Abstract W P230: Tetrahydrobiopterin Attenuates Cerebrovascular Oxidative Stress in Tg2576 Mouse Model of Alzheimer’s Disease

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Anantha Vijay R Santhanam ◽  
Livius V d'Uscio ◽  
Zvonimir S Katusic
Keyword(s):  
Oxidative Stress ◽  
Enzymatic Activity ◽  
Superoxide Anion ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Cerebral Microvessels ◽  
Double Mutation ◽  
Enos Uncoupling ◽  
Anion Production ◽  
Tg2576 Mice

Background: The present study was designed to test the hypothesis that supplementation of tetrahydrobiopterin (BH4) to transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (Tg2576 mice) results in restoration of BH4 levels required for activation of endothelial nitric oxide synthase (eNOS), and in turn, prevents oxidative stress in cerebral microvasculature. Methods: Cerebral microvessels were obtained from 4-5 months old female wild-type and Tg2576 mice. Biopterin levels, enzymatic activity of GTP cyclohydrolase I (GTPCH-I) and superoxide production were measured by HPLC. The effects of supplementation of BH4 on oxidative stress were studied by injecting wild-type and Tg2576 mice subcutaneously with 100 mol/kg (b.w.) of BH 4 ([ 6R ]-5,6,7,8-tetrahydro-L-biopterin dihydrochloride; [ 6R ]-BH4). Results: Enzymatic activity of GTPCH-I, rate limiting enzyme in BH4 biosynthesis, was not different between cerebral microvessels of wild-type and Tg2576 mice. However, bioavailability of BH4, was significantly reduced in cerebral microvessels of Tg2576 mice (P<0.05, n=8). Production of superoxide anions was significantly elevated in cerebral microvessels of Tg2576 mice (P<0.01, n=6), indicative of oxidative stress. This increased superoxide anion production was abolished by L-NAME, a NOS inhibitor, suggestive of eNOS uncoupling (P<0.05, n=6). Supplementation of [ 6R ]-BH4 to wild-type and Tg2576 mice resulted in significant increase in BH4 bioavailability (P<0.05, n=6). Notably, supplementation of [ 6R ]-BH4 abrogated the increase in superoxide anion production in cerebral microvessels of Tg2576 mice (P<0.05, n=5), while superoxide anion production remained unchanged in cerebral microvessels of WT mice. Furthermore, the inhibitory effects of L-NAME on superoxide anion production in cerebral microvessels of Tg2576 mice were abolished following [ 6R ]-BH4 supplementation (P<0.05, n=4). Conclusion: Supplementation of [ 6R ]-BH4 restored bioavailability of BH4, thereby abrogating superoxide anion production derived from eNOS. Our results suggest that uncoupling of eNOS contributes to oxidative stress in cerebral microvessels of Tg2576 mice.

Acute infusion of nicotine impairs nNOS-dependent reactivity of cerebral arterioles via an increase in oxidative stress

2007 ◽  
Vol 103 (6) ◽  
pp. 2062-2067 ◽  
Author(s):  
Denise M. Arrick ◽  
William G. Mayhan
Keyword(s):  
Oxidative Stress ◽  
Superoxide Anion ◽  
Potential Role ◽  
Acute Exposure ◽  
Cerebral Microcirculation ◽  
Superoxide Anion Production ◽  
Anion Production ◽  
Cerebral Arterioles ◽  
Oxide Synthase

Our goals were to determine whether acute exposure to nicotine alters neuronal nitric oxide synthase (nNOS)-dependent reactivity of cerebral arterioles and to identify a potential role for oxidative stress in nicotine-induced impairment in nNOS-dependent responses of cerebral arterioles. We measured in vivo diameter of cerebral arterioles to nNOS-dependent ( N-methyl-d-aspartate and kainate) and -independent (nitroglycerin) agonists before and during acute treatment with nicotine. We found that nNOS-dependent, but not -independent, vasodilatation was impaired during treatment with nicotine. In addition, treatment of the cerebral microcirculation with tempol (1 h before infusion of nicotine) prevented nicotine-induced impairment in nNOS-dependent vasodilatation. Furthermore, the production of superoxide anion (lucigenin chemiluminescence) was increased in parietal cortex tissue of rats by treatment with nicotine, and this increase in superoxide anion production could be inhibited by tempol. Our findings suggest that acute exposure to nicotine impairs nNOS-dependent dilatation of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide anion.

scholarly journals In vitro characterisation of fresh and frozen sex-sorted bull spermatozoa

2017 ◽  
Vol 29 (7) ◽  
pp. 1415 ◽  
Author(s):  
Shauna A. Holden ◽  
Craig Murphy ◽  
Juan F. Moreno ◽  
Stephen T. Butler ◽  
Andrew R. Cromie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Superoxide Anion ◽  
Superoxide Anion Production ◽  
Holstein Friesian ◽  
Anion Production ◽  
And Oxidative Stress

This study sought to compare the in vitro characteristics of fresh and frozen non-sorted (NS) and sex-sorted (SS) bull spermatozoa. Experiment 1: Holstein–Friesian ejaculates (n = 10 bulls) were split across four treatments and processed: (1) NS fresh at 3 × 106 spermatozoa, (2) X-SS frozen at 2 × 106 spermatozoa, (3) X-SS fresh at 2 × 106 spermatozoa and (4) X-SS fresh at 1 × 106 spermatozoa. NS frozen controls of 20 × 106 spermatozoa per straw were sourced from previously frozen ejaculates (n = 3 bulls). Experiment 2: Aberdeen Angus ejaculates (n = 4 bulls) were split across four treatments and processed as: (1) NS fresh 3 × 106 spermatozoa, (2) Y-SS fresh at 1 × 106 spermatozoa, (3) Y-SS fresh at 2 × 106 spermatozoa and (4) X-SS fresh at 2 × 106 spermatozoa. Controls were sourced as per Experiment 1. In vitro assessments for progressive linear motility, acrosomal status and oxidative stress were carried out on Days 1, 2 and 3 after sorting (Day 0 = day of sorting. In both experiments SS fresh treatments had higher levels of agglutination in comparison to the NS fresh (P < 0.001), NS frozen treatments had the greatest PLM (P < 0.05) and NS spermatozoa exhibited higher levels of superoxide anion production compared with SS spermatozoa (P < 0.05). Experiment 1 found both fresh and frozen SS treatments had higher levels of viable acrosome-intact spermatozoa compared with the NS frozen treatments (P < 0.01).

Extracellular superoxide anion production contributes to the virulence of Xanthomonas oryzae pv. oryzae

2009 ◽  
Vol 55 (2) ◽  
pp. 110-116 ◽  
Author(s):  
Xin Li ◽  
Xinyue Pang ◽  
Dejuan Zhi ◽  
Jinsheng Wang ◽  
Minquan Li ◽  
...  
Keyword(s):  
Electron Spin Resonance ◽  
Superoxide Anion ◽  
Positive Relationship ◽  
Xanthomonas Oryzae ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Spin Resonance ◽  
Anion Production ◽  
Type Strains ◽  
Extracellular Fraction

Endogenous superoxide anion production was determined by electron spin resonance in wild-type strains and avrXa7 mutants of Xanthomonas oryzae pv. oryzae . The localization of superoxide anion was carried out in the intra- and extra-cellular fractions. Results showed the presence of superoxide anion in multi-locations of X. oryzae pv. oryzae cells. The extracellular fraction was the major location of superoxide anion production. Furthermore, a positive relationship was shown between the levels of endogenous superoxide anion and the virulence of strains. These indubitable results suggested that the superoxide anion contributes to the virulence of X. oryzae pv. oryzae.

Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophagesThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

2010 ◽  
Vol 88 (3) ◽  
pp. 369-378 ◽  
Author(s):  
Lindsei K. Sarna ◽  
Nan Wu ◽  
Sun-Young Hwang ◽  
Yaw L. Siow ◽  
Karmin O
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Cell Viability ◽  
Superoxide Anion ◽  
Pcr Analysis ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Superoxide Anion Generation ◽  
Anion Production ◽  
Lps Treatment

Oxidative stress and amplified redox signaling contribute to the pathogenesis of many human diseases including atherosclerosis. The superoxide-generating phagocytic NADPH oxidase is a key source of oxidative stress in the developing atheroma. The aim of the present study was to examine the effect of berberine, a plant-derived alkaloid, on NADPH oxidase-mediated superoxide anion production in macrophages. Lipopolysaccharide (LPS) treatment activated NADPH oxidase in THP-1 monocyte-derived macrophages and increased the intracellular level of superoxide anions. Preincubation of cells with berberine demonstrated a concentration-dependent (10–50 µmol/L) and time-dependent (6–24 h) inhibition of superoxide anion generation in LPS-stimulated macrophages. Cell viability tests confirmed that berberine, at concentrations sufficient for inhibiting NADPH oxidase-mediated superoxide anion generation in macrophages, did not affect cell viability. Real-time PCR analysis revealed that addition of berberine to the culture medium was able to reduce gp91phox mRNA expression in LPS-treated cells. Berberine also restored superoxide dismutase (SOD) activity, which was found to be inhibited by LPS treatment. In conclusion, results from the present study demonstrate that berberine can effectively reduce intracellular superoxide levels in LPS- stimulated macrophages. Such a restoration of cellular redox by berberine is mediated by its selective inhibition of gp91phox expression and enhancement of SOD activity. The therapeutic relevance of berberine in the prevention and management of atherosclerosis remains to be further investigated.

scholarly journals Serum amyloid A3 confers protection against acute lung injury in Pseudomonas aeruginosa-infected mice

2020 ◽  
Vol 318 (2) ◽  
pp. L314-L322 ◽  
Author(s):  
Yu Fan ◽  
Gufang Zhang ◽  
Chi Teng Vong ◽  
Richard D. Ye
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Knockout Mice ◽  
Superoxide Anion ◽  
Inflammatory Responses ◽  
Serum Amyloid ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Anion Production

Pseudomonas aeruginosa is a gram-negative bacterium associated with serious illnesses, including ventilator-associated pneumonia and various sepsis syndromes in humans. Understanding the host immune mechanisms against P. aeruginosa is, therefore, of clinical importance. The present study identified serum amyloid A3 (SAA3) as being highly inducible in mouse bronchial epithelium following P. aeruginosa infection. Genetic deletion of Saa3 rendered mice more susceptible to P. aeruginosa infection with decreased neutrophil superoxide anion production, and ex vivo treatment of mouse neutrophils with recombinant SAA3 restored the ability of neutrophils to produce superoxide anions. The SAA3-deficient mice showed exacerbated inflammatory responses, which was characterized by pronounced neutrophil infiltration, elevated expression of TNF-α, KC/CXCL1, and MIP-2/CXCL2 in bronchoalveolar lavage fluid (BALF), and increased lung microvascular permeability compared with their wild-type littermates. BALF neutrophils from Saa3 knockout mice exhibited reduced superoxide anion production compared with neutrophils from wild-type mice. Adoptive transfer of SAA3-treated neutrophils to Saa3 knockout mice ameliorated P. aeruginosa-induced acute lung injury. These findings demonstrate that SAA3 not only serves as a biomarker for infection and inflammation, but also plays a protective role against P. aeruginosa infection-induced lung injury in part through augmentation of neutrophil bactericidal functions.

scholarly journals Exercise training restores impaired dilator responses of cerebral arterioles during chronic exposure to nicotine

2010 ◽  
Vol 109 (4) ◽  
pp. 1109-1114 ◽  
Author(s):  
William G. Mayhan ◽  
Denise M. Arrick ◽  
Hong Sun ◽  
Kaushik P. Patel
Keyword(s):  
Exercise Training ◽  
Superoxide Anion ◽  
Chronic Exposure ◽  
Superoxide Dismutase 1 ◽  
Superoxide Anion Production ◽  
Cerebral Microvessels ◽  
Anion Production ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Oxide Synthase

Our goal was to determine whether exercise training (ExT) alleviates impaired nitric oxide synthase (NOS)-dependent dilation of pial arterioles during chronic exposure to nicotine. We measured dilation of cerebral (pial) arterioles in sedentary and exercised control and nicotine-treated (2 mg·kg−1·day−1 for 4 wk via an osmotic minipump) rats to an endothelial NOS (eNOS)-dependent (ADP), a neuronal NOS (nNOS)-dependent [ N-methyl-d-aspartic acid (NMDA)], and a NOS-independent (nitroglycerin) agonist. In addition, we harvested brain tissue from sedentary and exercised control and nicotine-treated rats to measure the production of superoxide anion and measured superoxide dismutase-1 (SOD-1) protein in cerebral microvessels using Western blot. We found that eNOS-and nNOS-dependent, but not NOS-independent, vasodilation was impaired in nicotine-treated compared with control rats. In addition, the production of superoxide anion (lucigenin chemiluminescence) was increased, and SOD-1 protein decreased, in rats treated with nicotine compared with control rats. Further, although ExT did not significantly affect eNOS- or nNOS-dependent vasodilation in control rats, ExT restored impaired eNOS- and nNOS-dependent responses in nicotine-treated rats. In addition, the increase in superoxide anion production observed in nicotine-treated rats was reduced by ExT, and SOD-1 protein was increased in nicotine-treated rats by ExT. We suggest that ExT restores impaired NOS-dependent dilation of pial arterioles during chronic exposure to nicotine by a mechanism related to the formation of superoxide anion.

Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney

2011 ◽  
Vol 300 (1) ◽  
pp. F189-F198 ◽  
Author(s):  
Sun-Young Hwang ◽  
Yaw L. Siow ◽  
Kathy K. W. Au-Yeung ◽  
James House ◽  
Karmin O
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Folic Acid ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Folic Acid Supplementation ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Acid Supplementation ◽  
Anion Production

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. It is a common clinical finding in patients with chronic kidney diseases and occurs almost uniformly in patients with end-stage renal disease. Hyperhomocysteinemia is also a risk factor for cardiovascular disease. Our recent studies indicate that hyperhomocysteinemia can lead to renal injury by inducing oxidative stress. Oxidative stress is one of the important mechanisms contributing to Hcy-induced tissue injury. Folic acid supplementation is regarded as a promising approach for prevention and treatment of cardiovascular disease associated with hyperhomocysteinemia due to its Hcy-lowering effect. However, its effect on the kidney is not clear. The aim of this study was to examine the effect of folic acid supplementation on Hcy-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney during hyperhomocysteinemia. Hyperhomocysteinemia was induced in male Sprague-Dawley rats fed a high-methionine diet for 12 wk with or without folic acid supplementation. A group of rats fed a regular diet was used as control. There was a significant increase in levels of superoxide anions and lipid peroxides in kidneys isolated from hyperhomocysteinemic rats. Activation of NADPH oxidase was responsible for hyperhomocysteinemia-induced oxidative stress in the kidney. Folic acid supplementation effectively antagonized hyperhomocysteinemia-induced oxidative stress via its Hcy-lowering and Hcy-independent effect. In vitro study also showed that 5-methyltetrahydrofolate, an active form of folate, effectively reduced Hcy-induced superoxide anion production via NADPH oxidase. Xanthine oxidase activity was increased and superoxide dismutase (SOD) activity was decreased in the kidney of hyperhomocysteinemic rats, which might also contribute to an elevation of superoxide anion level in the kidney. Folic acid supplementation attenuated xanthine oxidase activity and restored SOD activity in the kidney of hyperhomocysteinemic rats. These results suggest that folic acid supplementation may offer renal protective effect against oxidative stress.

Abstract 1412: Critical Role Of Extracellular Sod For Protecting The Heart Against Myocardial Hypertrophy And Dysfunction After Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Elza D Deel ◽  
Zhongbing LU ◽  
Xin Xu ◽  
Guangshuo Zhu ◽  
Xinli Hu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Superoxide Anion ◽  
Left Ventricular ◽  
Wild Type ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Lv Remodeling ◽  
Anion Production ◽  
Lv Ejection Fraction

Extracellular SOD ( SOD3 ) contributes only a small fraction to total SOD activity in the normal heart, but is strategically located to scavenge free radicals in the extracellular compartment. SOD3 expression is decreased in the failing heart, but whether SOD3 can abrogate oxidative stress or modify left ventricular (LV) remodeling following myocardial infarction (MI) is unclear. To examine this question, we studied LV remodeling in SOD3 KO mice and wild type mice following MI. Under unstressed conditions, SOD3 KO had no effect on myocardial total SOD activity, SOD1 or SOD2 protein content, or myocardial nitrotyrosine or superoxide anion production, and caused no change in LV ejection fraction. However, 4 weeks or 8 weeks after MI, SOD3 KO mice developed more LV hypertrophy (8 weeks after MI, ventricular mass increased 1.64-fold in KO mice as compared to 1.35-fold in wild type mice, p<0.01) and had a greater reduction of LV ejection fraction (8 weeks after MI, LV ejection fraction was 35±2.4% in wild type mice as compared to 30±2.0% in KO mice, p<0.01). As compared with wild type mice, SOD3 KO mice had significantly greater increases of myocardial nitrotyrosine and superoxide anion production, a significantly greater decrease of ANP in the peri-infarct zone, and a significant more decrease of SERCA2a in both the peri-infarct and remote zones. In addition, MI caused greater activation of mitogen-activated protein kinase (MAPK) signaling pathways in SOD3 KO mice, as demonstrated by significantly greater increases of p-p38 Thr180/ Tyr182 , p-Erk Thr202/Tyr204 and p-JNK Thr183/Tyr185 in SOD3 KO mice 8 weeks after MI. The finding that SOD3 KO had no effect on myocardial total SOD activity, but significantly exacerbated MI induced LV remodeling implies that the specific extracellular location of SOD3 is more important than its contribution to overall SOD activity in protecting the heart against contractile dysfunction following myocardial infarct.

scholarly journals Nitric Oxide Synthesis and Oxidative Stress in the Renal Cortex of Rats with Diabetes Mellitus

2001 ◽  
Vol 12 (8) ◽  
pp. 1630-1639
Author(s):  
NAOHITO ISHII ◽  
KAUSHIK P. PATEL ◽  
PASCALE H. LANE ◽  
TRACI TAYLOR ◽  
KA BIAN ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Superoxide Anion ◽  
Renal Cortex ◽  
Early Stage ◽  
Diabetic Rats ◽  
No Synthase ◽  
Superoxide Anion Production ◽  
Anion Production

Abstract. Experiments were performed to test the hypothesis that diabetes mellitus disrupts the balance between synthesis and degradation of nitric oxide (NO) in the renal cortex. Diabetes was induced by injection of streptozotocin, and sufficient insulin was provided to maintain moderate hyperglycemia for the ensuing 2 wk. Despite an 80% increase in total NO synthase activity measured by L-citrulline assay, nicotinamide adenine dinucleotide phosphate-diaphorase staining was unaltered, and no changes in NO synthase isoform protein levels or their distribution were evident in renal cortex from diabetic rats. Superoxide anion production was accelerated twofold in renal cortical slices from diabetic rats, with an associated 50% increase in superoxide dismutase activity. Western blots prepared by use of a monoclonal antinitrotyrosine antibody revealed an approximately 70-kD protein in renal cortex from sham rats, the nitrotyrosine content of which was threefold greater in cortical samples from diabetic rats. These observations indicate that the early stage of diabetes mellitus provokes accelerated renal cortical superoxide anion production in a setting of normal or increased NO production. This situation can be expected to promote peroxynitrite formation, resulting in the tyrosine nitration of a single protein of unknown identity, as well as a decline in the bioavailability of NO. These events are consistent with the postulate that oxidative stress promotes NO degradation in the renal cortex during the early stage of diabetes mellitus.

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