Reactive oxygen species (ROS) are molecules or ions formed by the incomplete one-electron reduction of oxygen. Ofinterest, it seems that ROS manifest dual roles, cancer promoting or cancer suppressing, in tumorigenesi...Reactive oxygen species (ROS) are molecules or ions formed by the incomplete one-electron reduction of oxygen. Ofinterest, it seems that ROS manifest dual roles, cancer promoting or cancer suppressing, in tumorigenesis. ROS participate simultaneously in two signaling pathways that have inverse functions in tumorigenesis, Ras-Raf-MEK1/2-ERK1/2 signaling and the p38 mitogen-activated protein kinases (MAPK) pathway. It is well known that Ras-Raf-MEK1/2-ERK1/2 signaling is related to oncogenesis, while the p38 MAPK pathway contributes to cancer suppression, which involves oncogene-induced senescence, inflammationinduced cellular senescence, replicative senescence, contact inhibition and DNA-damage responses. Thus, ROS may not be an absolute carcinogenic factor or cancer suppressor. The purpose of the present review is to discuss the dual roles of ROS in the pathogenesis of cancer, and the signaling pathway mediating their role in tumorigenesis.展开更多
BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against...BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.展开更多
Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in hig...Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant(IR)HepG2 cells.All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4(GLUT4)and phosphor-glycogen synthase kinase(GSK-3β).These fl avonoids signifi cantly inhibited the production of reactive oxygen species(ROS)and advanced glycation end-products(AGEs),which were closely related to the suppression of the phosphorylation form of NF-κB and P65.The expression levels of insulin receptor substrate-1(IRS-1),insulin receptor substrate-2(IRS-2)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)pathway in IR-HepG2 cells were all partially activated by the fl avonoids,with variable effects.Furthermore,the intracellular metabolic conditions of the fl avonoids were also evaluated.展开更多
目的研究凋亡信号调节激酶(apoptosis signal regu lating k inase 1,ASK1)在高血压心脏肥大中的作用。方法复制腹主动脉缩窄高血压大鼠模型,用比色法测定假手术组和高血压组左心室活性氧(reactive oxygen spec ies,ROS)水平,用免疫印...目的研究凋亡信号调节激酶(apoptosis signal regu lating k inase 1,ASK1)在高血压心脏肥大中的作用。方法复制腹主动脉缩窄高血压大鼠模型,用比色法测定假手术组和高血压组左心室活性氧(reactive oxygen spec ies,ROS)水平,用免疫印迹法测定ASK1蛋白表达。结果高血压大鼠左心室质量指数、ROS水平、ASK1蛋白表达均显著高于假手术组(P<0.05)。结论压力超负荷下随着ROS的升高,激活的ASK1可能在心脏肥大信号传导途径中发挥重要作用。展开更多
目的探讨细胞外信号调节激酶1/2(ERK1/2)在转化生长因子-β1(TGF-β1)诱导的肺成纤维细胞合成Ⅰ、Ⅲ型胶原蛋白中的作用,及新型过氧化物酶Peroxiredoxin-1(Prx-1)对该作用的影响。方法体外培养肺成纤维细胞随机分为4组:对照组(0.4%血清)...目的探讨细胞外信号调节激酶1/2(ERK1/2)在转化生长因子-β1(TGF-β1)诱导的肺成纤维细胞合成Ⅰ、Ⅲ型胶原蛋白中的作用,及新型过氧化物酶Peroxiredoxin-1(Prx-1)对该作用的影响。方法体外培养肺成纤维细胞随机分为4组:对照组(0.4%血清)、TGF-β1组(5μg/L)、阴性转染组(TGF-β1+阴性对照si RNA)和Prx-1 si RNA转染组(TGF-β1+Prx-1 si RNA)。采用脂质体转染法转染si RNA,实时定量逆转录-聚合酶链反应(RT-PCR)检测转染后Prx-1 m RNA表达;Western blot检测Ⅰ和Ⅲ型胶原蛋白、ERK1/2及Prx-1表达;2,7-二氯荧光素二乙酸(DCFH-DA)检测活性氧(ROS)水平。结果 Prx-1 si RNA转染肺成纤维细胞后,Prx-1 m RNA表达明显降低,最大抑制率为92%。与对照组比较,TGF-β1组的Ⅰ和Ⅲ型胶原蛋白、ROS、磷酸化ERK1/2(p-ERK1/2)及Prx-1蛋白的表达水平均明显提高。与TGF-β1组比较,阴性转染组中的上述观察指标无明显变化,但Prx-1转染组的Ⅰ和Ⅲ型胶原蛋白、ROS、p-ERK1/2水平进一步提高,而Prx-1蛋白的表达被抑制。结论 TGF-β1能够诱导肺成纤维细胞生成ROS,并促进ERK1/2通路的激活,导致Ⅰ、Ⅲ型胶原蛋白合成增加,而Prx-1 si RNA可通过提高ROS水平进一步促进TGF-β1该作用。展开更多
AIM: To investigate the mechanisms of chloride intracellular channel 1 (CLIC1) in the metastasis of colon cancer under hypoxia-reoxygenation (H-R) conditions.
Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulato...Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition,neuronal homeostasis,precursor migration,plasticity,and neurodegeneration,its functions in the process of oxidative injury are largely uncharacterized.In this study,oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats.We used hydrogen peroxide(H2O2)to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes.After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes,Nogo-A expression was increased,and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death.Furthermore,knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2.Intervention with a Nogo-66 antibody,a LINGO1 blocker,or Y27632,an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway,did not affect the death of oligodendrocytes.Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes.In conclusion,Nogo-A aggravated reactive oxygen species damage in oligodendrocytes,and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process.This study was approved by the Ethics Committee of Peking University People’s Hospital,China(approval No.2018PHC081)on December 18,2018.展开更多
基金Supported by National Natural Science Foundation of China, No. 30750013 Key Science Research Project Natural Science Foundation of Xiamen, No. WKZ0501
文摘Reactive oxygen species (ROS) are molecules or ions formed by the incomplete one-electron reduction of oxygen. Ofinterest, it seems that ROS manifest dual roles, cancer promoting or cancer suppressing, in tumorigenesis. ROS participate simultaneously in two signaling pathways that have inverse functions in tumorigenesis, Ras-Raf-MEK1/2-ERK1/2 signaling and the p38 mitogen-activated protein kinases (MAPK) pathway. It is well known that Ras-Raf-MEK1/2-ERK1/2 signaling is related to oncogenesis, while the p38 MAPK pathway contributes to cancer suppression, which involves oncogene-induced senescence, inflammationinduced cellular senescence, replicative senescence, contact inhibition and DNA-damage responses. Thus, ROS may not be an absolute carcinogenic factor or cancer suppressor. The purpose of the present review is to discuss the dual roles of ROS in the pathogenesis of cancer, and the signaling pathway mediating their role in tumorigenesis.
文摘BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
基金supported by National Natural Science Foundation of China(32072212)Multi-Year Research Grant of University of Macao(MYRG2018-00169-ICMS)+5 种基金Science and Technology Development Fund of Macao(FDCT)(0098/2020/A)MICINN supporting the Ramón y Cajal grant for M.A.Prieto(RYC-201722891)Jianbo Xiao(RYC2020-030365-I)Xunta de Galicia supporting the Axudas Conecta Peme,the IN852A 2018/58 Neuro Food Project,the program EXCELENCIA-ED431F 2020/12the pre-doctoral grants of P.García-Oliveira(ED481A-2019/295)to Ibero-American Program on Science and Technology(CYTED-AQUA-CIBUS,P317RT0003).
文摘Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities.In this study,apigenin,luteolin,and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant(IR)HepG2 cells.All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4(GLUT4)and phosphor-glycogen synthase kinase(GSK-3β).These fl avonoids signifi cantly inhibited the production of reactive oxygen species(ROS)and advanced glycation end-products(AGEs),which were closely related to the suppression of the phosphorylation form of NF-κB and P65.The expression levels of insulin receptor substrate-1(IRS-1),insulin receptor substrate-2(IRS-2)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)pathway in IR-HepG2 cells were all partially activated by the fl avonoids,with variable effects.Furthermore,the intracellular metabolic conditions of the fl avonoids were also evaluated.
文摘目的研究凋亡信号调节激酶(apoptosis signal regu lating k inase 1,ASK1)在高血压心脏肥大中的作用。方法复制腹主动脉缩窄高血压大鼠模型,用比色法测定假手术组和高血压组左心室活性氧(reactive oxygen spec ies,ROS)水平,用免疫印迹法测定ASK1蛋白表达。结果高血压大鼠左心室质量指数、ROS水平、ASK1蛋白表达均显著高于假手术组(P<0.05)。结论压力超负荷下随着ROS的升高,激活的ASK1可能在心脏肥大信号传导途径中发挥重要作用。
文摘目的探讨细胞外信号调节激酶1/2(ERK1/2)在转化生长因子-β1(TGF-β1)诱导的肺成纤维细胞合成Ⅰ、Ⅲ型胶原蛋白中的作用,及新型过氧化物酶Peroxiredoxin-1(Prx-1)对该作用的影响。方法体外培养肺成纤维细胞随机分为4组:对照组(0.4%血清)、TGF-β1组(5μg/L)、阴性转染组(TGF-β1+阴性对照si RNA)和Prx-1 si RNA转染组(TGF-β1+Prx-1 si RNA)。采用脂质体转染法转染si RNA,实时定量逆转录-聚合酶链反应(RT-PCR)检测转染后Prx-1 m RNA表达;Western blot检测Ⅰ和Ⅲ型胶原蛋白、ERK1/2及Prx-1表达;2,7-二氯荧光素二乙酸(DCFH-DA)检测活性氧(ROS)水平。结果 Prx-1 si RNA转染肺成纤维细胞后,Prx-1 m RNA表达明显降低,最大抑制率为92%。与对照组比较,TGF-β1组的Ⅰ和Ⅲ型胶原蛋白、ROS、磷酸化ERK1/2(p-ERK1/2)及Prx-1蛋白的表达水平均明显提高。与TGF-β1组比较,阴性转染组中的上述观察指标无明显变化,但Prx-1转染组的Ⅰ和Ⅲ型胶原蛋白、ROS、p-ERK1/2水平进一步提高,而Prx-1蛋白的表达被抑制。结论 TGF-β1能够诱导肺成纤维细胞生成ROS,并促进ERK1/2通路的激活,导致Ⅰ、Ⅲ型胶原蛋白合成增加,而Prx-1 si RNA可通过提高ROS水平进一步促进TGF-β1该作用。
基金Supported by The "Eleventh Five-year Plan" for Medical Sci-ence Development of PLA,No.06MB243the National Natural Science Foundation of China,No.81101101 and No.51273165+1 种基金the Key Project of Chinese Ministry of Education,No.212149the Projects of Sichuan Province,No.2010SZ0294,No.2011JQ0032 and No.12ZB038
文摘AIM: To investigate the mechanisms of chloride intracellular channel 1 (CLIC1) in the metastasis of colon cancer under hypoxia-reoxygenation (H-R) conditions.
基金This work was supported by the National Natural Science Foundation of China,No.81870996(to JZ).
文摘Nogo-A is considered one of the most important inhibitors of myelin-associated axonal regeneration in the central nervous system.It is mainly expressed by oligodendrocytes.Although previous studies have found regulatory roles for Nogo-A in neurite outgrowth inhibition,neuronal homeostasis,precursor migration,plasticity,and neurodegeneration,its functions in the process of oxidative injury are largely uncharacterized.In this study,oligodendrocytes were extracted from the cerebral cortex of newborn Sprague-Dawley rats.We used hydrogen peroxide(H2O2)to induce an in vitro oligodendrocyte oxidative damage model and found that endogenously expressed Nogo-A is significantly upregulated in oligodendrocytes.After recombinant virus Ad-ZsGreen-rat Nogo-A infection of oligodendrocytes,Nogo-A expression was increased,and the infected oligodendrocytes were more susceptible to acute oxidative insults and exhibited a markedly elevated rate of cell death.Furthermore,knockdown of Nogo-A expression in oligodendrocytes by Ad-ZsGreen-shRNA-Nogo-A almost completely protected against oxidative stress induced by exogenous H2O2.Intervention with a Nogo-66 antibody,a LINGO1 blocker,or Y27632,an inhibitor in the Nogo-66-NgR/p75/LINGO-1-RhoA-ROCK pathway,did not affect the death of oligodendrocytes.Ad-ZsGreen-shRNA-Nogo-A also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and inhibited BCL2 expression in oligodendrocytes.In conclusion,Nogo-A aggravated reactive oxygen species damage in oligodendrocytes,and phosphorylated extracellular signal-regulated kinase 1/2 and BCL2 might be involved in this process.This study was approved by the Ethics Committee of Peking University People’s Hospital,China(approval No.2018PHC081)on December 18,2018.
