Kay D Beharry, Charles L Cai, Gloria B Valencia, Arwin M Valencia, Douglas R Lazzaro, Fayez Bany-Mohammed, Jacob V Aranda
Most of the major morbidities in the preterm newborn are caused by or are associated with oxygen-induced injuries and are aptly called "oxygen radical diseases in neonatology or ORDIN". These include bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis and others. Relative hyperoxia immediately after birth, immature antioxidant systems, biomolecular events favoring oxidative stress such as iron availability and the role of hydrogen peroxide as a key molecular mediator of these events are reviewed. Potential therapeutic strategies such as caffeine, antioxidants, non-steroidal anti-inflammatory drugs, and others targeted to these critical sites may help prevent oxidative radical diseases in the newborn resulting in improved neonatal outcomes.
{"title":"Neonatal Intermittent Hypoxia, Reactive Oxygen Species, and Oxygen-Induced Retinopathy.","authors":"Kay D Beharry, Charles L Cai, Gloria B Valencia, Arwin M Valencia, Douglas R Lazzaro, Fayez Bany-Mohammed, Jacob V Aranda","doi":"10.20455/ros.2017.805","DOIUrl":"https://doi.org/10.20455/ros.2017.805","url":null,"abstract":"<p><p>Most of the major morbidities in the preterm newborn are caused by or are associated with oxygen-induced injuries and are aptly called \"oxygen radical diseases in neonatology or ORDIN\". These include bronchopulmonary dysplasia, retinopathy of prematurity, periventricular leukomalacia, intraventricular hemorrhage, necrotizing enterocolitis and others. Relative hyperoxia immediately after birth, immature antioxidant systems, biomolecular events favoring oxidative stress such as iron availability and the role of hydrogen peroxide as a key molecular mediator of these events are reviewed. Potential therapeutic strategies such as caffeine, antioxidants, non-steroidal anti-inflammatory drugs, and others targeted to these critical sites may help prevent oxidative radical diseases in the newborn resulting in improved neonatal outcomes.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.20455/ros.2017.805","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36264908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michelle Quan, Charles L Cai, Gloria B Valencia, Jacob V Aranda, Kay D Beharry
Retinopathy of prematurity is a blinding disease that affects extremely low gestational age neonates. Its etiology is due to extrauterinehyperoxia in an immature antioxidant system culminating as oxidative stress on the retina. Our aim is to elucidate the role of pharmacological antioxidants in modulating the biochemical and molecular response of human retinal microvascular endothelial cells (HRECs) exposed to oxidative stress. HRECs were treated with MnTBAP [a superoxide dismutase (SOD) mimetic], catalase, EUK-134 (SOD + catalase), or saline prior to exposure to normoxia (Nx), hyperoxia (Hx), or intermittent hypoxia (IH). Media levels of SOD, catalase, glutathione peroxidase (GPx), 8-isoPGF2α, and H2O2; cellular SOD and catalase; cellular function (migration and tube formation); and antioxidant gene expression were assessed. Pharmacological antioxidants had delayed suppressive effect on 8-isoPGF2α. MnTBAP and catalase were more effective for H2O2 scavenging in the media than co-administration in the form of EUK-134. A delayed response was noted in SOD and catalase media activity in MnTBAP- and catalase-treated cells, respectively in 50% and IH. MnTBAP had progressively increased media GPx in all oxygen conditions. Antioxidants resulted in normal, but more abundant tubulogenesis in IH and Hx. The distinct temporal response to oxidative stress reflected the respective antioxidant's potency and catalytic properties. The cell permeability of the antioxidants limited the ability to scavenge intracellular free radicals. The results support that MnTBAP or catalase may be more effective for the prevention of oxidative stress in oxygen-induced retinopathy.
{"title":"MnTBAP or Catalase Is More Protective against Oxidative Stress in Human Retinal Endothelial Cells Exposed to Intermittent Hypoxia than Their Co-Administration (EUK-134).","authors":"Michelle Quan, Charles L Cai, Gloria B Valencia, Jacob V Aranda, Kay D Beharry","doi":"10.20455/ros.2017.801","DOIUrl":"10.20455/ros.2017.801","url":null,"abstract":"<p><p>Retinopathy of prematurity is a blinding disease that affects extremely low gestational age neonates. Its etiology is due to extrauterinehyperoxia in an immature antioxidant system culminating as oxidative stress on the retina. Our aim is to elucidate the role of pharmacological antioxidants in modulating the biochemical and molecular response of human retinal microvascular endothelial cells (HRECs) exposed to oxidative stress. HRECs were treated with MnTBAP [a superoxide dismutase (SOD) mimetic], catalase, EUK-134 (SOD + catalase), or saline prior to exposure to normoxia (Nx), hyperoxia (Hx), or intermittent hypoxia (IH). Media levels of SOD, catalase, glutathione peroxidase (GPx), 8-isoPGF<sub>2α</sub>, and H<sub>2</sub>O<sub>2</sub>; cellular SOD and catalase; cellular function (migration and tube formation); and antioxidant gene expression were assessed. Pharmacological antioxidants had delayed suppressive effect on 8-isoPGF<sub>2α</sub>. MnTBAP and catalase were more effective for H<sub>2</sub>O<sub>2</sub> scavenging in the media than co-administration in the form of EUK-134. A delayed response was noted in SOD and catalase media activity in MnTBAP- and catalase-treated cells, respectively in 50% and IH. MnTBAP had progressively increased media GPx in all oxygen conditions. Antioxidants resulted in normal, but more abundant tubulogenesis in IH and Hx. The distinct temporal response to oxidative stress reflected the respective antioxidant's potency and catalytic properties. The cell permeability of the antioxidants limited the ability to scavenge intracellular free radicals. The results support that MnTBAP or catalase may be more effective for the prevention of oxidative stress in oxygen-induced retinopathy.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967656/pdf/nihms967268.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36135433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huntington's disease (HD) is a rare, inherited, progressive, and fatal neurological disorder resulting from expanded polyglutamine repeats in the huntingtin protein. While HD is predominately characterized as a disease of the central nervous system, mortality surveys and epidemiological studies reveal heart disease as one of the leading causes of death in HD patients. Emerging evidence supports a link between HD and cardiovascular disease, such as cardiac amyloidosis (accumulation of aggregates in the heart). Experimental animal and clinical studies have attempted to explain the mechanisms of HD-induced cardiac pathology in the association of protein misfolding, autophagic defects, oxidative stress, mitochondrial dysfunction, and cell death. HD is increasingly understood as a complex disease with peripheral components of cardiac and skeletal muscle pathophysiology. While the discovery of these linkages and apparent pathological markers is promising, the mechanism of HD-induced cardiac pathology and the nature of its cell autonomy remain elusive. Further study of the wide-ranging cardiac function in HD patients is needed. This review highlights published literature on the pathological factors associated with HD-induced cardiac amyloidosis and other cardiovascular diseases, and addresses gaps in this expanding area of study. Through comprehensive experimental and clinical studies, potential drugs can be tested to attenuate and/or ameliorate HD-induced cardiac pathology and mortality.
亨廷顿氏病(Huntington's disease,HD)是一种罕见的遗传性、进行性和致命性神经系统疾病,由亨廷丁蛋白中的多聚谷氨酰胺重复序列扩增引起。虽然 HD 的主要特征是中枢神经系统疾病,但死亡率调查和流行病学研究显示,心脏病是导致 HD 患者死亡的主要原因之一。新的证据表明,HD 与心血管疾病(如心脏淀粉样变性(聚集在心脏中))之间存在联系。实验动物和临床研究试图从蛋白质错误折叠、自噬缺陷、氧化应激、线粒体功能障碍和细胞死亡等方面解释 HD 诱发心脏病变的机制。人们越来越认识到,HD 是一种复杂的疾病,具有心脏和骨骼肌病理生理学的外围成分。虽然发现这些联系和明显的病理标志物很有希望,但 HD 引发心脏病理变化的机制及其细胞自主性的性质仍然难以捉摸。需要对 HD 患者广泛的心脏功能进行进一步研究。本综述重点介绍了已发表的与 HD 诱导的心脏淀粉样变性和其他心血管疾病相关的病理因素的文献,并探讨了这一不断扩大的研究领域中存在的差距。通过全面的实验和临床研究,可以对潜在的药物进行测试,以减轻和/或改善 HD 引起的心脏病理变化和死亡率。
{"title":"Huntington's Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways.","authors":"Girish C Melkani","doi":"10.20455/ros.2016.859","DOIUrl":"10.20455/ros.2016.859","url":null,"abstract":"<p><p>Huntington's disease (HD) is a rare, inherited, progressive, and fatal neurological disorder resulting from expanded polyglutamine repeats in the huntingtin protein. While HD is predominately characterized as a disease of the central nervous system, mortality surveys and epidemiological studies reveal heart disease as one of the leading causes of death in HD patients. Emerging evidence supports a link between HD and cardiovascular disease, such as cardiac amyloidosis (accumulation of aggregates in the heart). Experimental animal and clinical studies have attempted to explain the mechanisms of HD-induced cardiac pathology in the association of protein misfolding, autophagic defects, oxidative stress, mitochondrial dysfunction, and cell death. HD is increasingly understood as a complex disease with peripheral components of cardiac and skeletal muscle pathophysiology. While the discovery of these linkages and apparent pathological markers is promising, the mechanism of HD-induced cardiac pathology and the nature of its cell autonomy remain elusive. Further study of the wide-ranging cardiac function in HD patients is needed. This review highlights published literature on the pathological factors associated with HD-induced cardiac amyloidosis and other cardiovascular diseases, and addresses gaps in this expanding area of study. Through comprehensive experimental and clinical studies, potential drugs can be tested to attenuate and/or ameliorate HD-induced cardiac pathology and mortality.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022757/pdf/nihms966717.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36276014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hong Zhu, Zhenquan Jia, Michael A Trush, Y Robert Li
Hydrogen peroxide (H2O2) is a major reactive oxygen species (ROS) produced by various cellular sources, especially mitochondria. At high levels, H2O2 causes oxidative stress, leading to cell injury, whereas at low concentrations, this ROS acts as an important second messenger to participate in cellular redox signaling. Detection and measurement of the levels or rates of production of cellular H2O2 are instrumental in studying the biological effects of this major ROS. While a number of assays have been developed over the past decades for detecting and/or quantifying biological H2O2formation, none has been shown to be perfect. Perhaps there is no perfect assay for sensitively and accurately quantifying H2O2 as well as other ROS in cells, wherein numerous potential reactants are present to interfere with the reliable measurement of the specific ROS. In this context, each assay has its own advantages and intrinsic limitations. This article describes a highly sensitive assay for real-time detection of H2O2 formation in cultured cells and isolated mitochondria. This assay is based on the luminol/horseradish peroxidase-dependent chemiluminescence that is inhibitable by catalase. The article discusses the usefulness and shortcomings of this chemiluminometric assay in detecting biological H2O2 formation induced by beta-lapachone redox cycling with both cells and isolated mitochondria.
{"title":"A Highly Sensitive Chemiluminometric Assay for Real-Time Detection of Biological Hydrogen Peroxide Formation.","authors":"Hong Zhu, Zhenquan Jia, Michael A Trush, Y Robert Li","doi":"10.20455/ros.2016.841","DOIUrl":"https://doi.org/10.20455/ros.2016.841","url":null,"abstract":"<p><p>Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) is a major reactive oxygen species (ROS) produced by various cellular sources, especially mitochondria. At high levels, H<sub>2</sub>O<sub>2</sub> causes oxidative stress, leading to cell injury, whereas at low concentrations, this ROS acts as an important second messenger to participate in cellular redox signaling. Detection and measurement of the levels or rates of production of cellular H<sub>2</sub>O<sub>2</sub> are instrumental in studying the biological effects of this major ROS. While a number of assays have been developed over the past decades for detecting and/or quantifying biological H<sub>2</sub>O<sub>2</sub>formation, none has been shown to be perfect. Perhaps there is no perfect assay for sensitively and accurately quantifying H<sub>2</sub>O<sub>2</sub> as well as other ROS in cells, wherein numerous potential reactants are present to interfere with the reliable measurement of the specific ROS. In this context, each assay has its own advantages and intrinsic limitations. This article describes a highly sensitive assay for real-time detection of H<sub>2</sub>O<sub>2</sub> formation in cultured cells and isolated mitochondria. This assay is based on the luminol/horseradish peroxidase-dependent chemiluminescence that is inhibitable by catalase. The article discusses the usefulness and shortcomings of this chemiluminometric assay in detecting biological H<sub>2</sub>O<sub>2</sub> formation induced by beta-lapachone redox cycling with both cells and isolated mitochondria.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959035/pdf/nihms966438.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36115046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Early work in the 1970s by Linus Pauling, a twice-honored Nobel laureate, led to his proposal of using high-dose vitamin C to treat cancer patients. Over the past several decades, a number of studies in animal models as well as several small-scale clinical studies have provided substantial support of Linus Pauling's early proposal. Production of reactive oxygen species (ROS) via oxidation of vitamin C appears to be a major underlying event, leading to the selective killing of cancer cells. However, it remains unclear how vitamin C selectively kills cancer cells while sparing normal cells and what the molecular targets of high-dose vitamin C are. In a recent article published in Science (2015 December 11; 350(6266):1391-6. doi: 10.1126/science.aaa5004), Yun et al. reported that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) through an ROS-dependent mechanism. This work by Yun et al. along with other findings advances our current understanding of the molecular basis of high-dose vitamin C-mediated cancer cell killing, which will likely give an impetus to the continued research efforts aiming to further decipher the novel biochemistry of vitamin C and its unique role in cancer therapy.
{"title":"Vitamin C, a Multi-Tasking Molecule, Finds a Molecular Target in Killing Cancer Cells.","authors":"Robert Li","doi":"10.20455/ros.2016.829","DOIUrl":"https://doi.org/10.20455/ros.2016.829","url":null,"abstract":"<p><p>Early work in the 1970s by Linus Pauling, a twice-honored Nobel laureate, led to his proposal of using high-dose vitamin C to treat cancer patients. Over the past several decades, a number of studies in animal models as well as several small-scale clinical studies have provided substantial support of Linus Pauling's early proposal. Production of reactive oxygen species (ROS) via oxidation of vitamin C appears to be a major underlying event, leading to the selective killing of cancer cells. However, it remains unclear how vitamin C selectively kills cancer cells while sparing normal cells and what the molecular targets of high-dose vitamin C are. In a recent article published in Science (2015 December 11; 350(6266):1391-6. doi: 10.1126/science.aaa5004), Yun et al. reported that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) through an ROS-dependent mechanism. This work by Yun et al. along with other findings advances our current understanding of the molecular basis of high-dose vitamin C-mediated cancer cell killing, which will likely give an impetus to the continued research efforts aiming to further decipher the novel biochemistry of vitamin C and its unique role in cancer therapy.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959041/pdf/nihms966425.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36115045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity and protein and mRNA levels. This induction was blunted in CYP2E1 knockout mice and by a CYP2E1 inhibitor, but was restored in CYP2E1 knockin mice, suggesting a role for CYP2E1 in the induction of CYP2A5 by alcohol. Since CYP2E1 actively generates ROS, the possible role of ROS in the induction of CYP2A5 by alcohol was determined. ROS production was elevated by ethanol treatment. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol-induced elevation of ROS and blunted the alcohol-mediated induction of CYP2A5. These results suggest that ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. Alcohol treatment activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor which up-regulates expression of CYP2A5. The antioxidants blocked the activation of Nrf2. The alcohol-induced elevation of CYP2A5, but not CYP2E1, was lower in Nrf2 knockout mice. We propose that increased generation of ROS from the alcohol-induced CYP2E1 activates Nrf2, which subsequently up-regulates the expression of CYP2A5. Thus, a novel consequence of the alcohol-mediated induction of CYP2E1 and increase in ROS is the activation of redox-sensitive transcription factors, such as Nrf2, and expression of CYP2A5. Further perspectives on this alcohol-CYP2E1-ROS-Nrf2-CYP2A5 pathway are presented.
{"title":"Alcohol Upregulation of CYP2A5: Role of Reactive Oxygen Species.","authors":"Yongke Lu, Arthur I Cederbaum","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity and protein and mRNA levels. This induction was blunted in CYP2E1 knockout mice and by a CYP2E1 inhibitor, but was restored in CYP2E1 knockin mice, suggesting a role for CYP2E1 in the induction of CYP2A5 by alcohol. Since CYP2E1 actively generates ROS, the possible role of ROS in the induction of CYP2A5 by alcohol was determined. ROS production was elevated by ethanol treatment. The antioxidants <i>N</i>-acetyl cysteine and vitamin C lowered the alcohol-induced elevation of ROS and blunted the alcohol-mediated induction of CYP2A5. These results suggest that ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. Alcohol treatment activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor which up-regulates expression of CYP2A5. The antioxidants blocked the activation of Nrf2. The alcohol-induced elevation of CYP2A5, but not CYP2E1, was lower in Nrf2 knockout mice. We propose that increased generation of ROS from the alcohol-induced CYP2E1 activates Nrf2, which subsequently up-regulates the expression of CYP2A5. Thus, a novel consequence of the alcohol-mediated induction of CYP2E1 and increase in ROS is the activation of redox-sensitive transcription factors, such as Nrf2, and expression of CYP2A5. Further perspectives on this alcohol-CYP2E1-ROS-Nrf2-CYP2A5 pathway are presented.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944604/pdf/nihms948930.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36095117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity and protein and mRNA levels. This induction was blunted in CYP2E1 knockout mice and by a CYP2E1 inhibitor, but was restored in CYP2E1 knockin mice, suggesting a role for CYP2E1 in the induction of CYP2A5 by alcohol. Since CYP2E1 actively generates ROS, the possible role of ROS in the induction of CYP2A5 by alcohol was determined. ROS production was elevated by ethanol treatment. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol-induced elevation of ROS and blunted the alcohol-mediated induction of CYP2A5. These results suggest that ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. Alcohol treatment activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor which up-regulates expression of CYP2A5. The antioxidants blocked the activation of Nrf2. The alcohol-induced elevation of CYP2A5, but not CYP2E1, was lower in Nrf2 knockout mice. We propose that increased generation of ROS from the alcohol-induced CYP2E1 activates Nrf2, which subsequently up-regulates the expression of CYP2A5. Thus, a novel consequence of the alcohol-mediated induction of CYP2E1 and increase in ROS is the activation of redox-sensitive transcription factors, such as Nrf2, and expression of CYP2A5. Further perspectives on this alcohol-CYP2E1-ROS-Nrf2-CYP2A5 pathway are presented.
{"title":"Alcohol Upregulation of CYP2A5: Role of Reactive Oxygen Species.","authors":"Yongke Lu, A. Cederbaum","doi":"10.20455/ros.2016.823","DOIUrl":"https://doi.org/10.20455/ros.2016.823","url":null,"abstract":"Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity and protein and mRNA levels. This induction was blunted in CYP2E1 knockout mice and by a CYP2E1 inhibitor, but was restored in CYP2E1 knockin mice, suggesting a role for CYP2E1 in the induction of CYP2A5 by alcohol. Since CYP2E1 actively generates ROS, the possible role of ROS in the induction of CYP2A5 by alcohol was determined. ROS production was elevated by ethanol treatment. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol-induced elevation of ROS and blunted the alcohol-mediated induction of CYP2A5. These results suggest that ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. Alcohol treatment activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor which up-regulates expression of CYP2A5. The antioxidants blocked the activation of Nrf2. The alcohol-induced elevation of CYP2A5, but not CYP2E1, was lower in Nrf2 knockout mice. We propose that increased generation of ROS from the alcohol-induced CYP2E1 activates Nrf2, which subsequently up-regulates the expression of CYP2A5. Thus, a novel consequence of the alcohol-mediated induction of CYP2E1 and increase in ROS is the activation of redox-sensitive transcription factors, such as Nrf2, and expression of CYP2A5. Further perspectives on this alcohol-CYP2E1-ROS-Nrf2-CYP2A5 pathway are presented.","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"67595076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01Epub Date: 2016-05-30DOI: 10.20455/ros.2016.853
Hong Zhu, Zhenquan Jia, Michael A Trush, Y Robert Li
The role of Nrf2, a key regulator of antioxidant and cytoprotective genes, in tumorigenesis remains controversial. Here we showed that Nrf2 deficiency led to increased local tumor growth in mice following subcutaneous injection of B16-F10 melanoma cells, as indicated by increased proportion of animals with locally palpable tumor mass and time-dependent increases in tumor volume at the injection site. In vivo bioluminescence imaging also revealed increased growth of melanoma in Nrf2-null mice as compared with wild-type mice. By using a highly sensitive bioluminometric assay, we further found that Nrf2 deficiency resulted in a remarkable increase in lung metastasis of B16-F10 melanoma cells as compared with wild-type mice. Taken together, the results of this short communication for the first time demonstrated that Nrf2 deficiency promoted melanoma growth and lung metastasis following subcutaneous inoculation of B16-F10 cells in mice.
{"title":"Nrf2 Deficiency Promotes Melanoma Growth and Lung Metastasis.","authors":"Hong Zhu, Zhenquan Jia, Michael A Trush, Y Robert Li","doi":"10.20455/ros.2016.853","DOIUrl":"10.20455/ros.2016.853","url":null,"abstract":"<p><p>The role of Nrf2, a key regulator of antioxidant and cytoprotective genes, in tumorigenesis remains controversial. Here we showed that Nrf2 deficiency led to increased local tumor growth in mice following subcutaneous injection of B16-F10 melanoma cells, as indicated by increased proportion of animals with locally palpable tumor mass and time-dependent increases in tumor volume at the injection site. In vivo bioluminescence imaging also revealed increased growth of melanoma in Nrf2-null mice as compared with wild-type mice. By using a highly sensitive bioluminometric assay, we further found that Nrf2 deficiency resulted in a remarkable increase in lung metastasis of B16-F10 melanoma cells as compared with wild-type mice. Taken together, the results of this short communication for the first time demonstrated that Nrf2 deficiency promoted melanoma growth and lung metastasis following subcutaneous inoculation of B16-F10 cells in mice.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926243/pdf/nihms960687.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36066142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-01Epub Date: 2016-05-25DOI: 10.20455/ros.2016.851
Rayudu Gopalakrishna, Usha Gundimeda, Sarah Zhou, Kristen Zung, Kaitlyn Forell, Arne Holmgren
Although several experimental studies showed cancer-preventive efficacy of supplemental dietary selenium, human clinical trials questioned this efficacy. Identifying its molecular targets and mechanism is important in understanding this discrepancy. Methylselenol, the active metabolite of selenium, reacts with lipid hydroperoxides bound to protein kinase C (PKC) and is oxidized to methylseleninic acid (MSA). This locally generated MSA selectively inactivates PKC by oxidizing its critical cysteine sulfhydryls. The peroxidatic redox cycle occurring in this process may explain how extremely low concentrations of selenium catalytically modify specific membrane-bound proteins compartmentally separated from glutathione and selectively induce cytotoxicity in promoting cells. Mammalian thioredoxin reductase (TR) is itself a selenoenzyme with a catalytic selenocysteine residue. Together with thioredoxin (Trx), it catalyzes reduction of selenite and selenocystine by NADPH generating selenide which in the presence of oxygen redox cycles producing reactive oxygen species. Trx binds with high affinity to PKC and reverses PKC inactivation. Therefore, established tumor cells overexpressing TR and Trx may escape the cancer-preventive actions of selenium. This suggests that in some cases, certain selenoproteins may counteract selenometabolite actions. Lower concentrations of selenium readily inactivate antiapoptotic PKC isoenzymes e and a which have a cluster of vicinal thiols, thereby inducing apoptosis. Higher concentrations of selenium also inactivate proapoptotic enzymes such as proteolytically activated PKCd fragment, holo-PKCz, caspase-3, and c-Jun N-terminal kinase, which all have a limited number of critical cysteine residues and make tumor cells resistant to selenium-induced apoptosis. This may explain the intriguing U-shaped curve that is seen with dietary selenium intake and the extent of cancer prevention.
虽然一些实验研究表明补充膳食硒具有预防癌症的功效,但人体临床试验对这种功效提出了质疑。确定其分子靶点和机制对于理解这种差异具有重要意义。甲基硒醇是硒的活性代谢物,与蛋白激酶C (PKC)结合的脂质氢过氧化物反应,氧化生成甲基硒酸(MSA)。这种局部生成的MSA通过氧化PKC的关键半胱氨酸巯基选择性地灭活PKC。在这个过程中发生的过氧化物氧化还原循环可以解释极低浓度的硒如何催化修饰从谷胱甘肽分离的特定膜结合蛋白,并选择性地诱导细胞毒性。哺乳动物硫氧还蛋白还原酶(TR)本身是一种具有催化硒半胱氨酸残基的硒酶。它与硫氧还氧蛋白(Trx)一起,通过NADPH催化亚硒酸盐和硒半胱氨酸的还原,产生硒化物,在氧氧化还原循环中产生活性氧。Trx以高亲和力结合PKC并逆转PKC失活。因此,过度表达TR和Trx的肿瘤细胞可能会逃避硒的防癌作用。这表明在某些情况下,某些硒蛋白可能会抵消硒代谢物的作用。较低浓度的硒容易使PKC抗凋亡同工酶e和a失活,这些同工酶具有邻近巯基簇,从而诱导细胞凋亡。较高浓度的硒还会使促凋亡酶失活,如蛋白水解激活的PKCd片段、holo-PKCz、caspase-3和c-Jun n -末端激酶,这些酶都具有有限数量的关键半胱氨酸残基,使肿瘤细胞对硒诱导的凋亡具有抗性。这或许可以解释膳食硒摄入量与癌症预防程度之间的有趣u型曲线。
{"title":"Imbalance in Protein Thiol Redox Regulation and Cancer-Preventive Efficacy of Selenium.","authors":"Rayudu Gopalakrishna, Usha Gundimeda, Sarah Zhou, Kristen Zung, Kaitlyn Forell, Arne Holmgren","doi":"10.20455/ros.2016.851","DOIUrl":"https://doi.org/10.20455/ros.2016.851","url":null,"abstract":"<p><p>Although several experimental studies showed cancer-preventive efficacy of supplemental dietary selenium, human clinical trials questioned this efficacy. Identifying its molecular targets and mechanism is important in understanding this discrepancy. Methylselenol, the active metabolite of selenium, reacts with lipid hydroperoxides bound to protein kinase C (PKC) and is oxidized to methylseleninic acid (MSA). This locally generated MSA selectively inactivates PKC by oxidizing its critical cysteine sulfhydryls. The peroxidatic redox cycle occurring in this process may explain how extremely low concentrations of selenium catalytically modify specific membrane-bound proteins compartmentally separated from glutathione and selectively induce cytotoxicity in promoting cells. Mammalian thioredoxin reductase (TR) is itself a selenoenzyme with a catalytic selenocysteine residue. Together with thioredoxin (Trx), it catalyzes reduction of selenite and selenocystine by NADPH generating selenide which in the presence of oxygen redox cycles producing reactive oxygen species. Trx binds with high affinity to PKC and reverses PKC inactivation. Therefore, established tumor cells overexpressing TR and Trx may escape the cancer-preventive actions of selenium. This suggests that in some cases, certain selenoproteins may counteract selenometabolite actions. Lower concentrations of selenium readily inactivate antiapoptotic PKC isoenzymes e and a which have a cluster of vicinal thiols, thereby inducing apoptosis. Higher concentrations of selenium also inactivate proapoptotic enzymes such as proteolytically activated PKCd fragment, holo-PKCz, caspase-3, and c-Jun N-terminal kinase, which all have a limited number of critical cysteine residues and make tumor cells resistant to selenium-induced apoptosis. This may explain the intriguing U-shaped curve that is seen with dietary selenium intake and the extent of cancer prevention.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961735/pdf/nihms966547.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36127166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell cycle progression requires the destruction of key cell cycle regulators by the multi-subunit E3 ligase called the anaphase promoting complex (APC/C). As the cell progresses through the cell cycle, the APC/C is sequentially activated by two highly conserved co-activators called Cdc20 and Cdh1. Importantly, APC/CCdc20 is required to degrade substrates in G2/M whereas APCCdh1 drives the cells into G1. Recently, Parkin, a monomeric E3 ligase that is required for ubiquitin-mediated mitophagy following mitochondrial stress, was shown to both bind and be activated by Cdc20 or Cdh1 during the cell cycle. This mitotic role for Parkin does not require an activating phosphorylation by its usual kinase partner PINK. Rather, mitotic Parkin activity requires phosphorylation on a different serine by the polo-like kinase Plk1. Interestingly, although ParkinCdc20 and ParkinCdh1 activity is independent of the APC/C, it mediates degradation of an overlapping subset of substrates. However, unlike the APC/C, Parkin is not necessary for cell cycle progression. Despite this, loss of Parkin activity accelerates genome instability and tumor growth in xenograft models. These findings provide a mechanism behind the previously described, but poorly understood, tumor suppressor role for Parkin. Taken together, studies suggest that the APC/C and Parkin have similar and unique roles to play in cell division, possibly being dependent upon the different subcellular address of these two ligases.
{"title":"Parkin New Cargos: a New ROS Independent Role for Parkin in Regulating Cell Division.","authors":"David C Stieg, Katrina F Cooper","doi":"10.20455/ros.2016.857","DOIUrl":"https://doi.org/10.20455/ros.2016.857","url":null,"abstract":"<p><p>Cell cycle progression requires the destruction of key cell cycle regulators by the multi-subunit E3 ligase called the anaphase promoting complex (APC/C). As the cell progresses through the cell cycle, the APC/C is sequentially activated by two highly conserved co-activators called Cdc20 and Cdh1. Importantly, APC/C<sup>Cdc20</sup> is required to degrade substrates in G2/M whereas APC<sup>Cdh1</sup> drives the cells into G1. Recently, Parkin, a monomeric E3 ligase that is required for ubiquitin-mediated mitophagy following mitochondrial stress, was shown to both bind and be activated by Cdc20 or Cdh1 during the cell cycle. This mitotic role for Parkin does not require an activating phosphorylation by its usual kinase partner PINK. Rather, mitotic Parkin activity requires phosphorylation on a different serine by the polo-like kinase Plk1. Interestingly, although Parkin<sup>Cdc20</sup> and Parkin<sup>Cdh1</sup> activity is independent of the APC/C, it mediates degradation of an overlapping subset of substrates. However, unlike the APC/C, Parkin is not necessary for cell cycle progression. Despite this, loss of Parkin activity accelerates genome instability and tumor growth in xenograft models. These findings provide a mechanism behind the previously described, but poorly understood, tumor suppressor role for Parkin. Taken together, studies suggest that the APC/C and Parkin have similar and unique roles to play in cell division, possibly being dependent upon the different subcellular address of these two ligases.</p>","PeriodicalId":91793,"journal":{"name":"Reactive oxygen species (Apex, N.C.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597248/pdf/nihms845938.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35521245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}