analyzed the viability and apoptosis of hRMEC by MTT assay and FACS assay, respectively. RESULTS:High glucose (HG) treatment enhanced expression of miR-221 and inhibited expression of SIRT1 and Nrf2. MiR-221 overexpression promoted apoptosis under HG condition. Moreover, miR-221 directly interacted with mRNA of SIRT1 and inhibited SIRT1 expression in hRMEC, through which miR-221 inhibited Nrf2 pathway and induced apoptosis of hRMEC. CONCLUSION:Our data demonstrated that miR-221/SIRT1/Nrf2 signal axis could promote apoptosis in hRMEC under HG conditions. This finding could provide theoretical support for future studies and may contribute to development of new treatment options to retard the process of DR development.

背景与目标： 背景：糖尿病性视网膜病（DR）是一种与糖尿病相关的严重症状，可能会给患者带来很多痛苦。在DR患者中，MiR-221，SIRT1和Nrf2与细胞凋亡和增殖有关，它们的表达也发生了改变。但是，它们在人视网膜微血管内皮细胞（hRMEC）中的作用和调节机制尚不清楚。
方法：采用qRT-PCR检测mRNA的表达。通过蛋白质印迹检测蛋白质表达。通过生物信息学分析预测了miR-221与SIRT1之间的相互作用，并通过双重萤光素酶报告基因分析验证了该相互作用。我们分别通过MTT法和FACS法分析了hRMEC的活力和凋亡。
结果：高糖（HG）处理可增强miR-221的表达，并抑制SIRT1和Nrf2的表达。在HG条件下，MiR-221过表达促进细胞凋亡。此外，miR-221与SIRT1的mRNA直接相互作用，并抑制hRMEC中SIRT1的表达，miR-221通过抑制Nrf2途径并诱导hRMEC凋亡。
结论：我们的数据表明，miR-221 / SIRT1 / Nrf2信号轴可促进HG条件下hRMEC的凋亡。这一发现可以为将来的研究提供理论支持，并可能有助于开发新的治疗选择以延缓DR的发展过程。

BACKGROUND & AIMS: INTRODUCTION:Exposure to airborne particulate matter (PM) increases the proportion of oral inflammatory diseases. During the formation of inflammatory conditions, the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation plays an important regulator. Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by heme oxygenase-1 (HO-1), has been shown to own cytoprotective effects including anti-inflammation and antioxidant. Here, we determined the novel mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human oral keratinocytes (HOKs). METHODS:The effects of CORM-2 on the expression of various inflammatory proteins induced by PM were determined by Western blot, real-time PCR, promoter assay, and ELISA. The involvement of signaling molecules in these responses was studied by using the selective pharmacological inhibitors and siRNAs. RESULTS:We proved that PM enhanced C-reactive protein (CRP) levels, NLRP3 inflammasome and caspase-1 activation, and IL-1β release, which were reduced by preincubation with CORM-2. Transfection with PKCα siRNA and preincubation with the ROS scavenger (N-acetyl-cysteine, NAC), an inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or the mitochondria-specific superoxide scavenger (MitoTEMPO) inhibited PM-mediated inflammatory responses. In addition, PM-regulated PKCα and NADPH oxidase activation as well as NADPH oxidase- and mitochondria-derived ROS generation were inhibited by CORM-2, but not inactivate CORM-2 (iCORM-2) pretreatment. At the end, we confirmed that CORM-2 improved PM-induced inflammatory responses via the induction of Nrf2 activation and HO-1 expression. CONCLUSION:We suggest that CORM-2 inhibits PM-induced inflammatory responses in HOKs via the inhibition of PKCα/ROS/NLRP3 inflammasome activation combined with the induction of Nrf2/HO-1 expression.

背景与目标： 简介：接触空气中的颗粒物（PM）会增加口腔炎性疾病的比例。在炎性疾病形成过程中，核苷酸结合结构域和富含亮氨酸的重复蛋白3（NLRP3）炎性小体激活起着重要的调节作用。由血红素降解产生的一氧化碳（CO）特别是被血红素加氧酶-1（HO-1）催化，已显示出具有细胞保护作用，包括抗炎和抗氧化剂。在这里，我们确定了一氧化碳释放分子2（CORM-2）对PM诱导的人类口腔角质形成细胞（HOKs）炎症反应的新机制。
方法：采用Western blot，实时荧光定量PCR，启动子检测和ELISA法检测CORM-2对PM诱导的多种炎症蛋白表达的影响。通过使用选择性药理抑制剂和siRNA，研究了信号分子参与这些应答的过程。
结果：我们证明了PM可以提高C反应蛋白（CRP）水平，NLRP3炎性小体和caspase-1的活化以及IL-1β的释放，与CORM-2一起预孵育可以降低PM。用PKCαsiRNA转染并与ROS清道夫（N-乙酰基-半胱氨酸，NAC），NADPH氧化酶抑制剂（二苯撑碘鎓，DPI）或线粒体特有的超氧化物清道夫（MitoTEMPO）预孵育可抑制PM介导的炎症反应。此外，CORM-2抑制了PM调节的PKCα和NADPH氧化酶的活化以及NADPH氧化酶和线粒体的ROS生成，但未灭活CORM-2（iCORM-2）预处理。最后，我们证实了CORM-2通过诱导Nrf2激活和HO-1表达改善了PM诱导的炎症反应。
结论：我们建议CORM-2通过抑制PKCα/ ROS / NLRP3炎性体激活并诱导Nrf2 / HO-1表达来抑制PM诱导的HOKs炎症反应。

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。