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
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...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 Westem 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
Background Increased production of reactive oxygen species （ROS） is thought to play a major role in the pathogenesis of obstructive sleep apnea-hypopnea syndrome （OSAHS）. The reduced nicotinamide adenine dinucleot...Background Increased production of reactive oxygen species （ROS） is thought to play a major role in the pathogenesis of obstructive sleep apnea-hypopnea syndrome （OSAHS）. The reduced nicotinamide adenine dinucleotide phosphate （NADPH） oxidase complex is an important source of ROS. The p22phox subunit is polymorphic with a C242T variant that changes histidine-72 for a tyrosine in the potential heme binding site. This study aimed to investigate the relationship between NADPH oxidase subunit p22phox gene polymorphism and OSAHS. Methods The genotypes of p22phox polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphisms （PCR-RFLP） assay in 176 unrelated subjects of the Han population in southern region of China （including 107 OSAHS subjects and 69 non-OSAHS subjects）, while the plasma concentration of superoxide dismutase （SOD） was detected in the two groups, and p22phox mRNA expression in peripheral blood mononuclear cell （PBMC） was determined with reverse transcription polymerase chain reaction （RT-PCR）. Results The phagocyte NADPH oxidase subunit p22phox mRNA expression was significantly increased in the OSAHS group than that in the non-OSAHS group （P 〈0.01）. Compared with the non-OSAHS control group （（85.31±9.23） U/ml）, the levels of SOD were lower in patients with OSAHS （（59.65±11.61） U/ml （P 〈0.01）. There were significant differences in genotypes distribution in p22phox polymorphism between the two groups （P=0.02）. Compared with the non-OSAHS control group, the OSAHS group had a significantly higher T allele frequency in p22phox polymorphism （P=0.03）. There were independent effects of p22phox polymorphism on body mass index （BMI）, neck circumference （NC）, waist-to-hip ratio （WHR） in the OSAHS group, and the carriers of the T allele of p22phox polymorphism had greater NC, WHR, systolic blood pressure （SBP）, diastolic blood pressure （DBP） and apnea-hypopnea index （AHI） （P 〈0.05）, but the carriers of the T allele had lower SOD （P 〈0.01） and lowest SaO2 （P=0.04）. There was no significant difference in p22phox mRNA expression between the OSAHS groups with or without T allele （P=0.45）. Conclusions The NADPH oxidase subunit p22phox gene polymorphism may be associated with susceptibility to OSAHS, and it may be an important candidate gene for OSAHS.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 decreas...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 fiavin-dependent. The pH and temperature optima for this enzyme were 9.8 and 40 ℃, 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 Cu^2＋. Treatment with 100 μmol/L Cu^2＋ generated a large amount of HzOz and thiobarbituric acid-reactive ...Tobacco BY-2 suspension cells were used to study the chemical damage and its associated mechanisms caused by Cu^2＋. Treatment with 100 μmol/L Cu^2＋ generated a large amount of HzOz 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） oxidaseoverexpressing 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 Cu^2＋. Moreover, the content of ascorbic acid （AsA）, an effective antioxidant, was sharply reduced in BY-2 cells exposed to excessive Cu^2＋. Furthermore, a significant downregulation of the enzymes of AsA biosynthesis and the antioxidant system was found. This evidence suggests that excessive Cu^2＋-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
Background The p22phox is a critical component of the superoxide-generating vascular nicotinamide adenine dinucleotide phosphate （NADPH） oxidase. Several polymorphisms in p22phox gene are studied for their associati...Background The p22phox is a critical component of the superoxide-generating vascular nicotinamide adenine dinucleotide phosphate （NADPH） oxidase. Several polymorphisms in p22phox gene are studied for their association with cardiovascular diseases. However, no publication is available to assess the relation of 549C〉T polymorphism in p22pho~ gene to coronary artery disease （CAD） risk. This study was to investigate the effect of the p22phox gene 549C〉T polymorphism on CAD risk. Methods Hospital-based case-control study was conducted with 297 CAD patients and 343 healthy persons as the control group. Polymerase chain reaction and pyrosequencing using PSQ 96 MA Pyrosequencer （Biotage AB） were used to detect the polymorphisms. Multiple Logistic regression model was used to adjust the potential confounders and to estimate odds ratio （OR） with 95% confidence intervals （CIs）. Results The observed genotype frequencies of this polymorphism obeyed the Hardy-Weinberg equilibrium in both cases （P=0.439） and controls （P=-0.668）. The frequency of mutant genotypes （＇I-I-＋CT） in cases （41.08%） was higher than that in controls （36.73%） with an OR=1.20 （95% C1=0.87-1.65）. After the adjustment of the potential confounders, there was a significant association of the mutant genotypes with increased risk of CAD （OR=1.57, 95% C1=1.01-2.46, P=0.047）. Conclusions The mutant genotypes of the p22phox gene 549C〉T polymorphism had a significant effect on the increased risk of CAD in this studied population.展开更多
Background Oxidative Stress and p38 mitogen-activated protein kinase （p38MAPK） play a vital role in renal fibrosis. Pioglitazone can protect kidney but the underlying mechanisms are less clear. The purpose of this s...Background Oxidative Stress and p38 mitogen-activated protein kinase （p38MAPK） play a vital role in renal fibrosis. Pioglitazone can protect kidney but the underlying mechanisms are less clear. The purpose of this study was to investigate the effect of pioglitazone on oxidative stress and whether the severity of oxidative stress was associated with the phosphorylation level of p38MAPK.展开更多
Studies have demonstrated that reactive oxygen species(ROS) are closely related to inflammatory disorders. Nicotinamide adenine dinucleotide phosphate oxidase(NOX), originally found in phagocytes, is the main source o...Studies have demonstrated that reactive oxygen species(ROS) are closely related to inflammatory disorders. Nicotinamide adenine dinucleotide phosphate oxidase(NOX), originally found in phagocytes, is the main source of ROS in nonphagocytic cells. Besides directly producing the detrimental highly reactive ROS to act on biomolecules(lipids, proteins, and nucleic acids), NOX can also activate multiple signal transduction pathways, which regulate cell growth, proliferation, differentiation and apoptosis by producing ROS. Recently, research on pancreatic NOX is no longer limited to inflammatory cells, but extends to the aspect of pancreatic acinar cells and pancreatic stellate cells, which are considered to be potentially associated with pancreatitis. In this review, we summarize the literature on NOX protein structure, activation, function and its role in the pathogenesis of pancreatitis.展开更多
AIM: To investigate the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in colon epithelial cells in the pathogenesis of acute and chronic colon inflammation in a mouse model of dextran sulphate so...AIM: To investigate the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in colon epithelial cells in the pathogenesis of acute and chronic colon inflammation in a mouse model of dextran sulphate sodium (DSS)-induced colitis.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
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 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 Westem 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.
文摘Background Increased production of reactive oxygen species （ROS） is thought to play a major role in the pathogenesis of obstructive sleep apnea-hypopnea syndrome （OSAHS）. The reduced nicotinamide adenine dinucleotide phosphate （NADPH） oxidase complex is an important source of ROS. The p22phox subunit is polymorphic with a C242T variant that changes histidine-72 for a tyrosine in the potential heme binding site. This study aimed to investigate the relationship between NADPH oxidase subunit p22phox gene polymorphism and OSAHS. Methods The genotypes of p22phox polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphisms （PCR-RFLP） assay in 176 unrelated subjects of the Han population in southern region of China （including 107 OSAHS subjects and 69 non-OSAHS subjects）, while the plasma concentration of superoxide dismutase （SOD） was detected in the two groups, and p22phox mRNA expression in peripheral blood mononuclear cell （PBMC） was determined with reverse transcription polymerase chain reaction （RT-PCR）. Results The phagocyte NADPH oxidase subunit p22phox mRNA expression was significantly increased in the OSAHS group than that in the non-OSAHS group （P 〈0.01）. Compared with the non-OSAHS control group （（85.31±9.23） U/ml）, the levels of SOD were lower in patients with OSAHS （（59.65±11.61） U/ml （P 〈0.01）. There were significant differences in genotypes distribution in p22phox polymorphism between the two groups （P=0.02）. Compared with the non-OSAHS control group, the OSAHS group had a significantly higher T allele frequency in p22phox polymorphism （P=0.03）. There were independent effects of p22phox polymorphism on body mass index （BMI）, neck circumference （NC）, waist-to-hip ratio （WHR） in the OSAHS group, and the carriers of the T allele of p22phox polymorphism had greater NC, WHR, systolic blood pressure （SBP）, diastolic blood pressure （DBP） and apnea-hypopnea index （AHI） （P 〈0.05）, but the carriers of the T allele had lower SOD （P 〈0.01） and lowest SaO2 （P=0.04）. There was no significant difference in p22phox mRNA expression between the OSAHS groups with or without T allele （P=0.45）. Conclusions The NADPH oxidase subunit p22phox gene polymorphism may be associated with susceptibility to OSAHS, and it may be an important candidate gene for OSAHS.
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 fiavin-dependent. The pH and temperature optima for this enzyme were 9.8 and 40 ℃, 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 Cu^2＋. Treatment with 100 μmol/L Cu^2＋ generated a large amount of HzOz 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） oxidaseoverexpressing 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 Cu^2＋. Moreover, the content of ascorbic acid （AsA）, an effective antioxidant, was sharply reduced in BY-2 cells exposed to excessive Cu^2＋. Furthermore, a significant downregulation of the enzymes of AsA biosynthesis and the antioxidant system was found. This evidence suggests that excessive Cu^2＋-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.
基金This study was sponsored by a grant from the Shandong Provincial Natural Science Foundation （No. Y2007C005）.
文摘Background The p22phox is a critical component of the superoxide-generating vascular nicotinamide adenine dinucleotide phosphate （NADPH） oxidase. Several polymorphisms in p22phox gene are studied for their association with cardiovascular diseases. However, no publication is available to assess the relation of 549C〉T polymorphism in p22pho~ gene to coronary artery disease （CAD） risk. This study was to investigate the effect of the p22phox gene 549C〉T polymorphism on CAD risk. Methods Hospital-based case-control study was conducted with 297 CAD patients and 343 healthy persons as the control group. Polymerase chain reaction and pyrosequencing using PSQ 96 MA Pyrosequencer （Biotage AB） were used to detect the polymorphisms. Multiple Logistic regression model was used to adjust the potential confounders and to estimate odds ratio （OR） with 95% confidence intervals （CIs）. Results The observed genotype frequencies of this polymorphism obeyed the Hardy-Weinberg equilibrium in both cases （P=0.439） and controls （P=-0.668）. The frequency of mutant genotypes （＇I-I-＋CT） in cases （41.08%） was higher than that in controls （36.73%） with an OR=1.20 （95% C1=0.87-1.65）. After the adjustment of the potential confounders, there was a significant association of the mutant genotypes with increased risk of CAD （OR=1.57, 95% C1=1.01-2.46, P=0.047）. Conclusions The mutant genotypes of the p22phox gene 549C〉T polymorphism had a significant effect on the increased risk of CAD in this studied population.
文摘Background Oxidative Stress and p38 mitogen-activated protein kinase （p38MAPK） play a vital role in renal fibrosis. Pioglitazone can protect kidney but the underlying mechanisms are less clear. The purpose of this study was to investigate the effect of pioglitazone on oxidative stress and whether the severity of oxidative stress was associated with the phosphorylation level of p38MAPK.
基金Supported by The National Natural Science Foundation of China,No.81173393the Natural Science Foundation of Tianjin City,No.12YFJZJC00800+1 种基金the Scientific Research Foundation(No.WHM201222,FYM201114)the Innovation Team Program(No.WHTD201310)from Logistics University of the Chinese People’s Armed Police Forces
文摘Studies have demonstrated that reactive oxygen species(ROS) are closely related to inflammatory disorders. Nicotinamide adenine dinucleotide phosphate oxidase(NOX), originally found in phagocytes, is the main source of ROS in nonphagocytic cells. Besides directly producing the detrimental highly reactive ROS to act on biomolecules(lipids, proteins, and nucleic acids), NOX can also activate multiple signal transduction pathways, which regulate cell growth, proliferation, differentiation and apoptosis by producing ROS. Recently, research on pancreatic NOX is no longer limited to inflammatory cells, but extends to the aspect of pancreatic acinar cells and pancreatic stellate cells, which are considered to be potentially associated with pancreatitis. In this review, we summarize the literature on NOX protein structure, activation, function and its role in the pathogenesis of pancreatitis.
文摘AIM: To investigate the role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in colon epithelial cells in the pathogenesis of acute and chronic colon inflammation in a mouse model of dextran sulphate sodium (DSS)-induced colitis.
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.
