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Selenium and Glutathione Peroxidase Levels in Sickle Cell Anemia

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Abstract

Levels of plasma selenium (Se) and glutathione peroxidase were measured in 20 sickle cell anemia (SCA) patients not in crisis and in 14 nonanemic control subjects. The results show that the levels of Se and glutathione peroxidase were significantly (p less than 0.005) lower than those of controls in both plasma and whole blood. These data are consistent with the previous reports that there is increased oxidative stress in SCA. Low blood Se levels and glutathione peroxidase activity observed in this research suggest that a weakened antioxidant potential may be associated with SCA patients. The low Se status in SCA patients may also affect the phenotypic expression of these patients.

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... Simultaneously, the antioxidant protective mechanisms are usually decreased in SCD patients [7,[13][14][15][16][17]. Those that provide enzymatic defense, including superoxide dismutase (SOD) [18,19], glutathione peroxidase (GPX) [16], catalase [18] and heme oxygenase (HO)-1, and those that scavenge free radicals, such as glutathione (GSH), vitamin C and vitamin E, are most affected [8,20]. ...
... Simultaneously, the antioxidant protective mechanisms are usually decreased in SCD patients [7,[13][14][15][16][17]. Those that provide enzymatic defense, including superoxide dismutase (SOD) [18,19], glutathione peroxidase (GPX) [16], catalase [18] and heme oxygenase (HO)-1, and those that scavenge free radicals, such as glutathione (GSH), vitamin C and vitamin E, are most affected [8,20]. ...
... Studies have also shown a decrease in the activities of GPX [14,16] and catalase [14,21], two enzymes involved in the reduction of H 2 O 2 to H 2 O and oxygen. Similarly, several studies have reported a decrease in SOD activity in SCD patients [19] and murine models of SCD [18]. ...
Article
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Sickle cell disease is a class of hemoglobinopathy in humans which is the most common inherited disease in the world. Although complications of sickle cell disease start from the polymerization of red blood cells during its deoxygenating phase, the oxidative stress resulting from the biological processes associated with this disease (ischemic and hypoxic injuries, hemolysis, and inflammation) has been shown to contribute to its pathophysiology. It is widely known that chronic exercise reduces oxidative stress in healthy people mainly via improvement of antioxidant enzymes efficiency. In addition, recent studies in other diseases, as well as in sickle-cell trait carriers and in a sickle cell disease mice model, show that regular physical activity could decrease oxidative stress. The purpose of this review is to summarize the role of oxidative stress in sickle cell disease and the effects of acute and chronic exercise on the pro-oxidant/antioxidant balance in sickle cell trait and sickle cell disease.
... Compared to normal controls, serum levels of Se were significantly lower among SCA patients in the present study. Though infrequently, low blood levels of Se have been reported among patients with SCA [26], suggesting a weak antioxidant potential. The antiinflammatory role of Se was recently demonstrated in an experimental study on adiponectin knockout mice where Se was shown to provide protection against chronic inflammation-induced colon cancer [27]. ...
... Glutathione peroxidases are selenoproteins and are the main antioxidants involved in neutralizing the production of ROS [29]. Low levels of glutathione peroxidase among patients with SCA [26] highlights the importance of Se in handling the oxidative stress associated with SCA. In addition, Se has been shown to provide protection against oxidative stress-induced lipid peroxidation and disturbances in fatty acid biosynthesis among patients with SCA [30]. ...
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Background/aim: Oxidative stress contributes to pathophysiological dysfunction in sickle cell anemia (SCA). Copper (Cu) is a prooxidant, whereas zinc (Zn) and selenium (Se) are antioxidant trace elements. This study investigates the serum levels of Cu, Zn, and Se among children with SCA. Materials and methods: This cross-sectional study was performed at King Khalid University Hospital, Riyadh. Thirty-three children with SCA in steady state and 33 age- and sex-matched normal healthy children were included in the study. Cu, Zn, and Se levels were measured by inductively coupled plasma-mass spectrometry (ICP-MS) instrument. Results: The median serum Cu levels among SCA patients (1.3 μg/mL) were higher than those of the controls (0.88 μg/mL; P < 0.0001). Zn (0.61 μg/mL) and Se (74 ng/mL) levels among SCA patients, however, were significantly lower than those of the controls (0.94 μg/mL; P < 0.0001) and (91.2 ng/mL; P < 0.0001), respectively. The Cu/Zn ratio among SCA patients (1.92) was higher than that of the controls (0.98). Conclusion: Decreased blood levels of antioxidant trace elements may contribute to the pathophysiology in SCA by promoting oxidative stress. The monitoring of trace element levels in SCA appears to be vital for decreasing morbidity associated with the disorder.
... In addition, an adequate selenium intake preserves GPx activity [30]. Thus, we suggest that reduced serum concentrations of selenium may be associated with impaired antioxidant capacity of erythrocytes caused by reduced activity of GPx and other selenoenzymes, as shown by Natta and colleagues [31], who observed low serum selenium concentrations and lower GPx activity in patients with SCD. That study suggests that there is low antioxidant capacity in these individuals, making proteins and lipids of the erythrocyte membrane more susceptible to oxidation and subsequent hemolysis [31]. ...
... Thus, we suggest that reduced serum concentrations of selenium may be associated with impaired antioxidant capacity of erythrocytes caused by reduced activity of GPx and other selenoenzymes, as shown by Natta and colleagues [31], who observed low serum selenium concentrations and lower GPx activity in patients with SCD. That study suggests that there is low antioxidant capacity in these individuals, making proteins and lipids of the erythrocyte membrane more susceptible to oxidation and subsequent hemolysis [31]. ...
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Sickle cell disease (SCD) is a genetic hemoglobinopathy characterized by chronic hemolysis. Chronic hemolysis is promoted by increased oxidative stress. Our hypothesis was that some antioxidant micronutrients (retinol, tocopherol, selenium, and zinc) would be determinant factors of the degree of hemolysis in SCD patients. We aimed to investigate the nutritional adequacy of these antioxidants and their relationships to hemolysis. The study included 51 adult SCD patients regularly assisted in two reference centers for hematology in the State of Rio de Janeiro, Brazil. Serum concentrations of retinol, alpha-tocopherol, selenium, and zinc were determined by high-performance liquid chromatography or atomic absorption spectrometry. Hematological parameters (complete blood count, reticulocyte count, hemoglobin, direct and indirect bilirubin, total bilirubin, lactate dehydrogenase) and inflammation markers (leukocytes and ultra-sensitive C-reactive protein) were analyzed. A linear regression model was used to test the associations between the variables. Most patients presented selenium deficiency and low selenium consumption. Linear regression analysis showed that selenium is the main determinant of hemolysis among the antioxidant nutrients analyzed. Thus, data from this study suggest that the nutritional care protocols for patients with SCD should include dietary sources of selenium in order to reduce the risk of hemolysis.
... In addition, the protective mechanisms afforded by antioxidants are decreased in SCD. SCD patients and animal models exhibit low levels of vitamins A, C, E, and zinc [8,9] and deficiency of glutathione reductase [10] and glutathione peroxidase (GPx) [11], while superoxide dismutase (SOD) protein expression or activity and catalase expression are either decreased [12,13] or increased [14]. ...
... Recent studies indicated a critical role of GPx1 in preserving NO bioavailability and protecting the cardiovascular system against oxidative stress [51,52]. The few studies that have examined antioxidant enzymes in patients or mice with SCD have yielded contradictory results with respect to levels of SOD and catalase [11,13]. Our studies demonstrate unaltered protein expressions of SOD1, SOD2, and catalase, and decreased protein expression of GPx1 in the SCD mouse penis. ...
Article
Introduction. Sickle cell disease (SCD) is a state of chronic vasculopathy characterized by endothelial dysfunction and increased oxidative stress, but the sources and mechanisms responsible for reactive oxygen species (ROS) production in the penis are unknown. Aims. We evaluated whether SCD activates NADPH oxidase, induces endothelial nitric oxide synthase (eNOS) uncoupling, and decreases antioxidants in the SCD mouse penis. We further tested the hypothesis that targeting NADPH oxidase decreases oxidative stress in the SCD mouse penis. Methods. SCD transgenic (sickle) mice were used as an animal model of SCD. Hemizygous (hemi) mice served as controls. Mice received an NADPH oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Penes were excised at baseline for molecular studies. Markers of oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NADPH oxidase subunits p67phox, p47phox, and gp91phox), and enzymatic antioxidants (superoxide dismutase [SOD]1, SOD2, catalase, and glutathione peroxidase-1 [GPx1]) were measured by Western blot in penes. Main Outcome Measures. Sources of ROS, oxidative stress, and enzymatic antioxidants in the SCD penis. Results. Relative to hemi mice, SCD increased (P < 0.05) protein expression of NADPH oxidase subunits p67phox, p47phox, and gp91phox, 4-HNE-modified proteins, induced eNOS uncoupling, and reduced Gpx1 expression in the penis. Apocynin treatment of sickle mice reversed (P < 0.05) the abnormalities in protein expressions of p47phox, gp91phox (but not p67phox) and 4-HNE, but only slightly (P > 0.05) prevented eNOS uncoupling in the penis. Apocynin treatment of hemi mice did not affect any of these parameters. Conclusion. NADPH oxidase and eNOS uncoupling are sources of oxidative stress in the SCD penis; decreased GPx1 further contributes to oxidative stress. Inhibition of NADPH oxidase upregulation decreases oxidative stress, implying a major role for NADPH oxidase as a ROS source and a potential target for improving vascular function in the SCD mouse penis. Musicki B, Liu T, Sezen SF, and Burnett AL. Targeting NADPH oxidase decreases oxidative stress in the transgenic sickle cell mouse penis. J Sex Med 2012;9:1980–1987.
... Hydroxyurea is the only approved drug for the treatment of sickle cell patients based upon the findings in a randomized phase III clinical trial in adult sickle cell patients. 103 Follow up for 17.5 years of patients included in this trial showed that long term use of hydroxyurea is safe and might decrease mortality. 104 Two recent systematic reviews found that while hydroxyurea has proven efficacious in treating adult sickle cell patients and children with severe sickle cell anemia, the paucity of long term studies and studies in children with less severe SCD limits conclusions about toxicity and efficacy in less severe sickle cell children respectively. ...
... Levels of carotenoids, flavonoids, vitamins C and E (hydrophobic antioxidants) and zinc (part of superoxide dismutase) are known to be decreased in sickle cell patients. 62,102,103 Treatment of erythrocytes from sickle cell patients with the flavonoid quercetin has been shown to provide protection against hemoglobin oxidation, lipid peroxidation and membrane deformity. 62 Zinc supplementation of sickle cell patients has been shown to decrease oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell patients. ...
Article
Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolytic anemia, increased susceptibility to infections and vaso-occlusion leading to a reduced quality of life and life expectancy. Oxidative stress is an important feature of SCD and plays a significant role in the pathophysiology of hemolysis, vaso-occlusion and ensuing organ damage in sickle cell patients. Reactive oxygen species (ROS) and the (end-)products of their oxidative reactions are potential markers of disease severity and could be targets for antioxidant therapies. This review will summarize the role of ROS in SCD and their potential implication for SCD management.
... 3 The production of ROS, with ensuing oxidative stress, further augments endothelial activation, cellular and tissue damage as well as contributing to reduce vascular nitric oxide bioavailability. 5 Oxidative stress results from the imbalance between enhanced generation of ROS produced and a low cellular content of enzymatic antioxidants such as glutathione peroxidase and superoxide dismutase (SOD) and non-enzymatic antioxidants including vitamins A, C and E. 5,6 Increased ROS generation, in SCD, may be the consequence of numerous mechanisms. For example, activities of enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and endothelial xanthine oxidase may be increased due to leukocytosis and endothelial activation. ...
... Production of ROS by control neutrophils, in the presence of SCD serum, was associated with a significant increase in superoxide anion production in these cells. Interestingly, levels of the SOD enzyme in the circulation of our population of steady-state SCD patients were found to be significantly decreased (as previously observed in other SCD populations), 6 and it may be hypothesized that decreased O 2 N2 breakdown, due to reduced SOD, may contribute to increased O 2 N2 levels in SCD serum incubated leukocytes. ...
Article
Oxidative stress plays a significant role in sickle cell disease (SCD), contributing to haemolysis, vaso-occlusive processes and endothelial dysfunction. To study the effects that the serum of SCD individuals has on the oxidative state of blood cells, sera were pooled from control individuals, steady-state SCD patients and SCD patients on hydroxyurea therapy (SCDHU), and their effects on markers of oxidative stress and damage in neutrophils isolated from healthy individuals observed. Incubation of control neutrophils, but not platelets nor red blood cells, with SCD serum (10% v/v; 2 hours) significantly augmented their production of reactive oxygen species (ROS). Increased ROS production in SCD serum-incubated neutrophils was associated with increased superoxide anion generation, apoptosis and increased nicotinamide adenine dinucleotide phosphate oxidase subunit expression. Although serum from SCDHU individuals also induced ROS generation in neutrophils, its oxidative capacity appeared to be lower. Results suggest that factors in the serum of SCD individuals contribute to ROS generation and oxidative damage in leukocytes.
... Il semblerait que la capacité antioxydante des patients drépanocytaires ne soit pas suffisante pour compenser la production excessive d'EORs. En effet, plusieurs études ont décrit une diminution du contenu en glutathion dans les GR et au niveau plasmatique (Amer et al., 2006;Gizi et al., 2011;Morris, 2008) ainsi qu'une diminution de l'activité de la SOD (Ama Moor et al., 2016; Antwi-Boasiako p. 47 et al., Biswal et al., 2019;Ren et al., 2008;Schacter et al., 1988), de la GPx (Biswal et al., 2019;Das & Nair, 1980;Natta et al., 1990;Ren et al., 2008;Renoux et al., 2018) patients drépanocytaires par rapport à des sujets sains. Cependant, malgré l'augmentation de l'activité de ces enzymes antioxydantes rapportée dans ces études, la production d'EORs au niveau plasmatique et du GR n'étaient pas compensée, conduisant alors tout de même à un stress oxydatif. ...
Thesis
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La drépanocytose est une maladie caractérisée par la production d’une hémoglobine mutée, l’hémoglobine S, dont les formes les plus répandues sont la forme homozygote S/S et double hétérozygote composite S/C. L’hémoglobine S possède la capacité de polymériser au sein du globule rouge en condition désoxygénée modifiant sa morphologie provoquant ainsi des complications cliniques multi-organiques. Ces patients présentent une capacité à l’exercice réduite dont les causes sont des altérations cardio-vasculaires cependant l’implication du muscle squelettique n’est pas encore totalement caractérisée dans la drépanocytose. En effet, le muscle squelettique drépanocytaire présente une amyotrophie, un remodelage profond de la microcirculation et une diminution de sa capacité à produire de la force cependant la présence d’une dysfonction musculaire à l’exercice n’a pas encore été décrite. Plusieurs études suggèrent que le stress oxydatif pourrait être élevé dans le muscle drépanocytaire expliquant ainsi en partie les altérations observées. Chez les sujets sains, l’exercice chronique aérobie est connu pour améliorer la capacité antioxydante musculaire notamment par l’augmentation de l’activité des enzymes antioxydantes. Cependant, les effets de ce type d’exercice sur le stress oxydatif n’ont pas encore été caractérisés dans la drépanocytose. Ainsi, les objectifs de cette thèse sont de 1) mettre en évidence une dysfonction musculaire chez des patients drépanocytaires S/S et S/C et de 2) déterminer les modifications induites par un exercice chronique aérobie sur le stress oxydatif au sein du muscle squelettique dans un modèle murin drépanocytaire. Lors d’une première étude, des sujets sains (A/A) et patients drépanocytaires S/S et S/C ont effectué un exercice mono-articulaire sous-maximal du quadriceps à une intensité correspondant à 25% de leur force maximale isométrique (Fmax) suivi d’un test de marche de 6 minutes (T6M). Fmax a été mesurée avant et après cet exercice mono-articulaire, et après le T6M et la perte de Fmax a été utilisée pour quantifier la fatigabilité musculaire. Au cours du protocole, les activités électromyographiques du Vastus Lateralis (VL) et du Vastus Medialis ainsi que l’oxygénation musculaire par spectroscopie proche infrarouge du VL ont été mesurés au cours de l’exercice. Le principal résultat de cette étude est que les patients drépanocytaires S/S et S/C présentent une fatigabilité musculaire accrue comparés aux sujets A/A. Cette fatigabilité accrue semble être provoquée par des altérations musculaires plutôt qu’une modification de l’oxygénation musculaire. De plus, il semblerait que les mécanismes d’apparition de la fatigue musculaire soient différents entre les S/S et S/C comme le suggère les modifications des paramètres électromyographiques. Ainsi, le muscle des patients S/C semble moins altéré que celui des patients S/S. Dans une seconde étude, des souris Townes A/A et S/S ont suivi un exercice chronique aérobie d’intensité modérée de 8 semaines puis la mesure de marqueurs permettant de caractériser la balance pro/anti-oxydant a été effectuée dans le gastrocnemius, le plantaris et le soleus. A l’issue de ces 8 semaines, nous avons observé des modifications uniquement dans le gastrocnemius des souris S/S entraînées. En effet, l’activité de la NADPH oxydase ainsi que de la superoxyde dismutase et de la catalase étaient plus élevées chez les souris S/S entraînées. Ces résultats suggèrent une altération de la balance pro/antioxydante en réponse à un exercice chronique aérobie d’intensité modérée au sein du muscle squelettique drépanocytaire. Enfin, contrairement aux souris S/S entraînées, nous n’observons pas de modifications de la balance pro/antioxydante dans les souris S/S sédentaires indiquant que le stress oxydatif ne serait pas augmenté dans le muscle drépanocytaire.
... Irrespective of the levels detected, the total antioxidant capacity in SCD patients is insufficient to neutralize excess ROS, resulting in oxidative stress (79). Other nonenzymatic antioxidants such as vitamin C and E (80,81), zinc (76), and selenium (69,77,80) are also decreased in SCD patients. ...
Article
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Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.
... Specifically in SCA, oxidative stress could play a role in microvascular dysfunction, in vaso-occlusion, and in the development of extensive organ damage observed in these patients (Wun, 2001;Wood & Granger, 2007). In addition, patients with chronic haemolysis have very low levels of several antioxidants as compared with normal subjects (Chiu et al, 1990;Natta et al, 1990;Suthutvoravut et al, 1993;Chan et al, 1999;Cesquini et al, 2003;Hasanato, 2006;Ray et al, 2007;Ren et al, 2008;Claster et al, 2009;Nur et al, 2011b). In this scenario, it is plausible to infer that antioxidants might be beneficial in their treatment (Amer et al, 2008a;Fibach & Rachmilewitz, 2008;Nur et al, 2011a,b). ...
Article
1063 Background Erythrocytes of sickle cell anemia (SCA) patients continuously produce larger amounts of pro-oxidants than normal cells, and oxidative stress seems to play a significant role in the pathophysiology of this disease. In erythrocytes, oxidative stress primarily affects the membrane and results in hemolysis. The use of antioxidants in vitro reduces the generation of pro-oxidants, which could prevent adhesion and phagocytosis of oxidized erythrocytes. Aims To evaluate the impact of antioxidant vitamins C (vitC) and E (vitE) supplementation in the hemolytic profile in SCA patients. Patients and methods Homozygous SCA or S-β-thalassemia patients, over 18 years, were randomly assigned to receive VitC 1,400 mg + VitE 800 mg per day or placebo, administered orally for 180 days. Pregnant women and patients with iron overload out of chelation therapy were excluded. Patients were evaluated clinically and blood samples were collected at days 0 and 180 for complete blood count, automated reticulocyte count, indirect bilirubin, lactate dehydrogenase (LDH), haptoglobin, uric acid, and serum levels of VitC and VitE. Results Overall, 83 patients were enrolled (44 vitamins, 39 placebo). The median (range) age was 27 (18–68) years, and 53 (64%) were female. There were no significant differences between the two groups as regards clinical complications of SCA or baseline laboratorial tests and serum vitC and vitE. Sixty percent of the patients were VitC deficient (30% with severe deficiency), 70% were VitE deficient (33% with severe deficiency) and 44% were deficient in both vitamins. Vitamin supplementation increased VitC from 27.2 to 62.6 μMol/L (p<0.0001) and VitE from 13.9 to 20.2 μMol/L (p<0.0001). No changes in vitC or vitE were observed in patients receiving placebo. No significant changes in hemoglobin levels, hematocrit, mean corpuscular volume were observed in either group. However, patients receiving vitamin supplementation presented a significant increase in the median reticulocyte count (from 152 to 195 ×106/μL, p=0.01), LDH (from 396 to 425 U/L, p=0.018), indirect bilirubin (from 1.45 to 1.73 mg/dL, p<0.0001), and uric acid (from 4.75 to 5.15 mg/dL, p=0.02), and a decrease in the haptoglobin levels (from 3.95 to 3.45 mg/dL, p=0.06). Conclusion Supplementation with vitamins C and E did not improve anemia and, surprisingly, increased markers of hemolysis in patients with SCA and S-β-thalassemia. The exact mechanisms to explain our findings and their clinical significance remain to be determined. Disclosures No relevant conflicts of interest to declare.
... Hence, they are known as 'Radical Scavengers' or 'Oxygen Quenchers' (Halliwell and Aruoma, 1991). Low level of antioxidants like vitamin C, glutathione peroxidase, catalase, superoxide dismutase and glutathione S transferase have been reported in sickled patients (Natta et al., 1990;Reid et al., 2006). ...
Article
Objective Present study was undertaken to study the association between sickle cell anemia (SCA) and glucose-6-phosphate dehydrogenase (G6PD) deficiency from Sahu and Kurmi population of Durg and Rajnandgaon district of Chhattisgarh, India. Method A random sampling of 1749 individuals was done. SCA and G6PD deficiency was detected by slide test followed by electrophoresis and Enzymatic reaction indicated by change in colour respectively. Further the samples were subjected to analyze glutathione-S-transferase (GST) i.e. GSTM1 and GSTT1 gene polymorphism, variance of G6PD among G6PD deficient samples by PCR-RFLP. Oxidative stress and DNA damage by comet assay was also analyzed. Results Present finding indicates positive correlation between SCA and G6PD deficiency in Durg and Rajnandgaon district [Durg: (r = 0.92; HbAS-G6PDd and r = 0.56; HbSS-G6PDd) Rajnandgaon: (r = 0.63; HbAS-G6PDd and r = 0.86; HbSS-G6PDd)]. Significant changes (P < 0.05) in antioxidant enzymatic parameters were observed in HbSS and G6PD with sickle positive individual. Assessment of DNA damage by Comet assay considering Head DNA percent, Tail DNA percent, Tail length and Tail moment also showed significant changes (P < 0.05) within all concerned parameters in HbSS and G6PD with sickle positive individual. Analysis of GST gene polymorphism showed that frequency of individuals carrying the GSTM1 null genotype was higher in HbAS (60%) and the frequency of individual carrying the GSTT1 null genotype was found higher in HbSS (66.6%). G6PD variants analysis also confirmed the presence of highest percentage of mutation among G6PD deficient population as compared to control and a positive correlation was observed between G6PD deficiency and mutant variants of G6PD gene [Rajnandgaon: (r = 0.67; G6PDd-Mahidol mutated and r = 0.90; G6PDd-Union mutated) Durg: (r = 0.91; G6PDd-Mahidol mutated and r = 0.01; G6PDd-Union mutated)] . Conclusion Thus present finding indicates positive correlation between SCA and G6PD deficiency in Chhattisgarh, India.
... Dialysis patients showed significantly lower plasma Se levels that correlated with decreased half-lives of erythrocytes and thrombocytes compared to healthy controls (10). In sickle cell anemia patients, Se deficiency was associated with decreased expression of the highly Se-responsive selenoprotein glutathione peroxidase-1 (GPX1) in addition to a weakened antioxidant potential (11). A causal association between hypothyroidism and anemia (12) and subclinical hypothyroidism, due to Se deficiency (and decreased selenoprotein deiodinases), was associated with lower hemoglobin levels (13). ...
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Low serum Se is independently associated with anemia in elderly population, dialysis patients, sickle-cells patients, and hypothyroidism patients. Previous work from our laboratory showed that dietary Se deficiency in mice showed mild anemia indicating activation of stress- erythropoietic mechanisms. Unlike steady state erythropoiesis that is primarily responsible for homeostasis to produce new erythrocytes at a constant rate, stress erythropoiesis predominates when the bone marrow cannot generate sufficient erythrocytes. During such a process, short-term reconstituting hematopoietic stem cells (CD34+Kit+Sca1+Linneg) migrate to the spleen leading to the proliferation and differentiation of stress-erythroid progenitors (SEPs). These cells lead to stress burst forming unit- erythroid cells (BFU-E) followed by terminal differentiation to erythrocytes. Recent studies demonstrate deficits in selenoproteins block the expansion and development of stress BFU-E with defects in terminal differentiation. Analysis of selenoprotein expression showed that selenoprotein W (SelenoW) was highly expressed in developing SEPs. CRISPR-Cas9 knockout of SelenoW blocked the proliferation of immature SEPs in murine and human stress erythropoiesis cultures demonstrating a central role for SelenoW in stress erythropoiesis. Using the two-culture system to generate SEPs, selenoprotein N (SelenoN) expression increased as the progenitors transition from self-renewing progenitors to form committed erythroid progenitors. SelenoN-/- mice showed significantly slower erythroid recovery following phenylhydrazine (PHZ)-induced acute hemolytic anemia. As in the muscle satellite cells where SelenoN regulates cellular Ca2+ signaling, SelenoN may also regulate Ca2+ signaling in SEPs to modulate pathways of differentiation. In summary, these data suggest that multiple selenoproteins, including SelenoN and SelenoW, coordinately regulate stress erythropoiesis.
... NADPH oxidases have been identified as a major source of ROS in SCD RBCs. The other known sources of ROS in RBCs in SCD are 1) HbS autoxidation, 2) the Fenton reaction, and 3) low levels of antioxidants, such as selenium and glutathione peroxidase 1, SOD, and catalase (9,47). In addition, Jagadeeswaran et al. (24) recently discovered that abnormally retained mitochondria in the SCD RBC are a source of ROS. ...
Article
Sickle cell disease (SCD) is caused by a mutation of the b-globin gene(21) that triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the U.S. and millions worldwide(53) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy(60, 70). Hematopoietic stem cell (HSC) transplantation can be curative, but the majority of patients do not have a suitable donor (80). Advanced gene editing technologies also offer the possibility of a cure (16, 34), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase HbF as a therapy for SCD has been a long sought goal because increased levels of Fetal Hemoglobin [(HbF(α2γ2)] inhibit the polymerization of HbS(56, 78) and are associated with reduced symptoms and an increased lifespan of SCD patients(54, 55). There are only two drugs FDA approved for sickle cell disease treatment, hydroxyurea (HU) and L-glutamine. HU is ineffective at Hb F induction in approximately 50% of patients(6). While polymerization of sickle hemoglobin (HbS) has been traditionally considered the driving force in the hemolysis of sickle cell disease (SCD), the excessive reactive oxygen species (ROS) generated from red blood cells with further amplification by intravascular hemolysis also are a major contributor to SCD disease pathology. This review article will highlight a new class of drugs, lysine specific demethylase (LSD1) inhibitors that induce HbF and reduce ROS.
... The beneficial biochemical role of Se in erythrocytes was first defined in 1973 in the form of selenoenzyme glutathione peroxidases (Gpxs) that highlighted the important role of dietary Se, which contributed, in part, to cellular stabilization [18]. In the recent years, Se deficiency has been linked to anemia associated with aging and chronic inflammatory diseases in humans [19][20][21][22]. In addition, rodent dietary models and transgenic models have been developed to demonstrate the direct biological functions of Se and selenoproteins in erythrocytes and erythropoiesis in mammalian systems [23][24][25][26][27]. Se and selenoproteins have emerged to be crucial and beneficial to erythroid cells and erythropoiesis, where they are intricately involved in multiple ways. ...
Article
Selenium (Se) is incorporated as the 21st amino acid selenocysteine (Sec) into the growing polypeptide chain of proteins involved in redox gatekeeper functions. Erythropoiesis presents a particular problem to redox regulation as the presence of iron, heme, and unpaired globin chains lead to high levels of free radical-mediated oxidative stress, which are detrimental to erythroid development and can lead to anemia. Under homeostatic conditions, bone marrow erythropoiesis produces sufficient erythrocytes to maintain homeostasis. In contrast, anemic stress induces an alternative pathway, stress erythropoiesis, which rapidly produces new erythrocytes at extramedullary sites, such as spleen, to alleviate anemia. Previous studies suggest that dietary Se protects erythrocytes from such oxidative damage and the absence of selenoproteins causes hemolysis of erythrocytes due to oxidative stress. Furthermore, Se deficiency or lack of selenoproteins severely impairs stress erythropoiesis exacerbating the anemia in rodent models and human patients. Interestingly, erythroid progenitors develop in close proximity with macrophages in structures referred to as erythroblastic islands (EBIs), where macrophage expression of selenoproteins appears to be critical for the expression of heme transporters to facilitate export of heme from macrophage stores to the developing erythroid cells. Here we review the role of Se and selenoproteins in the intrinsic development of erythroid cells in addition to their role in the development of the erythropoietic niche that supports the functional role of EBIs in erythroid expansion and maturation in the spleen during the recovery from anemia.
... Apart from cardiomyopathy as seen in Keshan disease, Se deficiency appears to be a cofactor in the anemia associated with chronic inflammatory diseases. [34][35][36] Furthermore, previous studies indicate a protective role for Se and selenoproteins in erythrocytes from oxidative damage. [37][38][39][40] However, the physiological functions of specific selenoproteins that are involved in erythropoiesis remain unclear. ...
Article
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Micronutrient selenium (Se) plays a key role in redox regulation through its incorporation into selenoproteins as the 21st amino acid selenocysteine (Sec). Because Se deficiency appears to be a cofactor in the anemia associated with chronic inflammatory diseases, we reasoned that selenoproteins may contribute to erythropoietic recovery from anemia, referred to as stress erythropoiesis. Here, we report that loss of selenoproteins through Se deficiency or by mutation of the Sec tRNA (tRNA[Sec]) gene (Trsp) severely impairs stress erythropoiesis at 2 stages. Early stress erythroid progenitors failed to expand and properly differentiate into burst-forming unit-erythroid cells , whereas late-stage erythroid progenitors exhibited a maturation defect that affected the transition of proerythroblasts to basophilic erythroblasts. These defects were, in part, a result of the loss of selenoprotein W (SelenoW), whose expression was reduced at both transcript and protein levels in Se-deficient erythroblasts. Mutation of SelenoW in the bone marrow cells significantly decreased the expansion of stress burst-forming unit-erythroid cell colonies, which recapitulated the phenotypes induced by Se deficiency or mutation of Trsp Similarly, mutation of SelenoW in murine erythroblast (G1E) cell line led to defects in terminal differentiation. In addition to the erythroid defects, the spleens of Se-deficient mice contained fewer red pulp macrophages and exhibited impaired development of erythroblastic island macrophages, which make up the niche supporting erythroblast development. Taken together, these data reveal a critical role of selenoproteins in the expansion and development of stress erythroid progenitors, as well as the erythroid niche during acute anemia recovery.
... Oxidative stress and inflammation are intrinsic to SCD and inextricably linked to its pathophysiology [23,96,. SCD patients have an imbalance between the production of oxidants and antioxidant capacity, which is a critical factor in endothelial cell dysfunction, inflammation, vasoocclusion, and organ pathology [162][163][164][165][166][167][168][169][170][171][172]. There are multiple potential sources of oxidants in SCD, including accelerated hemoglobin S (HbS) autoxidation [173], released heme/iron catalyzed Fenton reactions [174], increased expression and activity of various isoforms of NADPH oxidase (NOX) [23,135,175,176], xanthine oxidase [177], cytochrome P450, cyclo-oxygenase [178], mitochondria [179], and uncoupled NOS [180]. ...
Article
The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.
... and glutathione peroxidase compared with non-SCD patients (3,57). Heme release from RBCs during hemolysis is also evident in some pathologic events in the murine model of SCD (84). ...
Article
Significance: Inflammation can be defined as a protective immune response against harmful exogenous and endogenous stimuli. Nevertheless, prolonged or autoimmune inflammatory response are likely to cause pathological states associated with a production of inflammation-associated molecules along with ROS (reactive oxygen species). KEAP1-NRF2 (Kelch-like ECH-associated protein 1-Nuclear factor erythroid 2-related factor 2) signaling provides a cell protection mechanism against oxidative insults when endogenous stress defense mechanisms are imbalanced. Understanding the roles of the KEAP1-NRF2 system in inflammation caused by various types of stimuli may aid in the development of new therapies. Recent Advances: There have been tremendous advances in understanding the mechanism by which the KEAP1-NRF2 pathway abrogates inflammation. In addition to the well-established ROS-dependent pathway, recent studies have provided evidence of the direct repression of the transcription of pro-inflammatory cytokine genes, such as IL1b and IL6 (encoding Interleukin-1β and Interleukin-6, respectively). Furthermore, the expanding functions of NRF2 have elicited interest in the development of therapeutic modalities for inflammatory diseases including multiple sclerosis and sickle cell disease (SCD). Critical Issues and Future Directions: Despite progress in the understanding of molecular mechanisms supporting the roles NRF2 plays during inflammation, the relationship between NRF2 and other transcription factors and mediators of inflammation still remains ambiguous. Further studies are required to address the effects of functional polymorphisms in KEAP1 and NRF2 that modify susceptibility to specific disease-related inflammation. Comprehensive analyses in the future should explore tissue- or cell-type specific NRF2 activation to elaborate effects of NRF2 induction.
... Enzymatic antioxidant activity and capacity has been widely studied in patients with homozygous sickle cell disease (Das & Nair, 1980;Adelekan et al, 1989;Natta et al, 1990;Goswami & Ray, 2011;Chirico & Pialoux, 2012;El-Ghamrawy et al, 2014) and in murine models of sickle cell disease (Dasgupta et al, 2006;Charrin et al, 2015) compared to controls. However, to the best of our knowledge no study has previously compared enzymatic antioxidant activity between SS, SC and AA children. ...
Article
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Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). In this context microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end-products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated to nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain better preserved microvascular function in this group.
... The high sickle RBC turnover rate is likely to release large amount of heme and iron, which promote excessive ROS production [63] reflected by high splenic AOPP levels in SS mice concomitantly to reduced SOD and GPx activities. These latter results confirm those of Natta [64] and Schacter et al. [65] who respectively showed that GPx and SOD levels decreased proportionally to disease severity in homozygous SCD patients. These results suggest a more rapid degradation and/or an inhibition of the antioxidant enzymes possibly from oxygen radicals. ...
Article
The Townes mouse model of homozygous sickle cell disease (SS) has emerged as the major experimental model for studying pathophysiological mechanisms of human sickle cell disease (SCD). We therefore investigated hematological and hemorheological parameters as well as organ-specific inflammatory and oxidative stress molecular profiles in these animals in steady state conditions. Evidences of SCD-related intravascular hemolysis, impaired red blood cell (RBC) deformability, leukocytosis and altered plasma nitric oxide byproducts (NOx) level were found in the SS mice. The SS mice have damaged, enlarged and dysfunctional spleen as attested by high AOPP levels, low SOD and GPx activities and low pro-inflammatory cytokines mRNA expression. SS mice exhibited cardiomegaly, high cardiac mRNA levels of proinflammatory markers and low cardiac GPx activity. While lungs did not display any noticeable defects, liver and kidney were particularly sensitive to oxidative stress and inflammation as suggested by high AOPP levels in both organs, elevated renal NF-κB and TNF-α, and increased hepatic VCAM-1 and IL-1β. Our data indicate a tissue-specific phenotype regarding oxidative stress and inflammation in SS mice that may help to optimize the development of novel potential drug treatments.
... Asymmetric dimethylarginine (ADMA) formation and resulting hyperhomocysteinaemia in SCA may also lead to ROS generation and nitric oxide synthase may produce superoxide rather than NO, in the absence of l-arginine (Xia et al. 1996;Wood and Granger 2007). On the other hand, endogenous anti-oxidant defense mechanisms are altered in SCA, as individuals demonstrate a reduction in levels of important enzymatic antioxidants, including glutathione peroxidase and superoxide dismutase, and low levels of nonenzymatic antioxidants such as vitamins A, C and E (Amer et al. 2006;Natta et al. 1990;Schacter et al. 1988). ...
Chapter
Inflammatory processes play a key role in the initiation of the acute painful vaso-occlusive crises that constitute the main cause of hospitalization in individuals with sickle cell anemia, as well as many of its numerous complications, including autosplenectomy, pulmonary hypertension, acute chest syndrome, leg ulcers, nephropathy and stroke. Ischemia-reperfusion injury (due to microvascular and macrovascular occlusions), membrane alterations of the sickle red blood cell, and hemolysis may all trigger endogenous proinflammatory signals (damage-associated molecular patterns-DAMPs) that lead to the vicious circle of pan-cellular activation, inflammatory mediator release, leukocyte recruitment and occlusive mechanisms that result in the chronic inflammatory state that is associated with sickle cell anemia. We, herein, review the probable primary inflammatory triggers that initiate inflammatory mechanisms in the disease and postulate the cells and molecules that may contribute to establish chronic inflammation. The anti-inflammatory effects of hydroxyurea are discussed, as are novel anti-inflammatory approaches currently under study.
... 154 With advancement in screening technology it is possible to detect a greater range of disorders. 155 Glutathione deficiency has been linked to occupational exposure that causes oxidative stress, 156 coronary heart disease, 157 retinal dysfunction, 76 pulmonary inflammation, 88 cystic fibrosis, 75,158,159 diabetes, 160 sickle cell anaemia, 161 coeliac disease, 162 and lupus. 163 Glutathione stransferase is strongly associated with asthma, 164,165 with interventions that restore GSH balance proposed to combat GSH oxidation. ...
Article
This paper explores the introduction of a screening test to highlight impaired immune system status for newborn infants and its efficacy as a preventative clinical measure. Moreover, it is suggested that screening of the infantile immune system has the potential to highlight susceptibility to a range of infant and childhood diseases, bestowing an opportunity to introduce early intervention to reduce the incidence of these diseases. Development of the neonatal immune system is an important health issue, implicated in many childhood problems such as allergies, infection, and autoimmunity. The neonate has a limited immune system and ability to combat bacteria. Depleted levels of the tripeptide reduced glutathione (GSH) have been linked to numerous conditions and its intracellular level is acknowledged as an indicator of immune system function. Introduction of an immune system screening programme for infants is formally reviewed and assessed. Several benefits are reported in the treatment of impaired immune systems, a trial screening programme is proposed for at-risk infants to gather further evidence as to its efficacy. Infants at risk of impaired immune system function include cystic fibrosis, premature infants, and low birth weight infants. The interventions include breastfeeding, milk banks, and appropriate formula to support the immune system.
... GSH concentration is significantly reduced in SCD patients [51,57], with some studies noting a 50% decrease in sickle erythrocytes compared with normal erythrocytes [70]. GPx concentrations are also reduced [55,71], with a direct relationship to the disease severity [56]. A contrasting study by Gizi et al. [53] reported higher GPx activity compared to controls, while no significant difference was found regarding GR activity, a key enzyme on the regeneration of GSH from GSSG by using electrons from NADPH. ...
Article
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Erythrocytes have an environment of continuous prooxidant generation due to hemoglobin (Hb) presence that represents an additional and quantitatively significant source of superoxide (O2(•-)) generation in biological systems. In order to counteract oxidative stress, erythrocytes have a self-sustaining antioxidant defense system. Therefore, red blood cells (RBCs) uniquely function to protect Hb via a selective barrier allowing gaseous and other ligand transport as well as providing antioxidant protection not only to themselves but also to other tissues and organs in the body. HbS molecules suffer repeated polymerization/depolymerization generating greater extent of reactive oxygen species (ROS), which can lead to a cyclic cascade characterized by blood cell adhesion, hemolysis, vaso-occlusion, and ischemia-reperfusion injury. In other words, sickle cell disease is intimately linked to a pathophysiologic condition of multiple sources of prooxidant processes with consequent chronic and systemic oxidative stress. For this reason, newer therapeutic agents that can target oxidative stress may constitute valuable means for preventing or delaying the development of organ complications.
... Specifically in SCA, oxidative stress could play a role in microvascular dysfunction, in vaso-occlusion, and in the development of extensive organ damage observed in these patients (Wun, 2001;Wood & Granger, 2007). In addition, patients with chronic haemolysis have very low levels of several antioxidants as compared with normal subjects (Chiu et al, 1990;Natta et al, 1990;Suthutvoravut et al, 1993;Chan et al, 1999;Cesquini et al, 2003;Hasanato, 2006;Ray et al, 2007;Ren et al, 2008;Claster et al, 2009;Nur et al, 2011b). In this scenario, it is plausible to infer that antioxidants might be beneficial in their treatment (Amer et al, 2008a;Fibach & Rachmilewitz, 2008;Nur et al, 2011a,b). ...
Article
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Erythrocytes from sickle cell anaemia (SCA) patients continuously produce larger amounts of pro-oxidants than normal cells. Oxidative stress seems to primarily affect the membrane and results in haemolysis. The use of antioxidants in vitro reduces the generation of pro-oxidants. To evaluate the impact of vitamins C (VitC) and E (VitE) supplementation in SCA patients, patients over 18 years were randomly assigned to receive VitC 1400 mg + VitE 800 mg per day or placebo orally for 180 d. Eighty-three patients were enrolled (44 vitamins, 39 placebo), median age 27 (18-68) years, 64% female. There were no significant differences between the two groups regarding clinical complications or baseline laboratorial tests. Sixty percent of the patients were VitC deficient, 70% were VitE deficient. Supplementation significantly increased serum VitC and E. However, no significant changes in haemoglobin levels were observed, and, unexpectedly, there was a significant increase in haemolytic markers with vitamin supplementation. In conclusion, VitC + VitE supplementation did not improve anaemia and, surprisingly, increased markers of haemolysis in patients with SCA and S-β(0) -thalassaemia. The exact mechanisms to explain this findings and their clinical significance remain to be determined.
... In addition to the oxygen species that are formed in SCD, the protective mechanisms such as antioxidants are decreased. Those that provide enzymatic defense, including SOD, GPX, catalase, and heme oxygnease-1, and those that scavenge free radicals, such as glutathione, vitamin C, and vitamin E, are most affected (51). ...
Article
Sickle cell disease (SCD) is a class of hemoglobinopathy in humans, which causes a disruption of the normal activities in different systems. Although this disease begins with the polymerization of red blood cells during its deoxygenating phase, it can erupt into a cascade of debilitating conditions such as ischemia-reperfusion injury, inflammation, and painful vaso-occlusion crises. The purpose of this review is to discuss how these phenomena can result in the formation of oxidative stress as well as limit nitric oxide (NO) bioavailability and decrease antioxidant status. The cumulative effects of these traits cause an increase in other forms of reactive oxygen species (ROS), which in turn intensify the symptoms of SCD and generate a vicious circle. Finally, we will discuss antioxidant therapeutic strategies that limit ROS generation and subsequently increase NO bioavailability with respect to endothelial protection in SCD.
... A compensatory increase in antioxidants is expected in the setting of the high oxidative burden of SCD. Oxidative stress is believed to be a consequence of several mechanisms, including: hemolysis, causing NO depletion [71] and generation of oxidant species72737475767778; generation of reactive oxidative species by upregulation of NADPH oxidase and xanthine oxidase [72]; chronic ischemic reperfusion in the setting of intermittent microvascular vasoocclusion [79]; and loss of catalytic antioxidants80818283848586. Oxidative stress is thought to promote the formation of irreversibly sickled cells, which, in a vicious cycle, fuels further oxidative stress. ...
Article
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The expanding realm of exploratory proteomics has added a unique dimension to the study of the complex pathophysiology involved in sickle cell disease. A review of proteomic studies published on sickle cell erythrocytes and plasma shows trends of upregulation of antioxidant proteins, an increase in cytoskeletal defects, an increase in protein repair and turnover components, a decrease in lipid raft proteins and apolipoprotein dysregulation. Many of these findings are consistent with the pathophysiology of sickle cell disease, including high oxidant burden, resulting in damage to cytoskeletal and other proteins, and erythrocyte rigidity. More unexpected findings, such as a decrease in lipid raft components and apolipoprotein dysregulation, offer previously unexplored targets for future investigation and potential therapeutic intervention. Exploratory proteomic profiling is a valuable source of hypothesis generation for the cellular and molecular pathophysiology of sickle cell disease.
... The major defense systems include those that scavenge free radicals -such as glutathione, vitamin C and vitamin E -and the enzymatic defenses such as superoxide dismutase, glutathione peroxidase and catalase. 7,8 Even so, the ROS may cause deep lesions in erythrocytes, decreasing their period of life, particularly in patients with sickle cell anemia and thalassemias. These lesions include damage to biological macromolecules such as proteins and lipids. ...
Article
Oxidative stress plays a crucial role in the sickle cell disease. Alpha-lipoic acid (ALA) is a potent antioxidant that is employed in the treatment of several diseases. The objective of this study was to test the ALA effect in the sickle cell disease (SCD) treatment. Sixty subjects were selected and divided into groups according to the hemoglobin profile: AA (normal), AS (SCD trait subject) and SS (SCD patient). Patients were randomized into a placebo-controlled trial and treated with either ALA (200 mg) or vehicle. Blood samples were collected before supplementation and after 3 months of treatment. Catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and total antioxidant status (TAS) were evaluated as measure of antioxidant defense. Lipid and protein damages were quantified by malondialdehyde (MDA) and carbonyl assays, respectively. CAT activity significantly increased in the AS group after ALA treatment and GPx activity presented significant decrease in all groups. SOD activity was not different in any group. Data on MDA and carbonyl levels showed significant reduction in the AA group with ALA treatment. TAS decreased in the same group. ALA treatment protected AA individuals from oxidative damage to lipids and proteins. In SCD subjects, the dose applied was not effective to prevent the oxidative damage.
... Our data support the growing evidence that patients with SCA are subjected to chronic oxidative stress and are able to oxidative damage in biological macromolecules such as proteins and lipids. 16,17 Reactive oxygen species can cause damage to biological macromolecules such as proteins, lipids and DNA. [18][19][20] The unsaturated chain of membrane fatty acids can readily react with free radicals and undergo peroxidation. ...
Article
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Sickle cell anemia (SCA) is a hereditary disorder with higher potential for oxidative damage due to chronic redox imbalance in red cells. We measured antioxidant enzymes including catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). We also determined oxidative damage of proteins in hemolysate of red blood cells (RBCs) and plasma (carbonyl assay). We characterized the membrane damage in terms of lipid peroxidation by accumulation of malonaldehyde (MDA) by HPLC in 30 healthy controls and 20 SCA patients in steady-state condition. Twenty (9 males/11 females) adult SCA patients and 30 healthy controls were studied. All patients and control subjects had antioxidant (CAT, GPx, SOD, carbonyl and MDA) and hematological parameters done. Our data show that SCA patients had significant higher GPx and SOD activities than healthy controls. Carbonyl assay was noted in plasma but not in hemolysate. An enhanced production of MDA was observed in the serum of SCA patients. Our data support the growing evidence that patients with SCA are subjected to chronic oxidative stress and are able to oxidative damage in biological macromolecules such as proteins and lipids.
... Whether reduced anti-oxidant defences cause or are an effect of oxidative stress in SCD patients remains unclear. Low levels of vitamins A, C and E, 12-14 selenium and glutathione peroxidase 15 have been reported in SCD patients. Reports of low 16 to normal 17 levels of RBC GSH (with intact GSH synthesis) in sickle cell anaemia patients compared with normal controls 16 suggest an impaired anti-oxidant status in these patients. ...
Article
1. Sickle cell disease (SCD) is an inherited disorder of haemoglobin synthesis that is associated with significant morbidity and mortality due to sequelae of episodic vaso-occlusive events: pain crises and multiorgan damage. The microvascular responses to the initiation, progression and resolution of vaso-occlusive events are consistent with an inflammatory phenotype as suggested by activation of multiple cell types, an oxidatively stressed environment and endothelial cell dysfunction. 2. Decreased anti-oxidant defences in SCD patients and mice are accompanied by activation of enzymatic (NADPH oxidase, xanthine oxidase) and non-enzymatic (sickle haemoglobin auto-oxidation) sources of reactive oxygen species. The resultant oxidative stress leads to dysfunction/activation of arteriolar and venular endothelial cells, resulting in impaired vasomotor function and blood cell-endothelial cell adhesion. 3. Changes in substrate and cofactor availability for endothelial cell nitric oxide synthase may underlie reactive oxygen- and nitrogen-induced events that contribute to SCD-induced vasculopathy. 4. The emerging role of reactive oxygen and nitrogen species in the pathogenesis of SCD provides a platform for the development of novel agents to treat this painful and lethal disease.
Thesis
Le premier objectif de cette thèse était de déterminer les effets isolés et combinés de l'alpha thalassémie, des polymorphismes inducteurs (QTLs) de l'HbF et du génotype G6PD dans un contexte d'évolution naturelle de la drépanocytose (Etudes 1 et 2). L'étude 1 a permis d'évaluer pour la première fois les fréquences alléliques de ces gènes modificateurs chez 301 enfants sénégalais SS. Contrairement aux autres populations africaines, le Variant Betica de la G6PD était majoritaire par rapport au variant A(-). De plus, 12% de notre cohorte avait un déficit en G6PD combiné à une absence d'alpha-thalassémie. Ces patients-là seront à privilégier pour la réalisation d'un Doppler transcrânien. Les résultats obtenus dans l'étude 2 nous ont permis de conclure que l'alpha-thalassémie et les QTLs de l'HbF sont interdépendants et ne doivent pas être étudiés séparément pour une prédiction clinique précise. En effet, une combinaison d'alpha-thalassémie avec au moins 2 QTLs de l'HbF est nécessaire pour retarder de manière significative la première complication de la maladie. Cependant, une alpha-thalassémie homozygote, même associée à 3 à 6 QTLs de l'HbF, augmente la fréquence des CVO pendant l'enfance. Par conséquent, une alpha-thalassémie hétérozygote avec au moins deux QTL HbF constituerait le génotype le plus favorable relativement à la survenue des CVO. Le deuxième objectif de cette thèse était d'étudier les interrelations entre le stress oxydant (phénotype et génotype) et la sévérité clinique de la maladie (Etudes 3 à 4). La drépanocytose est caractérisée par un stress oxydatif élevé pouvant expliquer une partie des manifestations cliniques. Nos résultats ont montré que l'alpha-thalassémie homozygote semble diminuer le stress oxydatif, ce qui contribuerait à son effet protecteur sur certaines complications du sous-phénotype hémolytique. En outre, les patients qui ont le moins d'hospitalisations et de CVO semblent présenter une meilleure défense antioxydante (activités catalase et GPx augmentées). Dans l'étude 4 nous avons étudié 4 SNPs de gènes du stress oxydant (rs4880 du gène SOD2, rs207454 du gène XO, rs233322 du gène MPO et rs35652124 du gène NFE2L2). Le SNP rs4880 aurait un effet favorable au niveau biologique (réticulocytose moindre, activité GPx augmentée) mais sans traduction clinique associée. Il en est de même pour rs233322 qui serait associé à une hémolyse et à un stress oxydatif (AOPP) plus importants. En revanche, une tendance à un effet protecteur de rs207454 vis-à-vis de certaines complications (hospitalisations, ostéonécrose, sepsis, STA) a été observée. Notre travail contribue à la compréhension de l'impact des gènes modificateurs dans la drépanocytose. Il pourrait donc permettre, via une sélection positive des patients à risque, d'améliorer la prise en charge de la maladie dans les pays où les traitements de fond (hydroxyurée, doppler transcrânien, échanges transfusionnels) ne peuvent être proposés à tous
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Hereditary hemolytic anemias are one of the most widespread pathologies in the world and is also in Azerbaijan. Haemoglobinopathies-major and intermediate β-thalassemia, sickle cell anemia and of enzymopathy-deficiency enzyme glucose-6-phosphate dehydrogenase are the most frequently among these pathologies. The oxidation sensitivity of erythrocytes in these pathologies is high and study of the regulation mechanisms of the antioxidant systems, including the investigation of the role of selenium which is the one of its major components, is of interest. Metabolism of selenium depends on the regional supply, different types of pathology and we set a goal to study its participation in these pathologies. It is shown that the red blood cells of these patients have a high oxidation sensitivity (accumulation of products reacting with tiobarbiture acid), reduced content glutathione in them, the activity of antioxidant enzymes (catalase and glutathione peroxidase) and violated metabolism of selenium. Additionally, the relation between selenium content and glutathioneperoxidase activity slighly changes in the anemia and depends on its type. Citation: Guliyeva R.T., Huseynova S.Y., Huseynov T.M.*, 2016. A comparative characteristic of oxidative processes in erythrocytes at the hereditary hematological pathologies and selenium participation in them.
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Oxidative stress is a disturbance in the equilibrium among free radicals, reactive oxygen species, and endogenous antioxidant defense mechanisms. Oxidative stress is a result of imbalance between the production of reactive oxygen and the biological system’s ability to detoxify the reactive intermediates or to repair the resulting damage. Mounting evidence has implicated oxidative stress in various physiological and pathological processes, including DNA damage, proliferation, cell adhesion, and survival of cancer cells. Glutathione peroxidases (GPxs) (EC1.11.1.9) are an enzyme family with peroxidase activity whose main biological roles are to protect organisms from oxidative damage by reducing lipid hydroperoxides as well as free hydrogen peroxide. Currently, 8 sub-members of GPxs have been identified in humans, all capable of reducing H2O2 and soluble fatty acid hydroperoxides. A large number of publications has demonstrated that GPxs have significant roles in different stages of carcinogenesis. In this review, we will update recent progress in the study of the roles of GPxs in cancer. Better mechanistic understanding of GPxs will potentially contribute to the development and advancement of improved cancer treatment models.
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Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs) which accelerates their hemolysis. Normal RBC precursors eliminate their mitochondria during the terminal differentiation process. Strikingly, we observed an increased percentage of RBCs which retain mitochondria in SCD patients’ blood samples compared to healthy individuals In addition, we demonstrate that excessive levels of ROS in SCD are associated with this abnormal mitochondrial retention by an experimental SCD mouse model. Interestingly, LSD1 inhibitor RN-1 and mitophagy inducing agent mTOR inhibitor, Sirolimus, increased red blood cell lifespan and reduced ROS accumulation in parallel with reduction of mitochondria retaining RBCs in the SCD mouse model. Furthermore, gene expression analysis of SCD mice treated with RN-1 showed increased expression of mitophagy genes. Our findings suggest that reduction of mitochondria retaining RBCs may provide a new therapeutic approach to prevent excessive ROS in SCD.
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Instrumental Neutron Activation Analysis (INAA) and Proton-Induced X-ray Emission (PIXE) analysis (employed as a complementary technique) have been used to determine the concentration of 11 elements in blood samples and its components erythrocytes and plasma obtained, from three groups of subjects in Nigeria viz: sickle cell anaemia (SCA) subjects, subjects with sickle cell trait and normal control subjects. The results suggest that SCA subjects have significantly higher concentrations of Na, Cl, Ca and Cu in their whole blood and erythrocytes and a higher concentration, of Cl and Cu in their plasma relative to the control subjects. Furthermore, a significantly lower concentration of K, Fe, Zn, Se, Br and Rb were found in the whole blood and erythrocytes of the SCA subjects as compared to the controls while the concentration of K and Fe in the plasma of the SCA subjects were however, found to be significantly higher than that of the control group. The study also shows that there was no significant differences between the concentration of these 11 elements in the group with sickle cell trait and the normal control group.
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Whilst there is evidence of endothelial dysfunction in sickle cell disease (SCD), whether this affects regulation in the microcirculation is not known.  We studied 19 patients with SCD, eight with sickle cell-haemoglobin C (HbSC), 11 with homozygous sickle cell (HbSS) disease and 11 matched control subjects with normal haemoglobin genotype (HbAA). Vasodilator responses were evoked by iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) in finger and forearm, cutaneous red cell flux (RCF) being measured by laser Doppler fluximetry. Increases in RCF evoked in the finger by ACh were not different between SCD and HbAA subjects (P = 0·789), but were smaller in patients with HbSS than HbSC (P < 0·05). By contrast, increases in RCF evoked in forearm by ACh were greater in SCD than HbAA subjects (P < 0·05) and similar in patients with HbSC and HbSS. Increases in RCF evoked by SNP did not differ between patients with SCD and HbAA subjects in finger or forearm. Conclusions: Our results indicate that endothelium-dependent cutaneous vasodilatation is augmented in forearm of patients with SCD relative to HbAA subjects, but impaired in the finger of SCD patients with the more severe HbSS genotype. Thus, endothelial dysfunction associated with SCD is not accompanied by generalised impairment in endothelium-dependent dilatation, but with more localised impairment that includes the fingers of patients with HbSS.
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Chronic redox imbalance in erythrocytes of individuals with sickle cell disease (SCD) contributes to oxidative stress and likely underlies common etiologies of hemolysis. We measured the amounts of six antioxidant enzymes-SOD1, catalase, glutathione peroxidase 1 (GPx1), as well as peroxiredoxins (Prxs) I, II, and VI-in red blood cells (RBCs) of SCD patients and control subjects. The amounts of SOD1 and Prx VI were reduced by about 17% and 20%, respectively, in SCD RBCs compared with control cells. The amounts of Prx II and GPx1 did not differ between SCD and normal RBCs. However, about 18% of Prx II was inactivated in SCD RBCs as a result of oxidation to sulfinic Prx II, whereas inactive Prx II was virtually undetectable in control cells. Furthermore, GPx1 activity was reduced by about 33% in SCD RBCs, and the loss of activity was correlated with hemolysis in SCD patients. RBCs from SCD patients taking hydroxyurea demonstrated 90% higher GPx1 activity than did those from untreated SCD patients, with no differences seen for the other catalytic antioxidants. Hydroxyurea induced GPx1 expression in multiple cultured cell lines in a manner dependent on both p53 and NO-cGMP signaling pathways. GPx1 expression represents a previously unrecognized potential benefit of hydroxyurea treatment in SCD patients.
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Endothelial damage and inflammation make a significant contribution to the pathophysiology of sickle cell disease (SCD) and the beta-thalassemia syndromes. Endothelial dysfunction and ensuing vasculopathy are implicated in pulmonary hypertension in the hemoglobinopathies and endothelial activation and endothelial-blood cell adhesion, accompanied by inflammatory processes and oxidative stress, are imperative to the vaso-occlusive process in SCD. Herein, we discuss the role that the endothelium plays in all of these processes and the effect that genetic modifiers and hydroxyurea therapy may have upon endothelial interactions. Therapies targeting the endothelium and endothelial interactions may represent a promising approach for treating these diseases.
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Sickle cell disease is an inherited disorder of hemoglobin (Hb) synthesis, caused by a single nucleotide substitution (GTG>GAG) at the sixth codon of the beta-globin gene, leading to the production of a defective form of Hb, Hb S. When deoxygenated, Hb S polymerizes, damaging the sickle erythrocyte and it is this polymerization that is the primary indispensable event in the molecular pathogenesis of sickle cell disease. Hb S polymerization results in a series of cellular alterations in red cell morphology and function that shorten the red cell life span and leads to vascular occlusion. Sickle cell disease vaso-occlusion is now known to constitute a complex multifactorial process characterized by recurrent vaso-occlusion, ischemia-reperfusion injury, and oxidative stress with consequent vascular endothelial cell activation that induces a chronic inflammatory state in sickle cell disease individual and is propagated by elevated levels of circulating inflammatory cytokines. Activation of the endothelium results in the induction of endothelial adhesion molecule expression that mediates red and white cell adhesion to the vessel wall and the formation of heterocellular aggregates, followed by secondary red cell trapping, all of which contribute to reduced blood flow and eventually obstruction of the micro-circulation. Reduced nitric oxide bioavailability, caused principally by its consumption by cell-free Hb, liberated during intravascular hemolysis, contributes to this process by facilitating vasoconstriction and adhesion molecule activity.
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In previous studies, we found that homozygous sickle cell (HbSS) patients, compared with their healthy (HbAA) counterparts, had reduced levels of the omega-3 fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, in red cells, platelets, and mononuclear cells. These differences were not due to lower intake of the two fatty acids. We have investigated whether reduced antioxidant status in the patients could help explain the observed phenomenon. Blood specimens previously obtained for fatty acid study from Nigerian (26 HbSS and 30 HbAA) and British (30 HbSS, 9 sickle cell-hemoglobin C/HbSC, and 15 HbAA) subjects were analyzed for antioxidant status. The Nigerian HbSS patients compared with the controls had lower plasma retinol, alpha-tocopherol, and beta-carotene concentrations (p < 0.005) and reduced activity of red cell Cu/Zn-superoxide dismutase (Cu/Zn-SOD) (p < 0.05). Similarly, the British HbSS group had reduced concentrations of plasma alpha-tocopherol (p < 0.005), and activities of red cell Cu/Zn-superoxide dismutase (p < 0.05) and Se-glutathione peroxidase (Se-GPx) (p < 0.005) than the controls. In addition, the British patients in comparison with those who had HbSC, a mild form of the disease, had lower alpha-tocopherol than that of the HbAA controls (p < 0.005). In the British sickle cell patients, there was a positive correlation between red cell ethanolamine phosphoglyceride (EPG) DHA and Cu/Zn-SOD activity (r = 0.700, p < 0.05), choline phosphoglyceride (CPG) DHA and Se-GPx activity (r = 0.605, p < 0.05), and CPG EPA and Se-GPx activity (r = 0.558, p > 0.05). Similarly, the percent DHA in red cell EPG was positively related with the activity of Se-GPx in the patients with HbSC (r = 0.674, p < 0.05). These findings suggest that the lower levels of membrane EPA and DHA in blood cells of the HbSS patients could be due to peroxidation resulting from a compromised antioxidant competence.
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Poor growth and under-nutrition are common in children with sickle cell disease (SCD). This review summarises evidence of nutritional status in children with SCD in relation to anthropometric status, disease severity, body composition, energy metabolism, micronutrient deficiency and endocrine dysfunction. A literature search was conducted on the Medline/PUBMED, SCOPUS, SciELO and LILACS databases to July 2007 using the keywords sickle cell combined with nutrition, anthropometry, growth, height and weight, body mass index, and specific named micronutrients. Forty-six studies (26 cross-sectional and 20 longitudinal) were included in the final anthropometric analysis. Fourteen of the longitudinal studies were conducted in North America, the Caribbean or Europe, representing 78.8% (2086/2645) of patients. Most studies were observational with wide variations in sample size and selection of reference growth data, which limited comparability. There was a paucity of studies from Africa and the Arabian Peninsula, highlighting a large knowledge gap for low-resource settings. There was a consistent pattern of growth failure among affected children from all geographic areas, with good evidence linking growth failure to endocrine dysfunction, metabolic derangement and specific nutrient deficiencies. The monitoring of growth and nutritional status in children with SCD is an essential requirement for comprehensive care, facilitating early diagnosis of growth failure and nutritional intervention. Randomised controlled trials are necessary to assess the potential benefits of nutritional interventions in relation to growth, nutritional status and the pathophysiology of the disease.
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The generation of reactive oxygen species (ROS) is a steady-state cellular event in respiring cells. Their production can be grossly amplified in response to a variety of pathophysiological conditions such as inflammation, immunologic disorders, hypoxia, hyperoxia, metabolism of drug or alcohol, exposure to UV or therapeutic radiation, and deficiency in antioxidant vitamins. Uncontrolled production of ROS often leads to damage of cellular macromolecules (DNA, protein, and lipids) and other small antioxidant molecules. A number of major cellular defense mechanisms exist to neutralize and combat the damaging effects of these reactive substances. The enzymic system functions by direct or sequential removal of ROS (superoxide dismutase, catalase, and glutathione peroxidase), thereby terminating their activities. Metal binding proteins, targeted to bind iron and copper ions, ensure that these Fenton metals are cryptic. Nonenzymic defense consists of scavenging molecules that are endogenously produced (GSH, ubiquinols, uric acid) or those derived from the diet (vitamins C and E, lipoic acid, selenium, riboflavin, zinc, and the carotenoids). These antioxidant nutrients occupy distinct cellular compartments and among them, there are active recycling. For example, oxidized vitamin E (tocopheroxy radical) has been shown to be regenerated by ascorbate, GSH, lipoic acid, or ubiquinols. GSH disulfides (GSSG) can be regenerated by GSSG reductase (a riboflavin-dependent protein), and enzymic pathways have been identified for the recycling of ascorbate radical and dehydroascorbate. The electrons that are used to fuel these recycling reactions (NADH and NADPH) are ultimately derived from the oxidation of foods. Sickle cell anemia, thalassemia, and glucose-6-phosphate-dehydrogenase deficiency are all hereditary disorders with higher potential for oxidative damage due to chronic redox imbalance in red cells that often results in clinical manifestation of mild to serve hemolysis in patients with these disorders. The release of hemoglobin during hemolysis and the subsequent therapeutic transfusion in some cases lead to systemic iron overloading that further potentiates the generation of ROS. Antioxidant status in anemia will be examined, and the potential application of antioxidant treatment as an adjunct therapy under these conditions will be discussed.
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Possible pathogenetic processes in sickle cell disease include antioxidants, endothelial and platelet changes, and hypercoagulability. Hypothesizing relationships between these processes, we recruited 47 young adult patients (mean age 19 years) with homozygous sickle cell disease and 40 age-, race- and sex-matched healthy controls and measured plasma markers representative of these processes. We found raised plasma von Willebrand factor (P = 0.001) and intercellular adhesion molecule (P = 0.016, both marking endothelial perturbation, but the latter also marking inflammation), raised soluble P selectin (P = 0.002) (marking platelet activation) and inflammation marker C reactive protein (P = 0.021), but reduced antioxidant capacity (P = 0.002) in patients compared with controls. There was no difference in fibrinogen and there was no significant correlation between any of the indices. Our data suggest that changes in endothelial and platelet function in sickle cell disease are unrelated to reduced antioxidant capacity.
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Glutathione peroxidase deficiency is the most recently described erythrocyte enzyme abnormality. This enzyme occupies a critical position in the pathways leading to the decomposition of peroxides in the erythrocyte. On the basis of our studies of patients with GSH-P deficiency, it appears that a spectrum of disease quite similar to that found in G-6-PD deficiency is present; this includes compensated haemolytic disease, drug-induced haemolysis and neonatal jaundice.
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Plasma tocopherol levels of less than 0.8 microgram/g lipid were considered indicative of a vitamin E-deficient status. Based on this criterion, 10 out of 13 sickle cell anemia patients who were not in crisis, were considered deficient in vitamin E as compared to none of 24 normal control subjects. Sickle cell anemia patients treated with 150 IU vitamin E (dl-alpha-tocopheryl acetate) three times a day for 1 to 2 months had plasma tocopherol levels similar to control subjects. The possible role of vitamin E status on the manifestation of sickle cell anemia is discussed. The present study confirmed the vitamin E-deficient status of subjects with beta-thalassemia. Six of seven patients with beta-thalassemia had tocopherol levels of less than 0.8 mg/g lipid.
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The authors examined the ability of antioxidants to prevent in vitro oxidant damage to the sickle red blood cell (RBC). One millimolar ascorbic acid and alpha-mercaptopropionylglycine significantly (p less than 0.005) protected against RBC Heinz body formation during incubation with acetylphenylhydrazine, while cysteine, cysteamine, and methionine did not. The effect of ascorbic acid was concentration dependent with concentrations as low as 0.1 mM having significant antioxidant effects. Ascorbic acid protected the RBC against hydrogen peroxide induced hemolysis as well (p less than 0.05). Ascorbic acid had a significant stimulatory effect on the rate of glucose oxidation by the pentose phosphate shunt (PPS), especially in the sickle RBC. Ascorbic acid did not protect the RBC from a patient with chronic hemolytic anemia due to G6PDTorrance from Heinz body formation, suggesting that an intact PPS is necessary for ascorbic acid to express its antioxidant properties. These data suggest that clinical trials should be undertaken to examine the efficacy of ascorbic acid in the treatment of SCD.