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Acta Pharmaceutica Sinica B 2015年第4期5卷 285-299页

作者： Dhulfiqar Ali Abed Melanie Goldstein Haifa Albanyan Huijuan Jin Longqin Hu Department of Medicinal Chemistry Ernest Mario School of Pharmacy Rutgers The State University of New Jersey School of Pharmaceutical Sciences Shanxi Medical University

The keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the keap1–Nrf2 protein–protein interaction(PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of keap1–Nrf2PPI and they are electrophilic species that act by modifying the sulfhydryl groups of keap1's cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target keap1 Kelch domain protein. These non-covalent direct inhibitors of keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.

关键词： Oxidative stress keap1 Nrf2 Direct inhibitors of protein–protein interaction High throughput screening assays Structure–activity relationships X-ray crystallography

Reverse effect of curcumin on CDDP-induced drug-resistance via keap1/p62-Nrf2 signaling in A549/CDDP cell

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Asian Pacific Journal of Tropical Medicine 2017年第12期10卷 1190-1196页

作者： Jie Shen Ya-Juan Chen Yuan-Wei Jia Wen-Ying Zhao Guang-Hai Chen Ding-Feng Liu Yun-Yu Chen Chao Zhang Xiao-Ping Liu Anhui Provincial Center for Drug Clinical Evaluation Yijishan HospitalWannan Medical CollegeWuhuAnhui 241001China Pharmacy School Wannan Medical CollegeWuhuAnhui 241002China Department of Clinical Pharmacy Yijishan HospitalWannan Medical CollegeWuhuAnhui 241001China Anhui Provincial Engineering Research Center for Polysaccharides Drugs Wannan Medical CollegeWuhuAnhui 241001China oncology department yijishan hospital wannan medical college

Objective: To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy ***: A drug-resistant cell model was established by exposing A549/CDDP cell to2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM curcumin. The cell viability and apoptosis level, the signals of keap1/P62-Nrf2 and autophagy pathway were ***: CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile, curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP, and reversed the drug-resistant phenotype. Notably, curcumin combination augmented keap1 transcription. Furthermore, keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin, suggesting keap1 played a crucial role on reversal effect of ***: The present findings demonstrate that CDDP promotes abnormal activation of Nrf2 pathway and autophagy, leading to drug resistance of A549/CDDP *** attenuates this process and combat drug-resistance through its potent activation on keap1 transcription, which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.

关键词： Curcumin Drug-resistance keap1 Nrf2 Autophagy

Allosteric regulation of keap1 by 8β-hydroxy-acyclocostunolide for the treatment of acute lung injury

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4174-4178页

作者： Juan Zhang Min Zhang Qi-Meng Zhu Xin-Rong Xu Yan-Li Feng Sheng Lin Feng Qiu Cheng-Peng Sun School of Chinese Materia Medic1 Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese MedicineTianjin University of Traditional Chinese MedicineTianjin 301617China Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing Dongzhimen HospitalBeijing University of Chinese MedicineBeijing 100700China

To the Editor:Acute lung injury(ALI)is a debilitating lung disease characterized by pulmonary edema,diffuse alveolar damage,and uncontrolled neutrophil infiltration^(1).Severe cases of ALI can potentially lead to the development of acute respiratory distress syndrome(ARDS),which can lead to impaired respiratory function,multiorgan dysfunction,and an extremely high mortality rate^(2-4).ALI may be caused by various factors,including aspiration,severe pneumonia,sepsis,trauma,fatty embolism,pancreatitis,and blood transfusion^(3).Current clinical approaches to treating ALI/ARDS include mechanical ventilation,extracorporeal membrane oxygenation(ECMO),and other supportive therapies^(5,6).Therefore,ALI/ARDS is an urgent problem that needs to be addressed in the field of respiratory critical care and innovative mechanisms and therapies^(6).

关键词： Macrophage overactivation keap1 8β-Hydroxy-a-cyclocostunolide Nrf2 Acute lung injury

TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the keap1-Nrf2 Pathway

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Current Medical Science 2023年第5期43卷 1023-1032页

作者： Chen LIANG Han-yong ZHANG Yi-qian WANG Ling-ang YANG Yu-sen DU Ying LUO Tong-cun ZHANG Yao XU College of Life Sciences and Health Wuhan University of Science and TechnologyWuhan 430070China School of Stomatology Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Objective Cisplatin is the first-line treatment for breast cancer,but it faces challenges of drug *** study investigated new molecular mechanisms underlying cisplatin resistance in breast *** We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2(TMED2)and breast *** blotting,real-time PCR,CCK-8,and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell *** TMED2 was overexpressed in breast cancer and associated with poor ***2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1(keap1),relieving inhibition of keap1 on nuclear factor erythroid 2-related factor 2(Nrf2),and increasing expression of downstream drug resistance related genes,such as heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast *** results provide theoretical guidance for future clinical applications.

关键词： TMED2 keap1 Nrf2 cisplatin resistance breast cancer

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keap1翻译后修饰调控氧化应激相关疾病

基础医学与临床 2025年第01期 107-111页

作者：瞿瑛毛彩云钟晴张蓉宋运佳黑龙江中医药大学黑龙江中医药大学基础医学院药理教研组

keap1-Nrf2信号通路的激活是细胞对抗氧化应激的重要机制。氧化应激条件下，keap1受到谷胱甘肽化、烷基化以及S-巯基化等翻译后修饰(PTM)的影响，与Nrf2的结合被减弱，导致Nrf2积累、核易位以及下游解毒和抗氧化防御蛋白质的表达和转录... 详细信息

keap1-Nrf2信号通路的激活是细胞对抗氧化应激的重要机制。氧化应激条件下，keap1受到谷胱甘肽化、烷基化以及S-巯基化等翻译后修饰(PTM)的影响，与Nrf2的结合被减弱，导致Nrf2积累、核易位以及下游解毒和抗氧化防御蛋白质的表达和转录。keap1的PTM参与调控癌、帕金森病和动脉粥样硬化等多种氧化应激相关疾病，例如烷基化抑制腹主动脉瘤形成、甲基化促进乳腺癌固有抵抗以及S-巯基化改善动脉粥样硬化，为寻找新的药物靶点和生物标志物提供理论基础。

关键词： keap1 氧化应激翻译后修饰作用机制

E3泛素连接酶接头蛋白keap1的研究进展

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生物化学与生物物理进展 2022年第2期49卷 328-348页

作者：倪晓琦陈锡威金晓锋宁波大学医学院生物化学与分子生物学系宁波315211 宁波大学医学院浙江省病理生理学技术研究重点实验室宁波315211

Kelch样ECH关联蛋白1(Kelch-like ECH-associated protein 1,keap1)是E3泛素连接酶的底物识别亚单位,在蛋白质的泛素化修饰中起重要作用。蛋白质的泛素化修饰作为一种重要且复杂的蛋白质翻译后修饰,在自噬和蛋白酶体系统中作为降解信号... 详细信息

Kelch样ECH关联蛋白1(Kelch-like ECH-associated protein 1,keap1)是E3泛素连接酶的底物识别亚单位,在蛋白质的泛素化修饰中起重要作用。蛋白质的泛素化修饰作为一种重要且复杂的蛋白质翻译后修饰,在自噬和蛋白酶体系统中作为降解信号而被利用。野生型keap1能够识别、结合多种底物蛋白质并通过keap1-Cul3-Rbx1复合物泛素化。此外,keap1还作为一种抑癌蛋白而被广泛研究,已发现诸多keap1的体细胞突变或等位基因的异常缺失诱发人类多种疾病。当前的研究主要围绕在keap1-Nrf2系统而很少涉及到其他下游底物。鉴于keap1在细胞中的重要功能及广大的发展空间,这篇综述将对keap1目前的研究现状进行总结。包括:泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS),keap1的结构、功能、突变,keap1的泛素化底物及keap1的相关疾病,探讨keap1在疾病中的临床意义及研究中存在的机遇与挑战。

关键词：泛素化降解 keap1 Nrf2 突变

keap1-Nrf2-ARE信号通路及其激活剂的研究进展

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中国药理学通报 2019年第10期35卷 1342-1346页

作者：姚娟吴平安李芸李越峰刘东玲刘雪枫甘肃中医药大学药学院

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... 详细信息

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。

关键词： keap1 Nrf2 ARE 信号通路激活剂研究进展

keap1-Nrf2信号通路在肝再生中的作用及相关药物研究进展

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中国药理学通报 2019年第1期35卷 20-23页

作者：白庆云宜春学院化学与生物工程学院江西省天然药物活性成分研究重点实验室江西宜春336000

肝脏在化学损伤或手术切除组织后可以再生,肝再生是一个复杂的过程,涉及多种细胞因子和多个信号通路。核因子E2相关因子2(NF-E2-related factor 2, Nrf2)是氧化还原反应敏感转录因子,在细胞抗氧化防御、氧化还原平衡、炎症、中间代谢等... 详细信息

肝脏在化学损伤或手术切除组织后可以再生,肝再生是一个复杂的过程,涉及多种细胞因子和多个信号通路。核因子E2相关因子2(NF-E2-related factor 2, Nrf2)是氧化还原反应敏感转录因子,在细胞抗氧化防御、氧化还原平衡、炎症、中间代谢等过程中起到调控作用,并与细胞增殖密切相关。一些报告已证实在Nrf2缺失的情况下,肝脏切除术后肝再生出现了延迟现象,由此可见Nrf2信号通路参与了肝再生的过程。该文根据已有的研究结果,综述Nrf2信号通路在肝再生过程中的作用,并对影响肝再生或肝细胞增殖的药物进行总结,以期发现更多的治疗肝脏疾病的药物,并为药物作用机制的研究提供思路。

关键词： keap1 Nrf2 肝损伤肝再生抗氧化促肝再生药物

keap1在非小细胞肺癌中的表达及与化疗疗效相关性的研究

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中国肺癌杂志 2012年第10期15卷 591-596页

作者：曹宝山朱翔陈森肖宇梁莉北京大学第三医院肿瘤治疗中心化疗与放射病科北京100191 北京大学第三医院肿瘤治疗中心病理科北京100191

背景与目的已有研究表明Kelch样环氧氯丙烷相关蛋白1(Kelch-like ECH-associated protein1,keap1)与铂类耐药相关。本研究旨在探讨keap1在进展期非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达及其与一线含铂化疗方案疗效的... 详细信息

背景与目的已有研究表明Kelch样环氧氯丙烷相关蛋白1(Kelch-like ECH-associated protein1,keap1)与铂类耐药相关。本研究旨在探讨keap1在进展期非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达及其与一线含铂化疗方案疗效的相关性。方法应用免疫组化检测50例进展期NSCLC患者组织标本中keap1的表达。结果进展期NSCLC患者中keap1高表达率为26.0%;keap1表达水平与化疗疗效、无进展生存期(progression free survival,PFS)有关(P0.05)。keap1高表达组的中位PFS明显高于低表达组(P=0.002)。多因素分析表明keap1表达水平是一线化疗方案PFS的独立预测因素(P=0.007)。结论 keap1与进展期NSCLC一线化疗疗效和PFS有关,keap1可能成为新的化疗疗效预测指标。

关键词：肺肿瘤 keap1 化疗无进展生存期

金丝桃苷通过激活keap1/Nrf2/HO-1通路保护小鼠GC-2细胞的氧化损伤

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南方医科大学学报 2022年第5期42卷 673-680页

作者：朱妍妍王桐生戴宁邓梦云刘红娟童小慧李莉安徽中医药大学中西医结合学院药理学教研室安徽合肥230012 安徽中医药大学中药复方安徽省重点实验室安徽合肥230012 安徽中医药大学第一附属医院男科安徽合肥230601

目的从keap1/Nrf2/HO-1通路角度研究金丝桃苷(Hyp)对H2O2所诱导的小鼠精母细胞(GC-2)氧化损伤的保护作用。方法将GC-2细胞随机分为正常组、模型组、氮乙酰半胱氨酸组(阳性组,NAC,2.5 mmol/L)以及金丝桃苷组(50、100、200μmol/L),各组... 详细信息

目的从keap1/Nrf2/HO-1通路角度研究金丝桃苷(Hyp)对H2O2所诱导的小鼠精母细胞(GC-2)氧化损伤的保护作用。方法将GC-2细胞随机分为正常组、模型组、氮乙酰半胱氨酸组(阳性组,NAC,2.5 mmol/L)以及金丝桃苷组(50、100、200μmol/L),各组按剂量孵育48 h后,除正常组外其余各组细胞加入H_(2)O_(2)(150μmol/L)处理2 h,正常组给予等容量培养基。采用CCK-8法检测细胞的活力,流式细胞仪检测细胞凋亡水平,酶联免疫法检测超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、过氧化氢酶(CAT)活力以及丙二醛(MDA)含量,Westernblot和RT-qPCR检测Nrf2、keap1、HO-1蛋白及mRNA的相对表达水平,免疫荧光法检测Nrf2核转位水平。结果150μmol/L H_(2)O_(2)干预2 h可制备GC-2细胞氧化损伤模型。与正常组比较,模型组GC-2细胞增殖率以及SOD、GSH、CAT活力显著降低,MDA含量、细胞凋亡率,keap1和Nrf2 mRNA表达显著升高(Pkeap1蛋白表达水平显著升高(P1)。与模型组比较,NAC组和金丝桃苷200μmol/L组细胞增殖率和SOD、GSH-PX、CAT活力显著升高,MDA含量、细胞凋亡率显著下降(Pkeap1 mRNA表达显著下降,HO-1 mRNA表达显著升高(P1);金丝桃苷200μmol/L组Nrf2核蛋白(NEs-Nrf2)以及HO-1的蛋白表达显著升高(Pkeap1蛋白表达显著下降(P1);金丝桃苷组出现了明显的核转位现象(Pkeap1/Nrf2/HO-1信号通路,对H_(2)O_(2)诱导的GC-2细胞氧化损伤具有保护作用。

关键词：金丝桃苷氧化应激 Nrf2 HO-1 keap1 GC-2细胞