Nrf2/HO-1信号轴在氧化应激性疾病中的机制
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摘要
在氧化应激性疾病发生发展过程中,活性氧(reactive oxygen species,ROS)的清除障碍或生成过多导致爆发性释放后,可损伤机体各组织器官。最新研究证明:核因子E2相关因子2/血红素加氧酶-1(nuclear factor erythroid-2-related actor 2/heme oxygenase 1,Nrf2/HO-1)信号轴通过发挥抗炎、抗氧化、减少线粒体损伤、调节钙离子内流、调控细胞凋亡(apoptosis)、焦亡(pyroptosis)、铁死亡(ferroptosis)及自噬(autophagy)等作用,抵抗氧化应激损伤,这为它在不同脏器(呼吸、心血管、神经、消化、泌尿、血液)的氧化应激性疾病中的治疗潜力提供了分子机制上的理论基础。因此,有效调控Nrf2/HO-1信号轴可成为治疗氧化应激性疾病的重要靶点。
In the development of oxidative stress-relevant diseases, reactive oxygen species(ROS) removal obstacle or excess production results in the damage of the body tissues and organs. Recent studieshave demonstrated that nuclear factor E2-related factor 2/heme oxygenase-1(Nrf2/HO-1) axis played a significant role in anti-oxidative stress. The Nrf2/HO-1 axis counteracts oxidative stress injury by its resistance to inflammation, oxidation, mitochondrial damage and calcium influx, apoptosis, pyroptosis, ferroptosis and autophagy, which provides a theoretical basis for its therapeutic effect on various oxidative stress-relevant diseases in multiple organs(respiratory, cardiovascular, nervous, digestive, urinary and blood systems). Therefore, effective regulation of the Nrf2/HO-1 signal axis can be an important strategy for treatment of oxidative stress-relevant diseases.
In the development of oxidative stress-relevant diseases, reactive oxygen species(ROS) removal obstacle or excess production results in the damage of the body tissues and organs. Recent studieshave demonstrated that nuclear factor E2-related factor 2/heme oxygenase-1(Nrf2/HO-1) axis played a significant role in anti-oxidative stress. The Nrf2/HO-1 axis counteracts oxidative stress injury by its resistance to inflammation, oxidation, mitochondrial damage and calcium influx, apoptosis, pyroptosis, ferroptosis and autophagy, which provides a theoretical basis for its therapeutic effect on various oxidative stress-relevant diseases in multiple organs(respiratory, cardiovascular, nervous, digestive, urinary and blood systems). Therefore, effective regulation of the Nrf2/HO-1 signal axis can be an important strategy for treatment of oxidative stress-relevant diseases.
引文
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[7]Blajszczak C,Bonini MG.Mitochondria targeting by environmental stressors:Implications for redox cellular signaling[J].Toxicology,2017,391:84-89.
[8]Wang L,Yu Q,Han L,et al.Study on the effect of reactive oxygen species-mediated oxidative stress on the activation of mitochondrial apoptosis and the tenderness of yak meat[J].Food Chem,2018,244:394-402.
[9]Otterbein LE,Foresti R,Motterlini R.Heme oxygenase-1 and carbon monoxide in the heart the balancing act between danger signaling and pro-survival[J].Circ Res,2016,118(12):1940-1959.
[10]Piantadosi CA,Carraway MS,Babiker A,et al.Heme oxygenase-1regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory Factor-1[J].Circ Res,2008,103(11):1232-1260.
[11]Meng L,Li B,Li D,et al.Cyanidin-3-O-glucoside attenuates amyloidbeta(1-40)-induced oxidative stress and apoptosis in SH-SY5Y cells through a Nrf2 mechanism[J].J Funct Foods,2017,38(A):474-485.
[12]Wei Y,Liu D,Zheng Y,et al.Neuroprotective effects of kinetin against glutamate-induced oxidative cytotoxicity in HT22 cells:Involvement of Nrf2 and heme oxygenase-1[J].Neurotox Res,2018,33(4):725-737.
[13]Mylroie H,Dumont O,Bauer A,et al.PKCepsilon-CREB-Nrf2signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis[J].Cardiovasc Res,2015,106(3):509-519.
[14]徐健,李小莉,李一禄,等.诱导HO-1表达对慢性间歇性缺氧下INS-1细胞凋亡的影响[J].临床肺科杂志,2017,22(7):1241-1244.XU Jian,LI Xiaoli,LI Yilü,et al.Effects of HO-1 expression on the apoptosis of INS-1 cells induced by chronic intermittent hypoxia[J].Journal of Clinical Pulmonary Medicine,2017,22(7):1241-1244.
[15]Adedoyin O,Boddu R,Traylor AM,et al.Heme oxygenase-1mitigates ferroptosis in renal proximal tubule cells[J].Am J Physiol Renal Physiol,2018,314(5):702-714.
[16]Kwon M,Park E,Lee S,et al.Heme oxygenase-1 accelerates erastininduced ferroptotic cell death[J].Oncotarget,2015,6(27):24393-24403.
[17]Li R,Zhang L,Sun W.Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1signal pathway[J].Brain Res Bull,2017,130:236-244.
[18]Khakurel A,Park P.Globular adiponectin protects hepatocytes from tunicamycin-induced cell death via modulation of the inflammasome and heme oxygenase-1 induction[J].Pharmacol Res,2018,128:231-243.
[19]Yao L,Wang J,Tian B,et al.Activation of the Nrf2-ARE signaling pathway prevents hyperphosphatemia-induced vascular calcification by inducing autophagy in renal vascular smooth muscle cells[J].JCell Biochem,2017,118(12):4708-4715.
[20]Chung SD,Lai TY,Chien CT,et al.Activating Nrf-2 signaling depresses unilateral ureteral obstruction-evoked mitochondrial stress-related autophagy,apoptosis and pyroptosis in kidney[J].PLoS One,2012,7(10):e47299.
[21]Konrad FM,Zwergel C,Ngamsri K,et al.Anti-inflammatory effects of heme oxygenase-1 depend on adenosine A(2A)-and A(2B)-receptor signaling in acute pulmonary inflammation[J].Front Immunol,2017,8:1874.
[22]Wu D,Wang Y,Zhang H,et al.Acacetin attenuates mice endotoxininduced acute lung injury via augmentation of heme oxygenase-1activity[J].Inflammopharmacology,2018,26(2):635-643.
[23]Tsai C,Lin Y,Wang H,et al.Baicalein,an active component of Scutellaria baicalensis,protects against lipopolysaccharide-induced acute lung injury in rats[J].J Ethnopharmacol,2014,153(1):197-206.
[24]Qian J,Ma X,Xun Y,et al.Protective effect of forsythiaside A on OVA-induced asthma in mice[J].Eur J Pharmacol,2017,812:250-255.
[25]Lee T,Lin S,Chang N.Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling[J].Free Radic Biol Med,2014,77:71-81.
[26]Li H,Song F,Duan L,et al.Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress:Roles of Nrf2/HO-1 and PI3K/Akt pathway[J].Sci Rep,2016,6:23693.
[27]Hu T,Wei G,Xi M,et al.Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemiareperfusion injury are mediated through the Akt/Nrf2/HO-1pathway[J].Int J Mol Med,2016,38(1):83-94.
[28]Cui Y,Ma S,Zhang C,et al.Pharmacological activation of the Nrf2pathway by 3H-1,2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease[J].Behav Brain Res,2017,336:219-226.
[29]Huang T,Hao D,Wu B,et al.Uric acid demonstrates neuroprotective effect on Parkinson's disease mice through Nrf2-ARE signaling pathway[J].Biochem Biophys Res Commun,2017,493(4):1443-1449.
[30]Song D,Cheng Y,Li X,et al.Biogenic nanoselenium particles effectively attenuate oxidative stress-induced intestinal epithelial barrier injury by activating the Nrf2 antioxidant pathway[J].ACSAppl Mater Interfaces,2017,9(17):14724-14740.
[31]Cao M,Wang H,Guo L,et al.Dibenzoylmethane protects against CCl4-induced acute liver injury by activating Nrf2 via JNK,AMPK,and calcium signaling[J].AAPS J,2017,19(6):1703-1714.
[32]Liao W,Fu Z,Zou Y,et al.MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism[J].Exp Cell Res,2017,360(2):292-302.
[33]Stachurska A,Ciesla M,Kozakowska M,et al.Cross-talk between microRNA s,nuclear factor E2-related factor 2,and heme oxygenase-1 in ochratoxin A-induced toxic effects in renal proximal tubular epithelial cells[J].Mol Nutr Food Res,2013,57(3):504-515.
[34]Bolisetty S,Zarjou A,Agarwal A.Heme oxygenase-1 as a therapeutic target in acute kidney injury[J].Am J Kidney Dis,2017,69(4):531-545.
[35]Menegon S,Columbano A,Giordano S.The dual roles of NRF2 in cancer[J].Trends Mol Med,2016,22(7):578-593.
[36]Furfaro AL,Traverso N,Domenicotti C,et al.The Nrf2/HO-1 axis in cancer cell growth and chemoresistance[J].Oxid Med Cell Longev,2016,2016:1958174.
[2]Krajka-Kuzniak V,Paluszczak J,Baer-Dubowska W.The Nrf2-AREsignaling pathway:An update on its regulation and possible role in cancer prevention and treatment[J].Pharmacol Rep,2017,69(3):393-402.
[3]Loboda A,Damulewicz M,Pyza E,et al.Role of Nrf2/HO-1system in development,oxidative stress response and diseases:an evolutionarily conserved mechanism[J].Cell Mol Life Sci,2016,73(17):3221-3247.
[4]黄新宇,刘永林.白藜芦醇激活Nrf2/ARE信号通路降低心肌缺血再灌注损伤大鼠炎症和氧化应激[J].中华中医药学刊,2017,35(6):1516-1520.HUANG Xinyu,LIU Yonglin.Resveratrol activates Nrf2/AREsignaling pathway to reduce inflammation and oxidative stress in rats with myocardial ischemia/reperfusion injury[J].Chinese Archives of Traditional Chinese Medicine,2017,35(6):1516-1520.
[5]Konrad FM,Knausberg U,Hoene R,et al.Tissue heme oxygenase-1exerts anti-inflammatory effects on LPS-induced pulmonary inflammation[J].Mucosal Immunol,2016,9(1):98-111.
[6]董泗芹,徐松,侯训尧,等.Nrf2激活对AGEs诱导大鼠海马损伤的抗炎、抗氧化保护作用[J].卒中与神经疾病,2017,24(5):388-392.DONG Siqin,XU Song,HOU Xunyao,et al.Anti-inflammatory and anti-oxidative protective effects of Nrf2 activation on AGEs-induced hippocampal damage in rats[J].Stroke and Nervous Diseases,2017,24(5):388-392.
[7]Blajszczak C,Bonini MG.Mitochondria targeting by environmental stressors:Implications for redox cellular signaling[J].Toxicology,2017,391:84-89.
[8]Wang L,Yu Q,Han L,et al.Study on the effect of reactive oxygen species-mediated oxidative stress on the activation of mitochondrial apoptosis and the tenderness of yak meat[J].Food Chem,2018,244:394-402.
[9]Otterbein LE,Foresti R,Motterlini R.Heme oxygenase-1 and carbon monoxide in the heart the balancing act between danger signaling and pro-survival[J].Circ Res,2016,118(12):1940-1959.
[10]Piantadosi CA,Carraway MS,Babiker A,et al.Heme oxygenase-1regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory Factor-1[J].Circ Res,2008,103(11):1232-1260.
[11]Meng L,Li B,Li D,et al.Cyanidin-3-O-glucoside attenuates amyloidbeta(1-40)-induced oxidative stress and apoptosis in SH-SY5Y cells through a Nrf2 mechanism[J].J Funct Foods,2017,38(A):474-485.
[12]Wei Y,Liu D,Zheng Y,et al.Neuroprotective effects of kinetin against glutamate-induced oxidative cytotoxicity in HT22 cells:Involvement of Nrf2 and heme oxygenase-1[J].Neurotox Res,2018,33(4):725-737.
[13]Mylroie H,Dumont O,Bauer A,et al.PKCepsilon-CREB-Nrf2signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis[J].Cardiovasc Res,2015,106(3):509-519.
[14]徐健,李小莉,李一禄,等.诱导HO-1表达对慢性间歇性缺氧下INS-1细胞凋亡的影响[J].临床肺科杂志,2017,22(7):1241-1244.XU Jian,LI Xiaoli,LI Yilü,et al.Effects of HO-1 expression on the apoptosis of INS-1 cells induced by chronic intermittent hypoxia[J].Journal of Clinical Pulmonary Medicine,2017,22(7):1241-1244.
[15]Adedoyin O,Boddu R,Traylor AM,et al.Heme oxygenase-1mitigates ferroptosis in renal proximal tubule cells[J].Am J Physiol Renal Physiol,2018,314(5):702-714.
[16]Kwon M,Park E,Lee S,et al.Heme oxygenase-1 accelerates erastininduced ferroptotic cell death[J].Oncotarget,2015,6(27):24393-24403.
[17]Li R,Zhang L,Sun W.Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1signal pathway[J].Brain Res Bull,2017,130:236-244.
[18]Khakurel A,Park P.Globular adiponectin protects hepatocytes from tunicamycin-induced cell death via modulation of the inflammasome and heme oxygenase-1 induction[J].Pharmacol Res,2018,128:231-243.
[19]Yao L,Wang J,Tian B,et al.Activation of the Nrf2-ARE signaling pathway prevents hyperphosphatemia-induced vascular calcification by inducing autophagy in renal vascular smooth muscle cells[J].JCell Biochem,2017,118(12):4708-4715.
[20]Chung SD,Lai TY,Chien CT,et al.Activating Nrf-2 signaling depresses unilateral ureteral obstruction-evoked mitochondrial stress-related autophagy,apoptosis and pyroptosis in kidney[J].PLoS One,2012,7(10):e47299.
[21]Konrad FM,Zwergel C,Ngamsri K,et al.Anti-inflammatory effects of heme oxygenase-1 depend on adenosine A(2A)-and A(2B)-receptor signaling in acute pulmonary inflammation[J].Front Immunol,2017,8:1874.
[22]Wu D,Wang Y,Zhang H,et al.Acacetin attenuates mice endotoxininduced acute lung injury via augmentation of heme oxygenase-1activity[J].Inflammopharmacology,2018,26(2):635-643.
[23]Tsai C,Lin Y,Wang H,et al.Baicalein,an active component of Scutellaria baicalensis,protects against lipopolysaccharide-induced acute lung injury in rats[J].J Ethnopharmacol,2014,153(1):197-206.
[24]Qian J,Ma X,Xun Y,et al.Protective effect of forsythiaside A on OVA-induced asthma in mice[J].Eur J Pharmacol,2017,812:250-255.
[25]Lee T,Lin S,Chang N.Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling[J].Free Radic Biol Med,2014,77:71-81.
[26]Li H,Song F,Duan L,et al.Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress:Roles of Nrf2/HO-1 and PI3K/Akt pathway[J].Sci Rep,2016,6:23693.
[27]Hu T,Wei G,Xi M,et al.Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemiareperfusion injury are mediated through the Akt/Nrf2/HO-1pathway[J].Int J Mol Med,2016,38(1):83-94.
[28]Cui Y,Ma S,Zhang C,et al.Pharmacological activation of the Nrf2pathway by 3H-1,2-dithiole-3-thione is neuroprotective in a mouse model of Alzheimer disease[J].Behav Brain Res,2017,336:219-226.
[29]Huang T,Hao D,Wu B,et al.Uric acid demonstrates neuroprotective effect on Parkinson's disease mice through Nrf2-ARE signaling pathway[J].Biochem Biophys Res Commun,2017,493(4):1443-1449.
[30]Song D,Cheng Y,Li X,et al.Biogenic nanoselenium particles effectively attenuate oxidative stress-induced intestinal epithelial barrier injury by activating the Nrf2 antioxidant pathway[J].ACSAppl Mater Interfaces,2017,9(17):14724-14740.
[31]Cao M,Wang H,Guo L,et al.Dibenzoylmethane protects against CCl4-induced acute liver injury by activating Nrf2 via JNK,AMPK,and calcium signaling[J].AAPS J,2017,19(6):1703-1714.
[32]Liao W,Fu Z,Zou Y,et al.MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2/ARE pathway through a Keap1-independent mechanism[J].Exp Cell Res,2017,360(2):292-302.
[33]Stachurska A,Ciesla M,Kozakowska M,et al.Cross-talk between microRNA s,nuclear factor E2-related factor 2,and heme oxygenase-1 in ochratoxin A-induced toxic effects in renal proximal tubular epithelial cells[J].Mol Nutr Food Res,2013,57(3):504-515.
[34]Bolisetty S,Zarjou A,Agarwal A.Heme oxygenase-1 as a therapeutic target in acute kidney injury[J].Am J Kidney Dis,2017,69(4):531-545.
[35]Menegon S,Columbano A,Giordano S.The dual roles of NRF2 in cancer[J].Trends Mol Med,2016,22(7):578-593.
[36]Furfaro AL,Traverso N,Domenicotti C,et al.The Nrf2/HO-1 axis in cancer cell growth and chemoresistance[J].Oxid Med Cell Longev,2016,2016:1958174.