Pancreatitis and pancreatic cancer(PC)stand as the most worrisome ailments affecting the pancreas.Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases,yet their true nature continu...Pancreatitis and pancreatic cancer(PC)stand as the most worrisome ailments affecting the pancreas.Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases,yet their true nature continues to elude their grasp.Within this realm,oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC.Excessive accumulation of reactive oxygen species(ROS)can cause oxidative stress,and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides(NOX).NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells,activate pancreatic stellate cells,and mediate macrophage polarization.Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis,creating an oxidative microenvironment that can cause abnormal apoptosis,epithelial to mesenchymal transition and genomic instability.Therefore,understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases.In this review,we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders,aiming to provide novel insights into understanding the mechanisms underlying these diseases.展开更多
Nicotinamide adenine dinucleotide phosphate oxidase(NOX) is a multisubunit enzyme complex that utilizes nicotinamide adenine dinucleotide phosphate to produce superoxide anions and other reactive oxygen species. Under...Nicotinamide adenine dinucleotide phosphate oxidase(NOX) is a multisubunit enzyme complex that utilizes nicotinamide adenine dinucleotide phosphate to produce superoxide anions and other reactive oxygen species. Under normal circumstances, reactive oxygen species mediate a number of important cellular functions, including the facilitation of adaptive immunity. In pathogenic circumstances, however,excess reactive oxygen species generated by NOX promotes apoptotic cell death. In ischemic stroke, in particular, it has been shown that both NOX activation and derangements in glucose metabolism result in increased apoptosis. Moreover, recent studies have established that glucose, as a NOX substrate, plays a vital role in the pathogenesis of reperfusion injury. Thus, NOX inhibition has the potential to mitigate the deleterious impact of hyperglycemia on stroke. In this paper, we provide an overview of this research,coupled with a discussion of its implications for the development of NOX inhibition as a strategy for the treatment of ischemic stroke. Both inhibition using apocynin, as well as the prospect of developing more specific inhibitors based on what is now understood of the biology of NOX assembly and activation, will be highlighted in the course of our discussion.展开更多
BACKGROUND Metabolic reprogramming plays a key role in cancer progression and clinical outcomes;however,the patterns and primary regulators of metabolic reprogramming in colorectal cancer(CRC)are not well understood.A...BACKGROUND Metabolic reprogramming plays a key role in cancer progression and clinical outcomes;however,the patterns and primary regulators of metabolic reprogramming in colorectal cancer(CRC)are not well understood.AIM To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)in promoting progression of CRC.METHODS We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes.Consensus clustering was used to cluster CRC based on dysregulated metabolic genes.A prediction model was constructed based on survival-related metabolic genes.Sphere formation,migration,invasion,proliferation,apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC.mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells.In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth.RESULTS We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes.Among these genes,NOX4 was highly expressed in tumor tissues and correlated with worse survival.In vitro,NOX4 overexpression induced clone formation,migration,invasion,and stemness in CRC cells.Furthermore,RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway.Trametinib,a MEK1/2 inhibitor,abolished the NOX4-mediated tumor progression.In vivo,NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis,whereas trametinib treatment can reversed the metastasis.CONCLUSION Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis,suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.展开更多
Objective:To investigate the mechanism of Panax notoginseng saponins(PNS),an effective component extracted from Panax notoginseng,on atherosclerotic plaque angiogenesis in atherosclerosis-prone apolipoprotein E-knocko...Objective:To investigate the mechanism of Panax notoginseng saponins(PNS),an effective component extracted from Panax notoginseng,on atherosclerotic plaque angiogenesis in atherosclerosis-prone apolipoprotein E-knockout(ApoE-KO) mice fed with high-fat,high-cholesterol diet.Methods:Twenty ApoE-KO mice were divided into two groups,the model group and the PNS group.Ten normal C57BL/6J mice were used as a control group.PNS(60 mg/kg) was orally administered daily for 12 weeks in the PNS group.The ratio of plaque area to vessel area was examined by histological staining.The tissue sample of aortic root was used to detect the CD34 and vascular endothelial growth factor(VEGF) expression areas by immunohistochemistry.The expression of VEGF and nicotinamide adenine dinucleotide phosphate oxidase subunit 4(NOX4) were measured by reverse transcription polymerase chain reaction and Western blotting respectively.Results:After treatment with PNS,the plaque areas were decreased(P<0.05).CD34 expressing areas and VEGF expression areas in plaques were significantly decreased(P<0.05).Meanwhile,VEGF and NOX4 mRNA expression were decreased after treatment with PNS.VEGF and NOX4 protein expression were also decreased by about 72% and 63%,respectively(P<0.01).Conclusion:PNS,which decreases VEGF and NOX4 expression,could alleviate plaque angiogenesis and attenuate atherosclerosis.展开更多
The activity of plasma membrane (PM) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and its catalytic properties in rice was investigated under drought stress conditions. Drought stress led to decreased l...The activity of plasma membrane (PM) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and its catalytic properties in rice was investigated under drought stress conditions. Drought stress led to decreased leaf relative water content (RWC) and, as a result of drought-induced oxidative stress, the activities of antioxidant enzymes increased significantly. More interestingly, the intensity of applied water stress was correlated with increased production of H2O2 and O2- and elevated activity of PM NADPH oxidase, a key enzyme of reactive oxygen species generation in plants. Histochemical analyses also revealed increased H2O2 and O2- production in drought-stressed leaves. Application of diphenylene iodonium (DPI), an inhibitor of PM NADPH oxidase, did not alleviate drought-induced production of H2O2 and O2-. Catalysis experiments indicated that the rice PM NADPH oxidase was partially flavin-dependent. The pH and temperature optima for this enzyme were 9.8 and 40 °C, respectively. In addition, drought stress enhanced the activity under alkaline pH and high temperature conditions. These results suggest that a complex regulatory mechanism, associated with the NADPH oxidase-H2O2 system, is involved in the response of rice to drought stress.展开更多
Tobacco BY-2 suspension cells were used to study the chemical damage and its associated mechanisms caused by Cu2+. Treatment with 100 μmol/L Cu2+ generated a large amount of H2O2 and thiobarbituric acid-reactive subs...Tobacco BY-2 suspension cells were used to study the chemical damage and its associated mechanisms caused by Cu2+. Treatment with 100 μmol/L Cu2+ generated a large amount of H2O2 and thiobarbituric acid-reactive substances (TBARS) in cells. Using phospholipase D (PLD) specific inhibitor (1-butanol) or phosphatidic acid (PA), we demonstrated that PLD plays an important role in the generation of H2O2 and TBARS. Semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme activity assays with wild type and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-overexpressing BY-2 cells revealed that PLD and PA are the key factors leading to NADPH oxidase activation, which is responsible for H2O2 and TBARS production induced by Cu2+. Moreover, the content of ascorbic acid (AsA), an effective antioxidant, was sharply reduced in BY-2 cells exposed to excessive Cu2+. Furthermore, a significant downregulation of the enzymes of AsA biosynthesis and the antioxidant system was found. This evidence suggests that excessive Cu2+-elevated reactive oxygen species (ROS) production is caused by upregulated PLD that elevates the activity of NADPH oxidase and its collapsed antioxidant systems that scavenges ROS.展开更多
基金Supported by Youth Independent Innovation Science Fund Project from Chinese PLA General Hospital,No.22QNFC075.
文摘Pancreatitis and pancreatic cancer(PC)stand as the most worrisome ailments affecting the pancreas.Researchers have dedicated efforts to unraveling the mechanisms underlying these diseases,yet their true nature continues to elude their grasp.Within this realm,oxidative stress is often believed to play a causal and contributory role in the development of pancreatitis and PC.Excessive accumulation of reactive oxygen species(ROS)can cause oxidative stress,and the key enzyme responsible for inducing ROS production in cells is nicotinamide adenine dinucleotide phosphate hydrogen oxides(NOX).NOX contribute to pancreatic fibrosis and inflammation by generating ROS that injure acinar cells,activate pancreatic stellate cells,and mediate macrophage polarization.Excessive ROS production occurs during malignant transformation and pancreatic carcinogenesis,creating an oxidative microenvironment that can cause abnormal apoptosis,epithelial to mesenchymal transition and genomic instability.Therefore,understanding the role of NOX in pancreatic diseases contributes to a more in-depth exploration of the exact pathogenesis of these diseases.In this review,we aim to summarize the potential roles of NOX and its mechanism in pancreatic disorders,aiming to provide novel insights into understanding the mechanisms underlying these diseases.
基金partially supported by Merit Review Award(I01RX-001964-01)from the US Department of Veterans Affairs Rehabilitation Research and Development Service(to YD)the National Natural Science Foundation of China(81501141)+1 种基金Beijing New Star of Science and Technology Program of China(xx2016061)Beijing Tongzhou District Financial Fund,and Scientific Research Common Program of Beijing Municipal Commission of Education,China(KM201610025028)(to XG)
文摘Nicotinamide adenine dinucleotide phosphate oxidase(NOX) is a multisubunit enzyme complex that utilizes nicotinamide adenine dinucleotide phosphate to produce superoxide anions and other reactive oxygen species. Under normal circumstances, reactive oxygen species mediate a number of important cellular functions, including the facilitation of adaptive immunity. In pathogenic circumstances, however,excess reactive oxygen species generated by NOX promotes apoptotic cell death. In ischemic stroke, in particular, it has been shown that both NOX activation and derangements in glucose metabolism result in increased apoptosis. Moreover, recent studies have established that glucose, as a NOX substrate, plays a vital role in the pathogenesis of reperfusion injury. Thus, NOX inhibition has the potential to mitigate the deleterious impact of hyperglycemia on stroke. In this paper, we provide an overview of this research,coupled with a discussion of its implications for the development of NOX inhibition as a strategy for the treatment of ischemic stroke. Both inhibition using apocynin, as well as the prospect of developing more specific inhibitors based on what is now understood of the biology of NOX assembly and activation, will be highlighted in the course of our discussion.
基金Supported by Henan Province Medical Science and Technology Research Provincial and Ministry Co-constructed Projects,No.SBGJ202101010Major Public Welfare Projects in Henan Province,No.201300310400+1 种基金Joint Construction Project of Henan Medical Science and Technology Research Plan,No.LHGJ20220050Major Science and Technology Project of Henan Province,No.221100310100.
文摘BACKGROUND Metabolic reprogramming plays a key role in cancer progression and clinical outcomes;however,the patterns and primary regulators of metabolic reprogramming in colorectal cancer(CRC)are not well understood.AIM To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)in promoting progression of CRC.METHODS We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes.Consensus clustering was used to cluster CRC based on dysregulated metabolic genes.A prediction model was constructed based on survival-related metabolic genes.Sphere formation,migration,invasion,proliferation,apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC.mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells.In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth.RESULTS We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes.Among these genes,NOX4 was highly expressed in tumor tissues and correlated with worse survival.In vitro,NOX4 overexpression induced clone formation,migration,invasion,and stemness in CRC cells.Furthermore,RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway.Trametinib,a MEK1/2 inhibitor,abolished the NOX4-mediated tumor progression.In vivo,NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis,whereas trametinib treatment can reversed the metastasis.CONCLUSION Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis,suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.
文摘目的 探究代谢相关脂肪性肝病(MAFLD)患者血清几丁质酶样蛋白40(YKL-40)、烟酰胺腺嘌呤二核苷酸磷酸氧化酶2(NOX2)表达水平,并分析其与肝纤维化的关系。方法 选取2020年4月至2021年12月于保定市人民医院就诊的108例MAFLD患者为MAFLD组,选取同期该院108例健康体检者为对照组。肝纤维化程度评估根据瞬时弹性成像技术所得肝脏硬度值分为非纤维化组(60例,肝脏硬度值<8.0 k Pa)和纤维化组(48例,肝脏硬度值≥8.0 k Pa)。比较研究对象YKL-40、NOX2及临床资料差异。logistic回归分析MAFLD患者发生肝纤维化的影响因素。受试者工作特征(ROC)曲线评价YKL-40、NOX2对肝纤维化的预测效能。结果 MAFLD组血清YKL-40、NOX2水平高于对照组,差异有统计学意义(P<0.05)。纤维化组YKL-40、NOX2水平高于非纤维化组,差异有统计学意义(P<0.05)。回归分析显示,年龄(OR=1.647,95%CI:1.053~2.575,P=0.029)、HOMA-IR(OR=1.758,95%CI:1.083~2.853,P=0.022)、YKL-40(OR=2.016,95%CI:1.237~3.284,P=0.004)、NOX2(OR=2.292,95%CI:1.388~3.786,P=0.001)是MAFLD患者发生肝纤维化的影响因素(P<0.05)。YKL-40、NOX2单独预测MAFLD患者肝纤维化的曲线下面积(AUC)分别为0.833、0.838,YKL-40联合NOX2预测MAFLD患者肝纤维化的AUC为0.922,优于单一指标(Z_(二者联合-YKL-40)=2.268,P=0.023、Z_(二者联合-NOX2)=1.999,P=0.046)。结论 YKL-40、NOX2在MAFLD患者血清中水平增加,且与肝纤维化相关,YKL-40联合NOX2可作为预测肝纤维化的生物标志物。
基金Supported by the Plans for the Development of Traditional Chinese Medicine Science and Technology of Shandong Province(No.2011-203)
文摘Objective:To investigate the mechanism of Panax notoginseng saponins(PNS),an effective component extracted from Panax notoginseng,on atherosclerotic plaque angiogenesis in atherosclerosis-prone apolipoprotein E-knockout(ApoE-KO) mice fed with high-fat,high-cholesterol diet.Methods:Twenty ApoE-KO mice were divided into two groups,the model group and the PNS group.Ten normal C57BL/6J mice were used as a control group.PNS(60 mg/kg) was orally administered daily for 12 weeks in the PNS group.The ratio of plaque area to vessel area was examined by histological staining.The tissue sample of aortic root was used to detect the CD34 and vascular endothelial growth factor(VEGF) expression areas by immunohistochemistry.The expression of VEGF and nicotinamide adenine dinucleotide phosphate oxidase subunit 4(NOX4) were measured by reverse transcription polymerase chain reaction and Western blotting respectively.Results:After treatment with PNS,the plaque areas were decreased(P<0.05).CD34 expressing areas and VEGF expression areas in plaques were significantly decreased(P<0.05).Meanwhile,VEGF and NOX4 mRNA expression were decreased after treatment with PNS.VEGF and NOX4 protein expression were also decreased by about 72% and 63%,respectively(P<0.01).Conclusion:PNS,which decreases VEGF and NOX4 expression,could alleviate plaque angiogenesis and attenuate atherosclerosis.
基金Supported by the National Natural Science Foundation of China under GrantNo. 30871469the Zhejiang Province Natural Science Foundation of China under Grant No. Y306087
文摘The activity of plasma membrane (PM) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and its catalytic properties in rice was investigated under drought stress conditions. Drought stress led to decreased leaf relative water content (RWC) and, as a result of drought-induced oxidative stress, the activities of antioxidant enzymes increased significantly. More interestingly, the intensity of applied water stress was correlated with increased production of H2O2 and O2- and elevated activity of PM NADPH oxidase, a key enzyme of reactive oxygen species generation in plants. Histochemical analyses also revealed increased H2O2 and O2- production in drought-stressed leaves. Application of diphenylene iodonium (DPI), an inhibitor of PM NADPH oxidase, did not alleviate drought-induced production of H2O2 and O2-. Catalysis experiments indicated that the rice PM NADPH oxidase was partially flavin-dependent. The pH and temperature optima for this enzyme were 9.8 and 40 °C, respectively. In addition, drought stress enhanced the activity under alkaline pH and high temperature conditions. These results suggest that a complex regulatory mechanism, associated with the NADPH oxidase-H2O2 system, is involved in the response of rice to drought stress.
基金the State Key Basic Research and Development Plan ofChina (2003CB114300 and 2006CB100100)the National Natural ScienceFoundation of China (30170088 and 30370120)the Doctoral ProgramFoundation of the Educational Ministry of China (20020019030).
文摘Tobacco BY-2 suspension cells were used to study the chemical damage and its associated mechanisms caused by Cu2+. Treatment with 100 μmol/L Cu2+ generated a large amount of H2O2 and thiobarbituric acid-reactive substances (TBARS) in cells. Using phospholipase D (PLD) specific inhibitor (1-butanol) or phosphatidic acid (PA), we demonstrated that PLD plays an important role in the generation of H2O2 and TBARS. Semi-quantitative reverse-transcriptase polymerase chain reaction and enzyme activity assays with wild type and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-overexpressing BY-2 cells revealed that PLD and PA are the key factors leading to NADPH oxidase activation, which is responsible for H2O2 and TBARS production induced by Cu2+. Moreover, the content of ascorbic acid (AsA), an effective antioxidant, was sharply reduced in BY-2 cells exposed to excessive Cu2+. Furthermore, a significant downregulation of the enzymes of AsA biosynthesis and the antioxidant system was found. This evidence suggests that excessive Cu2+-elevated reactive oxygen species (ROS) production is caused by upregulated PLD that elevates the activity of NADPH oxidase and its collapsed antioxidant systems that scavenges ROS.
