Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The NAD(P)H oxidase in the syncytiotrophoblast of the term human placenta, which had previously been identified only by cytochemical methods, has been solubilized and a number of its biochemical properties have been defined. It is a protein composed of a 58 kDa and a 33 kDa subunit, with properties that clearly distinguish it from the respiratory burst oxidase of transient neutrophils and macrophages. The enzyme activity is constitutive in the trophoblast and is a source of reactive oxygen species (ROS) at the fetal-maternal interface.
Placenta 2001 Jan
PMID:Human placental NAD(P)H oxidase: solubilization and properties. 1116 53

Though various tissue macrophages possess high glucose-6-phosphate dehydrogenase (G6PD) activity, which plays an important role in their phagocytosis/bactericidal function, the presence of this enzyme in human placental villous macrophages (Hofbauer cells) has not been determined. We examined the ultrastructural localization of glucose-6-phosphate dehydrogenase (G6PD) in Hofbauer cells in first and second trimester placental villi, using a newly developed enzyme-cytochemistry (copper-ferrocyanide) method. Electron-dense deposits indicative of G6PD activity were clearly visible in the cytoplasm and on the cytosolic side of the endoplasmic reticulum of Hofbauer cells. Positive and negative cytochemical controls ensured specific detection of enzyme activity. These observations indicated that Hofbauer cells abundantly possessed enzyme-cytochemically detectable G6PD activity. Hofbauer cell G6PD may play a role in placental defense, by supplying NADPH-dependent enzymes (i.e. nitric oxide synthase or NADPH oxidase) with NADPH. This enzyme may also fuel Hofbauer cells with ribose 5-phosphate during their cell proliferation and cell division.
Placenta 2001 Nov
PMID:Enzyme-cytochemically detectable glucose-6-phosphate dehydrogenase in human villous macrophages (Hofbauer cells). 1171 77

Placental oxidative stress has been implicated in pre-eclampsia and miscarriage. The review briefly summarizes the definition of oxidative stress, methods of estimation and likely sources in the placenta. Experimental evidence favouring a role for trophoblast oxidative stress in pre-eclampsia includes reports of lipid peroxidation and deficiencies in antioxidant defences. The potential sources of free radical generation include enhanced enzymatic synthesis of superoxide by xanthine oxidase and NAD(P)H oxidase. Studies employing immunohistochemical markers of oxidative stress also implicate free radical induced damage in placentae from women with early pregnancy loss. The overwhelming evidence for oxidative stress in the placenta and the maternal circulation in pre-eclampsia has led to the suggestion that antioxidant prophylaxis may prevent oxidant stress and so ameliorate or prevent the disease. Several clinical trials currently underway will not only determine whether antioxidants are of use in pre-eclampsia prevention but also provide an ideal opportunity to investigate the aetiology and consequences of trophoblast oxidative stress.
Placenta 2004 Apr
PMID:Trophoblast oxidative stress, antioxidants and pregnancy outcome--a review. 1503 11

Oxidative stress plays an important role in the development of pre-eclampsia. Recently, the superoxide producing enzyme NAD(P)H oxidase was shown to be present in placental trophoblast. In this pilot-study we investigated the NAD(P)H oxidase associated superoxide production as modulator of placental oxidative stress in normotensive pregnancy (n = 19; gestational age 38(+6)+/-0(+1)weeks(+days)) and pre-eclampsia (n = 15; gestational age 34(+3)+/-1(+5)weeks(+days)) using a lucigenin assay. Specificity of superoxide generation by NAD(P)H oxidase was assessed using the inhibitors L-NAME, rotenone, allopurinol, DPI and TIRON. Superoxide production was measurable in all placenta tissues and was inhibited by DPI and TIRON. No significant differences for total superoxide production (O2*total), maximal superoxide production (O2*max), or the rate of superoxide production were found between normotensive and pre-eclamptic women. However, women with early onset of disease had a higher O2*total as compared to those with a late onset disease. We conclude that human placenta contains a functional NAD(P)H oxidase that is highly active, which could be an important source of superoxide during pregnancy and pre-eclampsia. These data justify more detailed investigation of the role of NAD(P)H oxidase and placental oxidative stress in complicated pregnancies.
Placenta 2004 Apr
PMID:NAD(P)H oxidase associated superoxide production in human placenta from normotensive and pre-eclamptic women. 1503 13

Increased oxidative stress in the placenta has been associated with preeclampsia (PE), a clinical syndrome involving placental pathology. The enzymatic sources of reactive oxygen species in the human placenta are as yet unidentified. We hypothesized that NADPH oxidase is a main source of reactive oxygen species in the placenta and its expression may change in PE. Employing RT-PCR, we have amplified a novel NADPH oxidase isoform Nox1 from human choriocarcinoma BeWo cells. Using polyclonal anti-peptide antiserum recognizing unique Nox1 peptide sequences, we identified by immunohistochemistry and cell fractionation that Nox1 protein localizes in the BeWo cell membrane structures. Immunohistochemistry of normal placental tissues showed that Nox1 was localized in syncytiotrophoblasts, in villous vascular endothelium, and in some stromal cells. At the immunohistochemical level Nox1 expression was significantly increased in syncytiotrophoblast and endothelial cells in placentas from patients with preeclampsia as compared to gestational age-matched controls. Western blot analysis of whole placental homogenate confirmed this increase. Our data suggests that increased Nox1 expression is associated with the increased oxidative stress found in these placentas.
Placenta
PMID:Expression of NADPH oxidase isoform 1 (Nox1) in human placenta: involvement in preeclampsia. 1599 42

Early placental development is characterised by rapid cell differentiation and migration, matrix remodelling and angiogenesis. The enzyme NAD(P)H oxidase is a major source of superoxide anions implicated in signalling pathways regulating these processes in other systems. It is also thought to be involved in oxygen sensing and regulation of the expression of antioxidant genes. We therefore investigated NAD(P)H oxidase activity in placental tissues in early pregnancy and at term, and correlated this with antioxidant capacity. We collected placental tissues from women undergoing termination of pregnancy (n=19; gestational age 11(+6)+/-1(+0) weeks), and those with elective caesarean section at term after uncomplicated pregnancy (n=15; gestational age 38(+6)+/-0(+4) weeks). Tissues were assayed for superoxide production, using lucigenin chemiluminescence, and three independent markers of antioxidant capacity. In human placentas from normal deliveries at term substantial basal NAD(P)H activity was present. Activity was almost threefold higher in early pregnancy (P<0.0001). This was paralleled by higher total antioxidant capacity (P<0.0001), tissue glutathione concentrations (P<0.01) and gluthathione S-transferase enzyme activity (P<0.05) when compared to corresponding term placental values. NAD(P)H oxidase mediated superoxide generation could be an important modulator of the antioxidant defence response in early pregnancy.
Placenta
PMID:Placental NAD(P)H oxidase mediated superoxide generation in early pregnancy. 1633 60

Hyperuricemia, a common clinical characteristic of preeclamptic pregnancies, has historically been considered a marker of reduced renal function in preeclamptic women. More recently it has been suggested that uric acid may directly contribute to pathological cell signaling events involved in disease progression as well as maternal and fetal pregnancy outcomes including fetal growth restriction. We hypothesize that the increased frequency of restricted fetal growth seen in relation to increasing uric acid concentrations in preeclamptic women is in part the result of uric acid-induced reductions in amino acid transport across the placenta. The objective of the current study was to examine the effects of uric acid on human placental System A amino acid transport using a primary placental villous explant model. Further, we examined the necessity of uric acid uptake and the role of redox signaling as a potential mechanism through which uric acid may attenuate System A activity. Placental uptake of a radiolabeled amino acid analogue, specific to the System A transporter, was reduced in a concentration-dependent fashion with increasing uric acid (0-7 mg/dL), corresponding to uric acid concentrations measured in healthy pregnant and preeclamptic women in the third trimester. Uric acid-induced reduction in System A activity was partially reversed by NADPH oxidase inhibition and completely eliminated by antioxidant treatment. This study demonstrates inhibition of placental System A amino acid transport with uric acid treatment, as a result of uric acid-induced stimulation of intracellular redox signaling cascades. These findings may be relevant to the increased frequency of fetal growth restriction observed in hyperuricemic preeclampsia. Additionally the results of this study, indicating a detrimental effect of hyperuricemia on amino acid transport in the placenta, at concentrations present in women with preeclampsia, also suggest a role for uric acid in the pathophysiology of preeclampsia.
Placenta 2009 Feb
PMID:Uric acid inhibits placental system A amino acid uptake. 1905 47

The placenta regulates fetal growth and development via transport of nutrients and gases, and synthesis and secretion of steroid and peptide hormones. These functions are determined by vascular development and blood flow and by growth and differentiation of the trophoblast, which contains receptors, transporters and enzymes. The placenta generates reactive oxygen species which may contribute to the oxidative stress seen even in normal pregnancy but this is increased in pregnancies complicated by preeclampsia, IUGR and pregestational diabetes where oxidative and nitrative stress have been clearly documented. Nitrative stress is the covalent modification of proteins and DNA by peroxynitrite formed by the interaction of superoxide and nitric oxide. We have demonstrated nitrative stress by localizing nitrotyrosine residues in these placentas and found increased expression of NADPH oxidase (NOX) enzyme isoforms 1 and 5 as a potential source of superoxide generation. The presence of nitrative stress was associated with diminished vascular reactivity of the fetal placental circulation, a situation that could be reproduced by treatment with peroxynitrite in vitro. We find many nitrated proteins in the placenta, including p38 MAP kinase which has a role in development of the villous vasculature. Nitration of p38 MAPK was increased in the preeclamptic placenta and associated with loss of catalytic activity. We hypothesize that nitration of proteins in the placenta including receptors, transporters, enzymes and structural proteins can alter protein and placental function and this influences fetal growth and development. Increasing nitrative stress but a decrease in oxidative stress, measured as protein carbonylation, is found in the placenta with increasing BMI. Formation of peroxynitrite may then consume superoxide, decreasing nitrative stress. As protein carbonylation is a covalent modification at Lys, Arg, Pro and Thr residues the switch from carbonylation to nitration at tyrosine residues may alter protein function and hence placental function.
Placenta 2010 Mar
PMID:Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta. 2011 Jan 25

Accumulation of advanced oxidation protein products (AOPPs) is prevalent in obesity, advanced maternal age, diabetes mellitus, and polycystic ovary syndrome. Alterations in the regulation and signaling of angiogenic pathways have been recognized as a link between these conditions and pre-eclampsia. To investigate the possible impact of AOPPs on soluble Fms-like tyrosine kinase 1 (sFlt-1) expression in trophoblasts. A trophoblast cell line (HRT-8/SVneo) was treated with various concentrations of AOPPs. The mRNA expression of sFlt-1, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in trophoblasts were measured with the use of real-time polymerase chain reaction; and the secretion of sFlt-1, VEGF, and PlGF protein from trophoblasts were detected with the use of ELISA. Exposure of HRT-8/SVneo cells to AOPPs induced overexpression of sFlt-1 at mRNA and protein levels in a dose dependent manner. These effects could be inhibited by apocynin, an inhibitors of NADPH oxidase. Our data identified AOPPs as a class of important mediator in the regulation and signaling of angiogenic pathways of trophoblasts. Accumulation of AOPPs might contributes to the pathogenesis of preeclampsia by promoting sFlt-1 production in trophoblasts.
Placenta 2013 Oct
PMID:Advanced oxidation protein products enhances soluble Fms-like tyrosine kinase 1 expression in trophoblasts: a possible link between oxidative stress and preeclampsia. 2389 70

Although abnormal soluble fms-like tyrosine kinase-1 (sFlt-1) production is thought to be an important factor in the pathogenesis of pre-eclampsia, the mechanisms that regulate the production of sFlt-1 during pre-eclampsia are unclear. Accumulation of advanced glycation end products (AGEs) is prevalent in obesity, advanced maternal age, diabetes mellitus, and polycystic ovary syndrome. Alterations in the regulation and signaling of angiogenic pathways have been considered as a link between these conditions and pre-eclampsia. The purpose of this study was to explore the possible effects of AGEs on sFlt-1 secretion in extravillous trophoblasts (EVT). A EVT cell line (HRT-8/SVneo) was treated with various concentrations of AGEs-BSA. The mRNA expression of sFlt-1, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in EVT were detected with real-time polymerase chain reaction. The secretion of sFlt-1, VEGF, and PlGF protein from EVT was measured with ELISA. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. Exposure of EVT to AGEs-BSA induced increased intracellular ROS generation and overexpression of sFlt-1 at mRNA and protein levels in a dose dependent manner. Anti-RAGE immunoglobulin G or apocynin (an inhibitors of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. Our data suggested that AGEs may be a new class of important mediator in the regulation of angiogenic pathways of EVT. Accumulation of AGEs might contribute to the pathogenesis of preeclampsia by promoting sFlt-1 production through activation of RAGE/NADPH oxidase dependent pathway in EVT.
Placenta 2013 Dec
PMID:Advanced glycation end products as an upstream molecule triggers ROS-induced sFlt-1 production in extravillous trophoblasts: a novel bridge between oxidative stress and preeclampsia. 2414 48


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