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Cysteine-based regulation of the CUL3 adaptor protein Keap1 总被引:1,自引:0,他引:1
Konjeti R. Sekhar 《Toxicology and applied pharmacology》2010,244(1):21-472
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Thymoquinone (TQ), an active constituent of Nigella sativa, possesses anti-inflammatory and anticancer properties. Multiple lines of evidence suggest that the induction of heme oxygenase-1 (HO-1) suppresses inflammation and carcinogenesis. In the present study, we examined the effect of TQ on HO-1 expression in human keratinocytes (HaCaT) and elucidated its underlying molecular mechanisms. TQ induced the expression of HO-1 in HaCaT cells in a concentration- and time-dependent manner. Treatment with TQ increased the localization of nuclear factor (NF)-erythroid2-(E2)-related factor-2 (Nrf2) in the nucleus and elevated the antioxidant response element (ARE)-reporter gene activity. Knockdown of Nrf2 abrogated TQ-induced HO-1 expression and the ARE luciferase activity. TQ induced the phosphorylation of extracellular signal-regulated kinase (ERK), Akt and cyclic AMP-activated protein kinase-α (AMPKα). Pharmacological inhibition of Akt or AMPKα, but not that of ERK, abrogated TQ-induced nuclear localization of Nrf2, the ARE-luciferase activity and the expression of HO-1. TQ also generated reactive oxygen species (ROS) and pretreatment with N-acetyl cysteine (NAC) abrogated TQ-induced ROS accumulation, Akt and AMPKα activation, Nrf2 nuclear localization, the ARE-luciferase activity, and HO-1 expression in HaCaT cells. Taken together, TQ induces HO-1 expression in HaCaT cells by activating Nrf2 through ROS-mediated phosphorylation of Akt and AMPKα. 相似文献
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目的研究煤焦沥青烟提取物对BEAS-2B细胞Nrf2、Keap1、NQO1的基因及其蛋白表达的影响,以探讨煤焦沥青烟提取物在造成细胞氧化损伤过程中Nrf2-Keap1/ARE通路的作用机制。方法设立未处理对照组、0.1%DMSO溶剂对照组、5μg/ml B(a)P阳性对照组、6μmol/L全反式维甲酸组、6μmol/L全反式维甲酸预处理0.5 h后5μg/ml CTP染毒组和CTP染毒组(1、5、10和20μg/ml),染毒3、6、12和24 h后提取总RNA;RT-PCR检测Nrf2、Keap1、NQO1 mRNA的相对表达量;Western blot测定Nrf2、Keap1、NQO1蛋白的相对表达量。结果不同CTP染毒剂量作用后各个基因mRNA相对表达量差异无统计学意义(P0.05),而不同时间点相对表达量差异有统计学意义(P0.05)。Western blot结果显示,随着CTP烟提取物染毒浓度的增加,Keap1蛋白无明显变化,NQO1蛋白表达量逐渐上升;Nrf2蛋白在5μg/ml染毒浓度时表达最高,在5μg/ml CTP染毒浓度作用下,BEAS-2B细胞Nrf2蛋白表达量随时间逐渐升高,在染毒6 h后达到最高,之后表达量又呈下降趋势。结论煤焦沥青烟提取物作用于BEAS-2B细胞后,代谢酶NQO1表达上调,推测Keap1-Nrf2/ARE通路可能通过上调细胞保护性基因NQO1的表达而对抗煤焦沥青毒性作用,降低细胞氧化损伤。 相似文献
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Angelica sinensis and its alkylphthalides induce the detoxification enzyme NAD(P)H: quinone oxidoreductase 1 by alkylating Keap1 总被引:1,自引:0,他引:1
Dietz BM Liu D Hagos GK Yao P Schinkovitz A Pro SM Deng S Farnsworth NR Pauli GF van Breemen RB Bolton JL 《Chemical research in toxicology》2008,21(10):1939-1948
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Involvement of Nrf2 and JNK1 in the Activation of Antioxidant Responsive Element (ARE) by Chemopreventive Agent Phenethyl Isothiocyanate (PEITC) 总被引:6,自引:0,他引:6
Purpose. Phenethyl isothiocyanate (PEITC) has been of great interest as a promising cancer chemopreventive agent. To better understand its chemopreventive activity, we examined the effect of PEITC on the antioxidant responsive element (ARE), which is an important gene regulatory element of many phase II drug-metabolizing/detoxification enzymes as well as cellular defensive enzymes.
Methods. HeLa cells were transiently transfected with different cDNA plasmids using calcium phosphate precipitation. Subsequently, the cells were maintained in fresh media, and various concentrations of PEITC were added to the transfected cells. After harvesting and lysing of the cells, ARE-luciferase reporter gene activity was measured and normalized against -galactosidase activity.
Results. Treatments of HeLa cells with PEITC transiently stimulated ARE-reporter gene expressions in a dose-dependent manner. Overexpression of wild-type NF-E2 related factor-2 (Nrf2) dramatically increased ARE-reporter gene expression in a dose-dependent manner. Similar effects were seen when wild-type c-Jun N-terminal kinase 1 (JNK1) was transfected, although the transactivating potential of JNK1 was much less than that of Nrf2. Cotransfection of Nrf2 and JNK1 showed additional enhancement of ARE reporter gene expression, implying that JNK1 might be an upstream activator of Nrf2. To support this, overexpression of dominant-negative JNK1 suppressed Nrf2-induced ARE reporter gene expression in a dose-dependent manner. When PEITC was added, slight enhancement of ARE reporter gene expression was observed in either Nrf2- or JNK1-transfected cells. Finally, ARE reporter activity induced by PEITC was substantially attenuated by transfection of either dominant-negative mutant of Nrf2 or dominant-negative mutant of JNK1.
Conclusion. Taken together, these data suggest that JNK1 acts as an upstream activator of Nrf2 and that PEITC activates ARE-mediated phase II drug metabolism gene expressions via the JNK1- and Nrf2-dependent pathways. 相似文献
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Benzothiophene compounds are selective estrogen receptor modulators (SERMs), which are recently found to activate antioxidant signaling. In this study the molecular mechanisms of antioxidant signaling activation by benzothiophene compound BC-1 were investigated.Methods:
HepG2 cells were stably transfected with antioxidant response element (ARE)-luciferase reporter (HepG2-ARE cells). The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in HepG2-ARE cells was suppressed using siRNA. The metabolites of BC-1 in rat liver microsome incubation were analyzed using LC-UV and LC-MS.Results:
Addition of BC-1 (5 μmol/L) in HepG2-ARE cells resulted in a 17-fold increase of ARE-luciferase activity. Pretreatment with the estrogen receptor agonist E2 (5 μmol/L) or antagonist ICI 182,780 (5 μmol/L) did not affect BC-1-induced ARE-luciferase activity. However, transfection of the cells with anti-Nrf2 siRNA suppressed this effect by 79%. Addition of BC-1 in rat microsome incubation resulted in formation of di-quinone methides and o-quinones, followed by formation of GSH conjugates. BC-1 analogues with hydrogen (BC-2) or fluorine (BC-3) at the 4′ position did not form the di-quinone methides. Both BC-2 and BC-3 showed comparable estrogenic activity with BC-1, but did not induce ARE-luciferase activity in HepG2-ARE cells.Conclusion:
Benzothiophene compound BC-1 activates ARE signaling via reactive metabolite formation that is independent of estrogen receptors. 相似文献16.
Keap1–Nrf2 pathway has emerged as a regulator for the endogenous antioxidant response, which is critical in defending cells against carcinogenesis. Herein, we demonstrated that depleting the cellular level of glutathione (GSH) by a novel electrophilic agent 2-(pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3-diynyl) thiophene (PYDDT) could activate Keap1–Nrf2 pathway. In above process, it was found that Keap1 was modified by S-glutathionylation, an important post-translational modification of protein cysteines with critical roles in oxidative stress and signal transduction. We concluded from our findings that conjugation with intracellular GSH by PYDDT might lead to Keap1 S-glutathionylation and was a key event involved in its Nrf2 inducing activity. 相似文献
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Nrf2 signaling and cell survival 总被引:2,自引:0,他引:2
Suryakant K. Niture 《Toxicology and applied pharmacology》2010,244(1):37-141
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目的 通过研究牛磺酸对胰岛素抵抗大鼠模型的血糖、血脂、氧化应激指标以及Keap1-Nrf2/ARE信号通路重要靶点的影响,并探讨其分子调控机制。方法 建立胰岛素抵抗SD大鼠模型,测定连续灌胃给药7周后正常组、模型组、二甲双胍组、牛磺酸高剂量组以及牛磺酸低剂量组的空腹血糖(fasting blood glucose,FBG)、空腹胰岛素、甘油三酯(triglyceride,TG)、总胆固醇(total cholesterol,TC)、高密度脂蛋白、低密度脂蛋白,计算胰岛素抵抗指数;采用酶联免疫吸附试验法测定肝组织中超氧化物歧化酶(superoxide dismutase,SOD)、丙二醛(malondialdehyde,MDA),运用RT-PCR技术检测肝组织中Nrf2、Keap1、HO-1、NQO1 mRNA的表达量。结果 给药7周后,与模型组比,牛磺酸高剂量组胰岛素抵抗大鼠FBG、空腹胰岛素降低(P<0.05),血清TC、TG水平也降低(P<0.05);大鼠肝组织的SOD升高、MDA降低(P<0.05);肝组织中HO-1、NQO1、Nrf2的mRNA水平上调(P<0.05), Keap1 mRNA水平下调(P<0.01)。结论 牛磺酸可调节糖尿病大鼠的血糖、血脂,改善模型大鼠氧化应激状态,减轻胰岛素抵抗,可能与其调控Keap1-Nrf2/ARE信号通路中关键基因表达从而改善氧化应激有关。 相似文献