Effects of <i>N</i>‐acetylcysteine on dense cell formation in sickle cell disease

Pace, Betty S.; Shartava, Archil; Pack-Mabien, Ardie; Mulekar, Mudhari; Ardia, Alfredo; Goodman, Steven R.

doi:10.1002/ajh.10321

Cited by 103 publications

(64 citation statements)

References 26 publications

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“…In this regard, it is very interesting that N-acetylcysteine (NAC) can raise intracellular GSH levels in sickle cells and decrease the formation of irreversibly sickle cells and dense cells in vitro and in vivo [52,53]. In the phase II human NAC trial, 2,400 mg of NAC per day lowered the crisis rate by >60% [53].…”

Section: Discussionmentioning

confidence: 99%

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Spectrin's E2/E3 ubiquitin conjugating/ligating activity is diminished in sickle cells

2005

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Erythrocyte spectrin contains E2/E3 ubiquitin conjugating/ligating activity in its a subunit. Ankyrin is a target of spectrin's E2/E3 ubiquitin conjugating/ligating activity in vitro and in vivo. We compare the ubiquitination levels of ankyrin mediated by control and sickle cell spectrin using a biotinylated ubiquitin cell-free assay. Sickle cell spectrin has diminished ability to transfer ubiquitin from an intermediate spectrin-ubiquitin thioester adduct (a 0 spectrin) to ankyrin, which may be due to glutathiolation of spectrin's E2 and/ or E3 active site cysteines. There is also a diminished ability of the sickle cell ankyrin to serve as target of spectrin's E2/E3 activity, probably due to oxidative damage to ankyrin. A direct correlation exists between the a 0 /a spectrin ratio and spectrin's ability to ubiquitinate ankyrin. There is also an inverse correlation between severity of the disease and the a 0 /a spectrin ratio in SS erythrocytes. These results suggest that reduced spectrin E2/ E3 activity is an important determinant of sickle cell severity. Am. J. Hematol. 79:89-96, 2005.

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Section: Discussionmentioning

confidence: 99%

“…In the phase II human NAC trial, 2,400 mg of NAC per day lowered the crisis rate by >60% [53]. One of the actions of NAC, via decreasing the GSSG/GSH ratio, would be to increase the ubiquitination of spectrin and other targets of its E2/E3 activity.…”

Section: Discussionmentioning

confidence: 99%

Spectrin's E2/E3 ubiquitin conjugating/ligating activity is diminished in sickle cells

2005

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“…44 In a phase 2 clinical trial of N-acetylcysteine in SCD patients, administration of the drug decreased the percentage of dense cells, normalized RBC glutathione levels, and decreased the frequency of vaso-occlusive crises. 45 One of the multiple beneficial mechanisms of hydroxyurea in SCD may be reduction of systemic oxidative stress in humans, 46,47 and there is an inverse correlation between hemoglobin F levels and markers of systemic oxidative stress in an SCD mouse model. 48 Trials of antioxidant agents in mouse models of SCD also appear to reduce markers of acute and chronic inflammation.…”

Section: Nadph Oxidase and Ros In Sickle Erythrocytes 2105mentioning

confidence: 99%

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

George

Pushkaran

Konstantinidis

et al. 2013

Blood

173

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• Sickle RBC ROS production is mediated in part by NADPH oxidase activity.• Sickle RBC ROS production can be induced by plasma signaling molecules.Chronic inflammation has emerged as an important pathogenic mechanism in sickle cell disease (SCD). One component of this inflammatory response is oxidant stress mediated by reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells (RBC). Sickle RBC ROS generation has been attributed to sickle hemoglobin auto-oxidation and Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane. In this study, we demonstrate that a significant part of ROS production in sickle cells is mediated enzymatically by NADPH oxidase, which is regulated by protein kinase C, Rac GTPase, and intracellular Ca 21 signaling within the sickle RBC. Moreover, plasma from patients with SCD and isolated cytokines, such as transforming growth factor b1 and endothelin-1, enhance RBC NADPH oxidase activity and increase ROS generation. ROS-mediated damage to RBC membrane components is known to contribute to erythrocyte rigidity and fragility in SCD. Erythrocyte ROS generation, hemolysis, vaso-occlusion, and the inflammatory response to tissue damage may therefore act in a positive-feedback loop to drive the pathophysiology of sickle cell disease. These findings suggest a novel pathogenic mechanism in SCD and may offer new therapeutic targets to counteract inflammation and RBC rigidity and fragility in SCD. (Blood. 2013;121(11):2099-2107 IntroductionVaso-occlusion and hemolysis from the rigid and concurrently fragile red blood cells (RBC) in patients with sickle cell disease (SCD) cause a variety of acute and chronic manifestations ranging from frequent and severe painful crises to stroke and chronic organ failure. Chronic inflammation has emerged as an important pathogenic mechanism in SCD, and oxidative stress is increasingly recognized as a component of this chronic inflammatory state, inducing damage to a variety of subcellular and tissue structures. 1,2Patients with SCD have decreased plasma levels of glutathione, vitamin C, and vitamin E, presumably due to consumption by increased oxidant production. [3][4][5] RBC and other cell types show evidence of lipid peroxidation and oxidative damage to structural proteins.6-8 Additionally, plasma from SCD patients has elevated levels of advanced glycation end products 9,10 and products of lipid peroxidation (F-2 isoprostanes, malonaldehyde, and 4-hydroxynonenal), [11][12][13] all of which are markers of oxidative stress. There are several postulated mechanisms for the increased oxidative stress in patients with SCD. Sickle (SS) RBC reactive oxygen species (ROS) generation has been attributed to sickle hemoglobin auto-oxidation and iron-mediated Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane.14 Plasma hemoglobin and free heme resulting from chronic hemolysis generate superoxide radicals via the same nonenzymatic mechanisms. 15 In...

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“…It is an important finding, because erythrocyte glutathione plays an important role in mitigating the damaging effects of reactive oxygen species (ROS) present in the circulation (Mak et al, 1994) which causes continuous oxidation of haemoglobin within the cytosol of the erythrocyte (Hsieh and Jaffe, 1975). GSH reacts with ROS and degrades hydrogen peroxide and lipid peroxides by glutathione peroxidase or modifies toxic xenobiotics by glutathione S-transferase (Pace et al, 2003). The activity of glutathione peroxidase did not vary significantly in red blood cell haemolysate, liver and kidney, but it was reduced in all treated groups in blood plasma.…”

Section: Discussionmentioning

confidence: 97%

Effect of short-term aflatoxin exposure in combination with medicinal herb mixture on lipid peroxidation and glutathione redox system in laying hens

et al. 2016

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Abstract:Aflatoxins are well known hepatotoxic mycotoxins, which mainly contaminate the cereal grains. Those induce lipid peroxidation and impair the antioxidant, including glutathione redox system in long-term studies. The purpose of present study was to investigate the short-term (36-hour) effect of feeding aflatoxin B1 (AFB1) contaminated diet alone or in combination with a medicinal herb mixture on lipid peroxidation (conjugated dienes and trienes, and malondialdehyde), and on parameters of the glutathione system (reduced glutathione and glutathione peroxidase) in blood plasma, red blood cell haemolysate, liver and kidney homogenate of 49-week old Bovans Goldline laying hens. The results revealed that AFB1 (125 m /kg feed) did not have effect on feed intake, body and liver weight, but increased malondialdehyde content was observed in blood plasma and red blood cell haemolysate as effect of feeding AFB1 and medicinal herb mixture at 36th hour of the trial. However, the same diet resulted in lower malondialdehyde content in liver, but not in kidney. Reduced glutathione concentrations showed variance among treatments; thus due to inclusion of medicinal herb mixture in the diet lower values were measured in red blood cell haemolysate. Glutathione peroxidase activity was significantly lower in all treated groups as compared to the control at 36th hour of the trial in blood plasma, but not in other tissues. The results are contradictory with previous findings, probably due to the short-term exposure, and/or to medicinal herb mixture supplementation as it could moderately modify the effect of AFB1.

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Effects of N‐acetylcysteine on dense cell formation in sickle cell disease

Cited by 103 publications

References 26 publications

Spectrin's E2/E3 ubiquitin conjugating/ligating activity is diminished in sickle cells

Spectrin's E2/E3 ubiquitin conjugating/ligating activity is diminished in sickle cells

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

Effect of short-term aflatoxin exposure in combination with medicinal herb mixture on lipid peroxidation and glutathione redox system in laying hens

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