scholarly journals Apocynin Attenuates Cerebral Infarction after Transient Focal Ischaemia in Rats

2007 ◽  
Vol 35 (4) ◽  
pp. 517-522 ◽  
Author(s):  
LL Tang ◽  
K Ye ◽  
XF Yang ◽  
JS Zheng
Keyword(s):  
Nadph Oxidase ◽  
Cerebral Infarction ◽  
Infarct Size ◽  
Oxidase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Treated Group ◽  
Oxidase Inhibitor ◽  
Sprague Dawley ◽  
Nadph Oxidase Activity ◽  
Focal Ischaemia

This study investigated whether inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase attenuates cerebral infarction after transient focal ischaemia in rats. Focal ischaemia (1.5 h) was produced in male Sprague-Dawley rats (250 − 280 g) by middle cerebral artery occlusion. Some rats also received treatment with 50 mg/kg apocynin, a NADPH oxidase inhibitor, by intraperitoneal injection 30 min prior to reperfusion. Two hours after reperfusion, brains were harvested to measure NADPH oxidase activity and superoxide levels. After 24 h, the remaining brains were harvested to investigate infarct size. NADPH oxidase activity and superoxide level were all augmented 2 h after reperfusion compared with controls. Apocynin treatment significantly reduced NADPH oxidase activity and superoxide levels. Cerebral infarct size was significantly smaller in the apocynin-treated group compared with those undergoing ischaemia/reperfusion alone. These results indicate that inhibition of NADPH oxidase attenuates cerebral infarction after transient focal ischaemia in rats, suggesting that inhibition of NADPH oxidase may provide a therapeutic strategy for ischaemic stroke.

scholarly journals PKC-α mediates flow-stimulated superoxide production in thick ascending limbs

2010 ◽  
Vol 298 (4) ◽  
pp. F885-F891 ◽  
Author(s):  
Nancy J. Hong ◽  
Guillermo B. Silva ◽  
Jeffrey L. Garvin
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Mesangial Cells ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Oxidase Inhibitor ◽  
Dominant Negative ◽  
Aortic Endothelial Cells ◽  
Nadph Oxidase Activity ◽  
Measured Flow

We showed that luminal flow increases net superoxide (O2−) production via NADPH oxidase in thick ascending limbs. Protein kinase C (PKC) activates NADPH oxidase activity in phagocytes, cardiomyocytes, aortic endothelial cells, vascular smooth muscle cells, and renal mesangial cells. However, the flow-activated pathway that induces NADPH oxidase activity in thick ascending limbs is unclear. We hypothesized that PKC mediates flow-stimulated net O2− production by thick ascending limbs. Initiation of flow (20 nl/min) increased net O2− production from 4 ± 1 to 61 ± 12 AU/s ( P < 0.007; n = 5). The NADPH oxidase inhibitor apocynin completely blocked the flow-induced increase in net O2− production (2 ± 1 vs. 1 ± 1 AU/s; P > 0.05; n = 5). Flow-stimulated O2− was also blocked in p47phox-deficient mice. We measured flow-stimulated PKC activity with a fluorescence resonance energy transfer (FRET)-based membrane-targeted PKC activity reporter and found that the FRET ratio increased from 0.87 ± 0.02 to 0.96 ± 0.04 AU ( P < 0.05; n = 6). In the absence of flow, the PKC activator phorbol 12-myristate 13-acetate (200 nM) enhanced net O2− production from 5 ± 2 to 92 ± 6 AU/s ( P < 0.001; n = 6). The PKC-α- and βI-selective inhibitor Gö 6976 (100 nM) decreased flow-stimulated net O2− production from 54 ± 15 to 2 ± 1 AU/s ( P < 0.04; n = 5). Flow-induced net O2− production was inhibited in thick ascending limbs transduced with dominant-negative (dn)PKC-α but not dnPKCβI or LacZ (Δ = 11 ± 3 AU/s for dnPKCα, 55 ± 7 AU/s for dnPKCβI, and 63 ± 7 AU/s for LacZ; P < 0.001; n = 6). We concluded that flow stimulates net O2− production in thick ascending limbs via PKC-α-mediated activation of NADPH oxidase.

scholarly journals Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat

2008 ◽  
Vol 295 (1) ◽  
pp. E103-E109 ◽  
Author(s):  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
Shawna A. Cooper ◽  
Vincent G. DeMarco ◽  
Melvin R. Hayden ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Myocardial Remodeling ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Nadph Oxidase Activity ◽  
Renin Inhibition

Angiotensin II (Ang II) stimulation of the Ang type 1 receptor (AT1R) facilitates myocardial remodeling through NADPH oxidase-mediated generation of oxidative stress. Components of the renin-angiotensin system constitute an autocrine/paracrine unit in the myocardium, including renin, which is the rate-limiting step in the generation of Ang II. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo renin inhibition and/or AT1R blockade in a rodent model of chronically elevated tissue Ang II levels, the transgenic (mRen2)27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, and cardiovascular damage. Young (6- to 7-wk-old) heterozygous (+/−) male Ren2 and age-matched Sprague-Dawley rats were treated with the renin inhibitor aliskiren, which has high preferential affinity for human and mouse renin, an AT1R blocker, irbesartan, or placebo for 3 wk. Myocardial NADPH oxidase activity and immunostaining for NADPH oxidase subunits and 3-nitrotyrosine were evaluated and remodeling changes assessed by light and transmission electron microscopy. Blood pressure, myocardial NADPH oxidase activity and subunit immunostaining, 3-nitrotyrosine, perivascular fibrosis, mitochondrial content, and markers of activity were significantly increased in Ren2 compared with SD littermates. Both renin inhibition and blockade of the AT1R significantly attenuated cardiac functional and structural alterations, although irbesartan treatment resulted in greater reductions of both blood pressure and markers of oxidative stress. Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure.

scholarly journals The Post-Ischemic Increase in GluA2 Ser880 Phosphorylation Involves NADPH Oxidase

2018 ◽  
Vol 4 (1) ◽  
pp. 170-181
Author(s):  
Darrell A. Jackson ◽  
Fanny Astruc-Diaz ◽  
Nicole M. Byrnes ◽  
Phillip H. Beske
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Hippocampal Slices ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Glucose Deprivation ◽  
Subunit Composition ◽  
Stress Signaling ◽  
Scaffolding Proteins ◽  
Nadph Oxidase Activity

Most 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptors (AMPARs) expressed on adult hippocampal pyramidal neurons contain the edited form of GluA2 (Q607R) and are thus impermeable to Ca2+/Zn2+ entry.  Following ischemic injury, these receptors undergo a subunit composition change, switching from a GluA2-containing Ca2+/Zn2+-impermeable AMPAR to a GluA2-lacking Ca2+/Zn2+-permeable AMPAR. Recent studies indicate that an oxidative stress signaling pathway is responsible for the I/R-induced changes in AMPAR subunit composition.  Studies suggest that nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), a superoxide generator, is the source that initiates the oxidative stress-signaling cascade during post-ischemic reperfusion. The objective of the present study was to determine if suppression of NADPH oxidase activity prevents the increase in phosphorylation and subsequent internalization of the GluA2 AMPAR subunit during reperfusion of post-ischemic hippocampal slices. In this study, we demonstrated that exposure of adult rat hippocampal slices to oxygen glucose deprivation/reperfusion (OGD/R) results in an increase in Ser880 phosphorylation of the GluA2 subunit.  The increase in Ser880 phosphorylation resulted in the dissociation of GluA2 from the scaffolding proteins Glutamate receptor-interacting protein 1 (GRIP1) and AMPAR binding protein (ABP), thus enabling the association of GluA2 with protein interacting with C kinase 1 (PICK1). OGD/R also resulted in an increase in the association of activated protein kinase C ? (PKC?) with PICK1. We have found that pharmacological inhibition of NADPH oxidase with apocynin diminishes the OGD/R-induced increase in activated PKC? association with PICK1 and subsequent Ser880 phosphorylation of GluA2. Suppression of NADPH oxidase activity also blunted OGD/R-induced decreased association of GluA2 with the scaffolding proteins GRIP1 and ABP.  Protein phosphatase 2A (PP2A), which regulates PKC? activity by dephosphorylating the kinase, was inactivated by OGD/R-induced increase in tyrosine phosphorylation of the phosphatase (Y307). Inhibition of NADPH oxidase activity ameliorated OGD/R-induced PP2A phosphorylation and inactivation. Our findings are consistent with a model of OGD/R-induced Ser880 phosphorylation of GluA2 that implicates NADPH oxidase mediated inactivation of PP2A and sustained PKC? phosphorylation of GluA2.

Abstract 352: Anti-aging Gene Klotho Deficiency Causes Hypertension and Vascular Dysfunction via Upregulation of Mammalian Target of Rapamycin (mTOR)

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ying Song ◽  
Zhongjie Sun
Keyword(s):  
Blood Pressure ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Aging Process ◽  
Vascular Dysfunction ◽  
Mammalian Target Of Rapamycin ◽  
Genetic Mutation ◽  
Oxidase Inhibitor ◽  
Nadph Oxidase Activity ◽  
Induced Hypertension

Klotho is a recently discovered anti-aging gene. Genetic mutation of klotho expedites the aging process and shortens the lifespan while overexpression of klotho slows down the aging process and extends the lifespan by 20%. Interestingly, blood pressure (BP) was elevated significantly and vasodilatory responses to acetylcholine and sodium nitroprusside were impaired in klotho heterozygeous (+/-) mice, suggesting that klotho deficiency causes hypertension and vascular dysfunction. It is noted that klotho deficiency is associated with upregulation of mTOR expression and NADPH oxidase activity and downregulation of Mn-SOD expression in aortas and kidneys. Inhibition of mTOR by rapamycin abolished the upregulation of NADPH oxidase activity and O 2 - production and the downregulation of Mn-SOD expression and decreased BP to the control levels. Inhibition of mTOR also abolished vascular endothelial dysfunction and macrophage infiltration in kidneys in klotho (+/-) mice. The upregulation of NADPH oxidase activity and downregulation of Mn-SOD may be involved in klotho deficiency-induced hypertension which can be decreased significantly by apocynin (NADPH oxidase inhibitor) or Tempol (O 2 - scavenger). These results demonstrate, for the first time, that klotho is essential in the maintenance of normal blood pressure. Klotho deficiency-induced hypertension and vascular dysfunction are mediated by upregulation of mTOR. This study also reveals a previously unidentified role of mTOR in the regulation of NADPH oxidase and MnSOD. (Supported by HL105302 and HL102074).

scholarly journals Alteration of the Gut Microbiota and Its Effect on AMPK/NADPH Oxidase Signaling Pathway in 2K1C Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Hui Yu ◽  
Lei Qin ◽  
Hai Hu ◽  
Zhanli Wang
Keyword(s):  
Gut Microbiota ◽  
Nadph Oxidase ◽  
Signaling Pathway ◽  
Oxidase Activity ◽  
High Throughput Sequencing ◽  
Plasma Concentrations ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Adenosine Monophosphate ◽  
Short Chain Fatty Acids ◽  
Nadph Oxidase Activity

Background. The purpose of this study was to evaluate the alteration of the gut microbiota and its effect on adenosine monophosphate-activated protein kinase (AMPK)/nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) signaling pathway in two-kidney one-clip (2K1C) rats. Methods. The 2K1C rat models were established. The rats were randomly divided into the following 2 groups: 2K1C group and sham group. Alterations of the gut microbiota were analyzed based on the high throughput sequencing method. Plasma concentrations of short chain fatty acids (SCFAs) were measured by chromatography. The protein expression of phosphorylated AMPK and acetyl-CoA carboxylase (ACC) was determined by western blotting. NADPH oxidase activity was measured by a luminometer. Results. Microbial community analyses revealed that the structure and composition of the gut microbiota were significantly disrupted in 2K1C rats when compared to sham rats. This disruption was associated with the drastic increase in relative abundance of the genera Prevotella and the decrease in SCFA-producing bacterial population. We further confirm that SCFAs produced by the gut microbiota influence NADPH oxidase activity through AMPK. Conclusions. Our data implicated the important role of gut microbiota in the regulation of AMPK/NADPH oxidase signaling pathway.

Abstract WP274: Inhibition of Na+/H+ Exchanger Isoform 1 and/or Voltage Gated Proton Channel Improves Outcomes in an Embolic Stroke Model

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Rebecca Ward ◽  
Jingping Sun ◽  
Xinyue Guo ◽  
Adviye Ergul ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Infarct Size ◽  
Oxidase Activity ◽  
Embolic Stroke ◽  
Proton Channel ◽  
Experimental Stroke ◽  
Dependent Manner ◽  
Nadph Oxidase Activity ◽  
Voltage Gated ◽  
Significant Difference

While Na+/H+ exchanger isoform 1 inhibitor (NHEi) has been reported to be neuro- and cardio-protective in experimental stroke and myocardial infarction, respectively, clinical use of NHEi for cardioprotection has stalled due to increased cerebrovascular events. NHEi has been demonstrated to increase Hv1 activity and we recently showed that NHEi activates NADPH oxidase and results in amplified superoxide formation in a voltage gated proton channel Hv1-dependent manner. In the CNS, Hv1 is localized primarily to microglia and deletion of Hv1 is neuroprotective after permanent and transient middle cerebral artery occlusion (MCAO). In the current study, we hypothesized that beneficial effect of NHEi after MCAO will be greater in a rat model lacking Hv1 due to loss of a potentially deleterious increase in Hv1 activation and NADPH oxidase activity. The wild type (WT) and Hv1 knockout (KO) rats (n=4-6) were treated with vehicle or NHEi (KR-32568, 2 mg/kg, i.v.) at 30 min after embolic MCAO. The neurological deficiency, infarct size, HT index, and edema ratio were assessed 3 days after surgery (Table). Compare to WT rats, KO rats had smaller infarct, less edema, and better neurological outcomes as previously found in the suture model. NHEi decreased infarct size and edema in both strains. While there was no significant difference in HT between WT and KO rats, the HT was less in WT rats with NHEi. Functional outcomes were significantly improved with NHEi in WT group, while the KO groups had a trend for a better outcomes with NHEi. These data indicate that NHE inhibition in the acute stroke period is similarly effective in both WT and Hv1 KO animals in providing neurovascular protection. Our data do not support the hypothesis that a deleterious increase in Hv1 dependent NADPH oxidase activity limits the beneficial actions of NHEi in embolic stroke. Further studies are needed to explore the underlying mechanism of the interaction between NHEi and the Hv1 channel in ischemic stroke.

Potential sources of oxidative stress that induce postexercise proteinuria in rats

2008 ◽  
Vol 104 (4) ◽  
pp. 1063-1068 ◽  
Author(s):  
Günnur Koçer ◽  
Ümit Kemal Şentürk ◽  
Oktay Kuru ◽  
Filiz Gündüz
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Protein Carbonyl ◽  
Exhaustive Exercise ◽  
Carbonyl Content ◽  
Protein Carbonyl Content ◽  
Nadph Oxidase Activity ◽  
Exercise Induced

Exercise-induced proteinuria is a common consequence of physical activity and is caused predominantly by alterations in renal hemodynamics. Although it has been shown that exercise-induced oxidative stress can also contribute to the occurrence of postexercise proteinuria, the sources of reactive oxygen species that promote it are unknown. We investigated the enzymes nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase (XO) as possible sources of oxidative stress in postexercise proteinuria. First, we evaluated the effect of blocking the NADPH oxidase enzyme on postexercise proteinuria. We found a significant increase in urinary protein level, kidney thiobarbituric acid-reactive substances (TBARS), and protein carbonyl content after exhaustive exercise, and NADPH oxidase activity was induced by exercise. Rats that were treated with an NADPH oxidase inhibitor for 4 days before exhaustive exercise showed no increase in kidney TBARS or protein carbonyl derivative level and no proteinuria or NADPH oxidase activation. In the next set of experiments, we investigated the effect of XO blockage on postexercise proteinuria. Oxypurinol, an XO inhibitor was administered to rats for 3 days before exercise. Although XO inhibition significantly decreased kidney TBARS levels and protein carbonyl content in exercised rats, the inhibition did not prevent exercise-induced proteinuria. However, plasma and kidney XO activity was not induced by exercise, but rather it was suppressed under oxypurinol treatment. These results suggest that increased NADPH oxidase activity induced by exhaustive exercise is an important source of elevated oxidative, stress during exercise, which contributes to the occurrence of postexercise proteinuria.

scholarly journals NADPH oxidase is involved in regulation of gene expression and ROS overproduction in soybean (Glycine max L.) seedlings exposed to cadmium

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Jagna Chmielowska-Bąk ◽  
Magdalena Arasimowicz-Jelonek ◽  
Karolina Izbiańska ◽  
Marina Frontasyeva ◽  
Inga Zinicovscaia ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Regulation Of Gene Expression ◽  
Cadmium Stress ◽  
Oxidase Inhibitor ◽  
Short Term ◽  
Cd Uptake ◽  
Nadph Oxidase Activity ◽  
Soybean Seedlings

Cadmium-induced oxidative burst is partially mediated by NADPH oxidase. The aim of the present research was to evaluate the role of NADPH oxidase in soybeans’ response to short-term cadmium stress. The application of an NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI), affected expression of two Cd-inducible genes, encoding DOF1 and MYBZ2 transcription factors. This effect was observed after 3 h of treatment. Interestingly, Cd-dependent increases in NADPH oxidase activity occurred only after a period of time ranging from 6 and 24 h of stress. Stimulation of the enzyme correlated in time with a significant accumulation of reactive oxygen species (ROS). Further analysis revealed that pharmacological inhibition of NADPH oxidase activity during 24 h of Cd stress does not affect Cd uptake, seedling growth, or the level of lipid peroxidation. The role of NADPH oxidase in the response of soybean seedlings to short-term Cd exposure is discussed.

D5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure

2006 ◽  
Vol 290 (1) ◽  
pp. R96-R104 ◽  
Author(s):  
Zhiwei Yang ◽  
Laureano D. Asico ◽  
Peiying Yu ◽  
Zheng Wang ◽  
John E. Jones ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Reactive Oxygen ◽  
Receptor Activation ◽  
Oxidase Inhibitor ◽  
Ros Production ◽  
Oxygen Species ◽  
Nadph Oxidase Activity

Activation of D1-like receptors (D1 and/or D5) induces antioxidant responses; however, the mechanism(s) involved in their antioxidant actions are not known. We hypothesized that stimulation of the D5 receptor inhibits NADPH oxidase activity, and thus the production of reactive oxygen species (ROS). We investigated this issue in D5 receptor-deficient (D5−/−) and wild-type (D5+/+) mice. NADPH oxidase protein expression (gp91phox, p47phox, and Nox 4) and activity in kidney and brain, as well as plasma thiobarbituric acid-reactive substances (TBARS) were higher in D5−/− than in D5+/+ mice. Furthermore, apocynin, an NADPH oxidase inhibitor, normalized blood pressure, renal NADPH oxidase activity, and plasma TBARS in D5−/− mice. In HEK-293 cells that heterologously expressed human D5 receptor, its agonist fenoldopam decreased NADPH oxidase activity, expression of one of its subunits (gp91phox), and ROS production. The inhibitory effect of the D5 receptor activation on NADPH oxidase activity was independent of cAMP/PKA but was partially dependent on phospholipase D2. The ability of D5 receptor stimulation to decrease ROS production may explain, in part, the antihypertensive action of D5 receptor activation.

scholarly journals Ca2+/Nicotinamide Adenine Dinucleotide Phosphate-Dependent H2O2 Generation Is Inhibited by Iodide in Human Thyroids

2001 ◽  
Vol 86 (9) ◽  
pp. 4339-4343 ◽  
Author(s):  
Luciene C. Cardoso ◽  
Denise C. L. Martins ◽  
Marcia D. L. Figueiredo ◽  
Doris Rosenthal ◽  
Mario Vaisman ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Thyroid Nodules ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nadph Oxidase Activity ◽  
Thyroid Hormone Biosynthesis ◽  
H2o2 Generation ◽  
Toxic Goiter ◽  
Cold Thyroid Nodules

A calcium and NAD(P)H-dependent H2O2-generating activity has been studied in paranodular thyroid tissues from four patients with cold thyroid nodules and from nine diffuse toxic goiters. H2O2 generation was detected both in the particulate (P 3,000 g) and in the microsomal (P 100,000 g) fractions of paranodular tissue surrounding cold thyroid nodules (PN), with the same biochemical properties described for NADPH oxidase found in porcine and human thyroids. In PN tissues, the particulate NADPH oxidase activity (224 ± 38 nmol H2O2·h−1·mg−1 protein) was similar to that described for the porcine thyroid enzyme. However, no NADPH oxidase activity was detectable in the particulate fractions from eight diffuse toxic goiter patients treated with iodine before surgery; all but one also received propylthiouracil or methimazole in the preoperative period. Thyroid cytochrome c reductase (diffuse toxic goiters = 438 ± 104 nmol NADP+·h−1·mg−1 protein; PN = 78 ± 10 nmol NADP+·h−1·mg−1 protein) and thyroperoxidase (diffuse toxic goiters = 621 ± 179 U·g−1 protein; PN = 232 ± 121 U·g−1 protein) activities were unaffected by iodide. Thus, the human NADPH oxidase seems to be inhibited by iodinated compounds in vivo and probably is an enzyme involved in the Wolff-Chaikoff effect. Our findings reinforce the hypothesis that thyroid NADPH oxidase is responsible for the production of H2O2 necessary for thyroid hormone biosynthesis.

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