This study aims to analyze the clinical significance and mechanism of nuclear factor erythroid 2-related factor 2(NRF2)and glutathione peroxidase 4(GPX4)in primary hepatic carcinoma(PHC).Methods:The expression of NRF2...This study aims to analyze the clinical significance and mechanism of nuclear factor erythroid 2-related factor 2(NRF2)and glutathione peroxidase 4(GPX4)in primary hepatic carcinoma(PHC).Methods:The expression of NRF2 and GPX4 in peripheral blood of patients with PHC was determined to analyze the diagnostic value of the two combined for PHC.The prognostic significance of NRF2 and GPX4 was evaluated by 3-year followup.Human liver epithelial cells THLE-2 and human hepatocellular carcinoma cells HepG2 were purchased,and the expression of NRF2 and GPX4 in the cells was determined.NRF2 and GPX4 aberrant expression vectors were constructed and transfected into HepG2,and changes in cell proliferation and invasion capabilities were observed.Results:The expression of NRF2 and GPX4 in patients with PHC was higher than that in patients with LC or VH(p<0.05),and the two indicators combined was excellent in diagnosing PHC.Moreover,patients with high expression of NRF2 and GPX4 had a higher risk of death(p<0.05).In in vitro experiments,both NRF2 and GPX4 expression was elevated in HepG2(p<0.05).HepG2 activity was enhanced by increasing the expression of the two,vice versa(p<0.05).Conclusion:NRF2 and GPX4 combined is excellent in diagnosing PHC,and promotes the malignant development of PHC.展开更多
Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In t...Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2（Nrf2）pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside（30 mg/kg）reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.展开更多
OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a ...OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a widely concerned drug target.Recent research has identified that Nrf2 is involved in the pathology of Alzheimer disease(AD),whereas the mechanism is unknown.The purpose of this study is to figure out the role of Nrf2 in the pathologic process of AD through Nrf2-Keap1-ARE pathway and the effects of Keap1-Nrf2 inhibitor in AD mice models.METHODS Amyloid β^(1-42)(Aβ^(1-42))was injected into the bilateral hippocampus to induce the cognitive dysfunction in eight-week old male mice.The mice were treated with Keap1-Nrf2 inhibitor NXPZ of three doses as well as donepezil as a positive control by intragastric administration one time a day for one week.Several behavior tests were used to analyze the mice learning and memory ability.Additionally,we detected Nrf2 and Aβ in the plasma in mice with ELISA kits,as well as some factors related to oxidative stress in the hippocampus and cortex.The expression levels of Nrf2,Keap1,Tau and p-Tau were measured in the murine brain tissue with Western blotting.SH-SY5 Y cells were studied as an in vitro model to further clarify the mechanism.RESULTS The treatment of NXPZ ameliorated learning and memory dysfunction in AD mice in a dose-dependent manner,and the high dose group recovered better than the positive drug group.The plasma Nrf2 level was increased in a dose-dependent manner in the treatment groups;however,the plasma Aβ was decreased.What′ s more,superoxide dismutase(SOD) and glutathione reductase(GSSH) in the hippocampus and cortex were increased in the treatment group,while the malondialdehyde(MDA) was decreased,meaning that NXPZ treatment promoted expression of the anti-oxidative factors and inhibited the expression of the oxidative factors in the down-stream.Western blotting analysis of hippocampus and cortex showed up-regulated Nrf2,decreased Keap1 and decreased p-Tau in NXPZ treatment mice.In ex vivo experiments,when SH-SY5 Y cells were treated with Aβ,Nrf2 in the cytoplasm was increased,as well as the expression Nrf2 in the nuclear was decreased.The treatment of NXPZ increased nuclear Nrf2,decreased cytoplasm Nrf2,and decreased the expression of p-Tau.CONCLUSION Nrf2 has an important role in neuron function.Nrf2 activation by selective Keap1-Nrf2 inhibitor NXPZ may contribute to improve cognitive function in AD mice.The mechanism may be related to increased generation and release of Nrf2 induced by more disaggregation with Keap1,leading to more expression of anti-oxidative molecules to protect the damage caused by Aβ.These results indicates that Nrf2 may be a novel therapeutic target of AD and Keap1-Nrf2 inhibitor may be a novel medication for protecting the loss of learning and memory ability.展开更多
目的探讨胃衡汤调控核因子E2相关因子2(Nrf2)-Kelch样环氧氯丙烷相关蛋白(Keap)信号通路抑制老年胃癌前病变(Precancerous lesions of gastric cancer,PLGC)患者氧化应激反应的作用。方法选取2022年3月-2023年3月期间于南京中医药大学...目的探讨胃衡汤调控核因子E2相关因子2(Nrf2)-Kelch样环氧氯丙烷相关蛋白(Keap)信号通路抑制老年胃癌前病变(Precancerous lesions of gastric cancer,PLGC)患者氧化应激反应的作用。方法选取2022年3月-2023年3月期间于南京中医药大学第二附属医院消化腔镜中心和脾胃病科就诊的PLGC老年患者60例,按随机数字表法分为基础治疗组与胃衡汤治疗组,每组各30例。另选择同期常规胃镜体检的慢性浅表性胃炎患者30例为对照组。对照组仅入组接受研究相关指标检测,不予治疗。基础治疗组患者给予雷贝拉唑钠肠溶胶囊,胃衡汤组在基础治疗组上加用胃衡汤治疗,均治疗6个月。观察比较两组PLGC患者临床疗效、安全性,治疗前后中医证候评分、胃镜病理分级及Nrf2-Keap通路相关蛋白检测。结果治疗后胃衡汤治疗组中医证候疗效总有效率93.33%(28/30)明显高于基础治疗组76.67%(23/30),差异有统计学意义(P<0.05)。治疗后胃衡汤治疗组病理组织学疗效总有效率83.33%(25/30)明显高于基础治疗组63.33%(19/30),差异有统计学意义(P<0.05)。治疗后两组患者中医证候各项积分及总积分均较治疗前降低,差异有统计学意义(P<0.05);且胃衡汤治疗组中医证候各项积分及总积分均明显低于基础治疗组,差异有统计学意义(P<0.05)。治疗后两组患者胃黏膜组织学各项积分及总分均较治疗前降低,差异有统计学意义(P<0.05);且胃衡汤治疗组胃黏膜组织学各项积分及总分均明显低于基础治疗组,差异有统计学意义(P<0.05)。治疗后两组患者Nrf2和SOD表达高于治疗前,Keap1和MDA表达较治疗前降低,差异有统计学意义(P<0.05);且胃衡汤治疗组Nrf2和SOD表达明显高于基础治疗组,Keap1和MDA表达明显低于基础治疗组,差异有统计学意义(P<0.05)。治疗期间,两组患者治疗前后肝肾功能、三大常规及心电图检查均未发现异常。结论胃衡汤治疗老年PLGC能够改善临床症状,抑制甚至逆转病理学改变,提高治疗效果,其机制与调节Nrf2-Keap信号通路而抑制氧化应激反应有关。展开更多
文摘This study aims to analyze the clinical significance and mechanism of nuclear factor erythroid 2-related factor 2(NRF2)and glutathione peroxidase 4(GPX4)in primary hepatic carcinoma(PHC).Methods:The expression of NRF2 and GPX4 in peripheral blood of patients with PHC was determined to analyze the diagnostic value of the two combined for PHC.The prognostic significance of NRF2 and GPX4 was evaluated by 3-year followup.Human liver epithelial cells THLE-2 and human hepatocellular carcinoma cells HepG2 were purchased,and the expression of NRF2 and GPX4 in the cells was determined.NRF2 and GPX4 aberrant expression vectors were constructed and transfected into HepG2,and changes in cell proliferation and invasion capabilities were observed.Results:The expression of NRF2 and GPX4 in patients with PHC was higher than that in patients with LC or VH(p<0.05),and the two indicators combined was excellent in diagnosing PHC.Moreover,patients with high expression of NRF2 and GPX4 had a higher risk of death(p<0.05).In in vitro experiments,both NRF2 and GPX4 expression was elevated in HepG2(p<0.05).HepG2 activity was enhanced by increasing the expression of the two,vice versa(p<0.05).Conclusion:NRF2 and GPX4 combined is excellent in diagnosing PHC,and promotes the malignant development of PHC.
基金supported by the Independent Research Project of Fujian Academy of Traditional Chinese Medicine in China,No.2012fjzyyk-4the Natural Science Foundation of Fujian Province in China,No.2014J01340+1 种基金the Research Project of Fujian Provincial Health and Family Planning Commission,No.2014-ZQN-JC-32a grant from the Platform for Preclinical Studies of Traditional Chinese Medicine and Quality Control Engineering Technology Research Center of Fujian Province in China,No.2009Y2003
文摘Salidroside,the main active ingredient extracted from Rhodiola crenulata,has been shown to be neuroprotective in ischemic cerebral injury,but the underlying mechanism for this neuroprotection is poorly understood.In the current study,the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2（Nrf2）pathway was investigated in a rat model of middle cerebral artery occlusion.Salidroside（30 mg/kg）reduced infarct size,improved neurological function and histological changes,increased activity of superoxide dismutase and glutathione-S-transferase,and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion.Furthermore,salidroside apparently increased Nrf2 and heme oxygenase-1 expression.These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved.The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke.
基金National Natural Science Foundation of China(81703520).
文摘OBJECTIVE Nuclear factor erythroid 2-related factor 2(Nrf2) is found to be ubiquitiously expressed in many tissues,and works as the key regulator against oxidative stress damage in cells and organs,which makes Nrf2 a widely concerned drug target.Recent research has identified that Nrf2 is involved in the pathology of Alzheimer disease(AD),whereas the mechanism is unknown.The purpose of this study is to figure out the role of Nrf2 in the pathologic process of AD through Nrf2-Keap1-ARE pathway and the effects of Keap1-Nrf2 inhibitor in AD mice models.METHODS Amyloid β^(1-42)(Aβ^(1-42))was injected into the bilateral hippocampus to induce the cognitive dysfunction in eight-week old male mice.The mice were treated with Keap1-Nrf2 inhibitor NXPZ of three doses as well as donepezil as a positive control by intragastric administration one time a day for one week.Several behavior tests were used to analyze the mice learning and memory ability.Additionally,we detected Nrf2 and Aβ in the plasma in mice with ELISA kits,as well as some factors related to oxidative stress in the hippocampus and cortex.The expression levels of Nrf2,Keap1,Tau and p-Tau were measured in the murine brain tissue with Western blotting.SH-SY5 Y cells were studied as an in vitro model to further clarify the mechanism.RESULTS The treatment of NXPZ ameliorated learning and memory dysfunction in AD mice in a dose-dependent manner,and the high dose group recovered better than the positive drug group.The plasma Nrf2 level was increased in a dose-dependent manner in the treatment groups;however,the plasma Aβ was decreased.What′ s more,superoxide dismutase(SOD) and glutathione reductase(GSSH) in the hippocampus and cortex were increased in the treatment group,while the malondialdehyde(MDA) was decreased,meaning that NXPZ treatment promoted expression of the anti-oxidative factors and inhibited the expression of the oxidative factors in the down-stream.Western blotting analysis of hippocampus and cortex showed up-regulated Nrf2,decreased Keap1 and decreased p-Tau in NXPZ treatment mice.In ex vivo experiments,when SH-SY5 Y cells were treated with Aβ,Nrf2 in the cytoplasm was increased,as well as the expression Nrf2 in the nuclear was decreased.The treatment of NXPZ increased nuclear Nrf2,decreased cytoplasm Nrf2,and decreased the expression of p-Tau.CONCLUSION Nrf2 has an important role in neuron function.Nrf2 activation by selective Keap1-Nrf2 inhibitor NXPZ may contribute to improve cognitive function in AD mice.The mechanism may be related to increased generation and release of Nrf2 induced by more disaggregation with Keap1,leading to more expression of anti-oxidative molecules to protect the damage caused by Aβ.These results indicates that Nrf2 may be a novel therapeutic target of AD and Keap1-Nrf2 inhibitor may be a novel medication for protecting the loss of learning and memory ability.
文摘目的探讨胃衡汤调控核因子E2相关因子2(Nrf2)-Kelch样环氧氯丙烷相关蛋白(Keap)信号通路抑制老年胃癌前病变(Precancerous lesions of gastric cancer,PLGC)患者氧化应激反应的作用。方法选取2022年3月-2023年3月期间于南京中医药大学第二附属医院消化腔镜中心和脾胃病科就诊的PLGC老年患者60例,按随机数字表法分为基础治疗组与胃衡汤治疗组,每组各30例。另选择同期常规胃镜体检的慢性浅表性胃炎患者30例为对照组。对照组仅入组接受研究相关指标检测,不予治疗。基础治疗组患者给予雷贝拉唑钠肠溶胶囊,胃衡汤组在基础治疗组上加用胃衡汤治疗,均治疗6个月。观察比较两组PLGC患者临床疗效、安全性,治疗前后中医证候评分、胃镜病理分级及Nrf2-Keap通路相关蛋白检测。结果治疗后胃衡汤治疗组中医证候疗效总有效率93.33%(28/30)明显高于基础治疗组76.67%(23/30),差异有统计学意义(P<0.05)。治疗后胃衡汤治疗组病理组织学疗效总有效率83.33%(25/30)明显高于基础治疗组63.33%(19/30),差异有统计学意义(P<0.05)。治疗后两组患者中医证候各项积分及总积分均较治疗前降低,差异有统计学意义(P<0.05);且胃衡汤治疗组中医证候各项积分及总积分均明显低于基础治疗组,差异有统计学意义(P<0.05)。治疗后两组患者胃黏膜组织学各项积分及总分均较治疗前降低,差异有统计学意义(P<0.05);且胃衡汤治疗组胃黏膜组织学各项积分及总分均明显低于基础治疗组,差异有统计学意义(P<0.05)。治疗后两组患者Nrf2和SOD表达高于治疗前,Keap1和MDA表达较治疗前降低,差异有统计学意义(P<0.05);且胃衡汤治疗组Nrf2和SOD表达明显高于基础治疗组,Keap1和MDA表达明显低于基础治疗组,差异有统计学意义(P<0.05)。治疗期间,两组患者治疗前后肝肾功能、三大常规及心电图检查均未发现异常。结论胃衡汤治疗老年PLGC能够改善临床症状,抑制甚至逆转病理学改变,提高治疗效果,其机制与调节Nrf2-Keap信号通路而抑制氧化应激反应有关。
