ascorbic-acid and Anemia--Sickle-Cell

Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017.. To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination.. We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers.. Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status.. Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE).. We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.

Topics: Acute Chest Syndrome; Adolescent; Adult; Anemia, Sickle Cell; Angiotensin-Converting Enzyme Inhibitors; Antisickling Agents; Ascorbic Acid; Captopril; Child; Creatinine; Humans; Hydroxyurea; Kidney Failure, Chronic; Lisinopril; Proteinuria

Sickle cell anemia is a genetically inherited disease in which the "SS" individual possesses an abnormal beta globin gene. A single base substitution in the gene encoding the human β -globin subunit results in replacement of β 6 glutamic acid by valine, leading to the devastating clinical manifestations of sickle cell disease. This substitution causes drastic reduction in the solubility of sickle cell hemoglobin (HbS) when deoxygenated. Under these conditions, the HbS molecules polymerize to form long crystalline intracellular mass of fibers which are responsible for the deformation of the biconcave disc shaped erythrocyte into a sickle shape. First-line clinical management of sickle cell anemia include, use of hydroxyurea, folic acid, amino acids supplementation, penicillinprophylaxis, and antimalarial prophylaxis to manage the condition and blood transfusions to stabilize the patient's hemoglobin level. These are quite expensive and have attendant risk factors. However, a bright ray of hope involving research into antisickling properties of medicinal plants has been rewarding. This alternative therapy using phytomedicines has proven to not only reduce crisis but also reverse sickling (in vitro). The immense benefits of phytomedicines and nutraceuticals used in the management of sickle cell anemia are discussed in this paper.

Topics: Anemia, Sickle Cell; Animals; Antioxidants; Antisickling Agents; Ascorbic Acid; Cajanus; Carica; Dietary Supplements; Erythrocytes; Hemoglobin, Sickle; Humans; Oxidative Stress; Phytotherapy; Plant Extracts; Plant Leaves

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.

Topics: Anemia; Anemia, Sickle Cell; Animals; Antioxidants; Ascorbic Acid; Glucosephosphate Dehydrogenase Deficiency; Humans; Nutrition Disorders; Oxidative Stress; Thalassemia; Vitamin E

Pathogenic organism can be considered as pro-oxidant agents because they produce cell death and tissue damage. In addition organism can be eliminated by specific cell defense mechanism which utilize in part, reactive oxygen radicals formed by oxidative stress responses. The cause of the necessarily defense process results in cell damage thereby leading to development of inflammation, a characteristic oxidative stress situation. This fact shows the duality of oxidative stress in infections and inflammation: oxygen free radicals protect against microorganism attack and can produce tissue damage during this protection to trigger inflammation. Iron, a transition metal which participates generating oxygen free radicals, displays also this duality in infection. We suggest also that different infectious pathologies, such as sickle cell anemia/malaria and AIDS, may display in part this duality. In addition, it should be noted that oxidative damage observed in infectious diseases is mostly due the inflammatory response than to the oxidative potential of the pathogenic agent, this last point is exemplified in cases of respiratory distress and in glomerulonephritis. This review analyzes these controversial facts of infectious pathology in relation with oxidative stress.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anemia, Sickle Cell; Animals; Antioxidants; Arachidonic Acid; Ascorbic Acid; Cells, Cultured; Child; Endotoxins; Fetus; Free Radicals; Glomerulonephritis; Humans; Infections; Inflammation; Iron; Malaria; Mice; Oxidative Stress; Phagocytosis; Rabbits; Respiratory Distress Syndrome; Sheep

This paper reviews the factors governing the rate of iron loading and iron toxicity in the thalassaemia syndromes and sickle cell disease. It outlines the main determinants of iron mobilization by the iron-chelating drug, desferrioxamine, together with the effects of this drug in clinical practice.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Deferoxamine; Drug Administration Schedule; Forecasting; Humans; Iron; Iron Chelating Agents; Sickle Cell Trait; Thalassemia

Topics: Altitude; Anemia; Anemia, Macrocytic; Anemia, Sickle Cell; Ascorbic Acid; Celiac Disease; Climate; Deficiency Diseases; Female; Folic Acid; Hematology; Humans; Infant; Metabolism; Nutrition Disorders; Parasitic Diseases; Pharmaceutical Preparations; Poisons; Polycythemia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Radiation Effects; Seasons; Sprue, Tropical; Vitamin B 12

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.

Topics: Adolescent; Adult; Aged; Anemia, Sickle Cell; Antioxidants; Ascorbic Acid; Biomarkers; Dietary Supplements; Double-Blind Method; Drug Utilization; Female; Hemolysis; Hospitalization; Humans; Inflammation; Male; Middle Aged; Oxidative Stress; Quality of Life; Reactive Oxygen Species; Sickle Cell Trait; Thalassemia; Vitamin E; Young Adult

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.

Topics: Adult; Anemia, Hemolytic, Autoimmune; Anemia, Sickle Cell; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Drug Evaluation; Erythrocytes; Erythrocytes, Abnormal; Heinz Bodies; Humans; In Vitro Techniques; Pentose Phosphate Pathway; Phenylhydrazines; Reticulocytes; Thalassemia; Tiopronin; Vitamin E; Vitamin E Deficiency

Topics: Anemia, Sickle Cell; Ascorbic Acid; Child; Child, Preschool; Drug Therapy, Combination; Folic Acid; Humans; Infant; Pilot Projects

Red cell rigidity is common in sickle cell disease (SCD). The contribution of oxidative stress on deformability remains unknown. This study investigated red blood cell (RBC) vitamin C concentrations in pediatric SCD (n=43) compared with healthy controls ( n =23) and developed a protocol to raise RBC vitamin C concentrations to measure the effect on deformability. Sickle cell RBC vitamin C concentrations seem low (20.5 μM, SD: 16.2 vs. 51.7 μM, SD: 15.8; P <0.0001). Vitamin C can be successfully loaded into sickle cell RBCs but seems to have minimal effect on deformability. Future studies are needed to understand the clinical implications of vitamin C deficiency in pediatric SCD.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Child; Erythrocyte Deformability; Erythrocytes; Erythrocytes, Abnormal; Humans; Vitamins

The sickle cell disease (SCD) is a hemolytic genetic anemia characterized by free heme and hemoglobin release into intravascular spaces, with endothelial activation. Heme is a proinflammatory molecule able to directly activate vascular endothelium, thus, endothelial dysfunction and vascular disease are major chronic events described in SCD. The aim of this study was to evaluate the production of endothelial nitric oxide synthase (eNOS), nitrite and hypoxia inducible factor alpha (HIF-α) in HUVECs (human umbilical vein endothelial cells) activated by heme in response to simvastatin, hydroxyurea (HU), and ascorbic acid therapies. eNOS and HIF-α production were evaluated by ELISA and nitrite was measured by the Griess technique. The production of HIF-α increased when the cells were stimulated by heme (p<0.01), while treatment with HU and simvastatin reduced the production (p<0.01), and treatment with ascorbic acid increased HIF-1a production by the cells (p<0.01). Heme increased eNOS production, (p<0.01) but showed a heterogeneous pattern, and the lowest concentrations of all the treatments reduced the enzyme production (p<0.01). The nitrite production by HUVECs was enhanced by stimulation with heme (p<0.001) and was reduced by treatment with HU (p<0.001), ascorbic acid (p<0.001) and simvastatin (p<0.01). In summary, our results suggest that the hemolytic vascular microenvironment in SCD requires different therapeutic approaches to promote clinical improvement, and that a combination of therapies may be a viable strategy for treating patients.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Cells, Cultured; Dose-Response Relationship, Drug; Heme; Human Umbilical Vein Endothelial Cells; Humans; Hydroxyurea; Hypoxia-Inducible Factor 1, alpha Subunit; Nitric Oxide Synthase Type III; Nitrites; Simvastatin

Metabolic signatures of specialized circulating hematopoietic cells in physiological or human hematological diseases start to be described. We use a simple and highly reproductive extraction method of erythrocytes metabolites coupled with a liquid chromatography-mass spectrometry based metabolites profiling method to determine metabolomes of normal and sickle cell erythrocytes. Sickle cell erythrocytes and normal erythrocytes metabolomes display major differences in glycolysis, in glutathione, in ascorbate metabolisms and in metabolites associated to membranes turnover. In addition, the amounts of metabolites derived from urea cycle and NO metabolism that partly take place within erythrocyte were different between normal and sickle cell erythrocytes. These results show that metabolic profiling of red blood cell diseases can now be determined and might indicate new biomarkers that can be used for the follow-up of sickle cell patients.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Cell Separation; Erythrocyte Count; Erythrocytes; Glutathione; Glycolysis; Humans; Metabolomics; Reference Values

The understanding of the oxidative stress mechanisms helps to explain many of the processes of cellular lesion and death, especially those related to the hemolytic diseases. Sickle cell anemia, thalassemias and G6-PD deficiency are among the more frequent genetic anomalies accompanied by oxidative stress. In the sickle cells, one of the factors that predisposes to the hemolytic process is the oxidative degradation of the hemoglobin S due to its deoxigenation leading to hemichrome formation and precipitation as Heinz bodies. The oxidative stress contributes to the sickle process and shortening of the erythrocyte survival. Here we analyzed the oxidative process in erythrocytes of patients with two different genotypes for HbS (AS and SS). Units of blood from donors of the Center of Hematology and Hemotherapy of Paraná (HEMEPAR), from normal individuals (AA) and from heterozygote individuals (AS), and venous blood collected from patients with sickle cell anemia (SS) were analyzed. In order to evaluate the protective action of the vitamins C and E in oxidative stress, erythrocytes were treated with antioxidant substances, vitamin C and vitamin E, and then treated with the oxidant tert-butilhydroperoxide (TBHP). The oxidative action induced by TBHP was observed in erythrocytes AA

Topics: Anemia, Sickle Cell; Ascorbic Acid; Blood Donors; Erythrocytes; Glutathione; Heinz Bodies; Hemoglobin, Sickle; Humans; Oxidation-Reduction; Oxidative Stress; Reference Values; Vitamin E

This study seeks to examine the effects of vitamin C supplementation or/and warmth on forearm blood flow (FBF) and forearm vascular resistance (FVR) in sickle cell anaemia (SCA) subjects in the steady state. Sixteen (16) SCA subjects of both sexes (mean age, 23.4+/-1.5 yrs.) were studied. Blood pressure (BP, mm Hg) and FBF (ml/min) measurements were made at rest, with warmth stimulation, after vitamin C supplementation for 6 weeks at 300 mg per day and with warmth stimulation after vitamin C supplementation. Warmth stimulation was induced by immersing the left foot in a bowl of water at a temperature of 40 degrees C for 2 minutes. Forearm blood flow (FBF) [corrected] was measured by means of a forearm plethysmograph. Forearm vascular resistance (FVR, arbitrary units) was calculated by dividing mean arterial pressure (MAP) with FBF. Warmth stimulation at 40 C significantly decreased systolic blood pressure (SBP) (p<0.05), diastolic blood pressure (DBP) (p<0.01), MAP (p<0.01) and FVR (p<0.01) but significantly increased FBF (p<0.01). Vitamin C supplementation also significantly reduced SBP (p<0.001), DBP (p<0.01), MAP (p<0.01) and FVR (p<0.05) but significantly increased FBF (p<0.01). After vitamin C supplementation, warmth stimulation potentiated the reduction in SBP (p<0.001), DBP (p<0.01), FVR (p <0.01) and increase in FBF (p<0.01). In conclusion, warmth stimulation at 40 [corrected] degrees C or vitamin C supplementation caused a decrease in arterial blood pressure, forearm vascular resistance and increase in forearm blood flow in sickle cell anaemia subjects. Pretreatment with vitamin C enhanced the vasodilator effect of warmth.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Antioxidants; Ascorbic Acid; Blood Pressure; Female; Forearm; Hot Temperature; Humans; Male; Regional Blood Flow; Vascular Resistance; Vasodilation

The effect of ascorbic acid supplementation (100 mg/day for 6 weeks) on blood pressure, packed cell volume, irreversibly sickled cells, per cent fetal hemoglobin, hemoglobin concentration, and erythrocyte osmotic fragility was assessed in children suffering from sickle cell anemia. Fifteen children whose ages ranged from 4 to 11 years (7.5 +/- 0.75 years) were studied. Ascorbic acid supplementation reduced systolic blood pressure by 10.9 +/- 3.4 mmHg (p < 0.01), diastolic blood pressure by 7.3 +/- 2.0 mmHg (p < 0.01) and mean arterial pressure by 9.4 +/- 2.6 mmHg (p < 0.01). It significantly increased packed cell volume (p < 0.001), hemoglobin concentration (p < 0.001) and per cent fetal hemoglobin (p < 0.001), but reduced per cent irreversibly sickled cells (p < 0.001). Ascorbic acid supplementation also abolished the long tail of the erythrocyte osmotic fragiligram and increased the resistance of the cells to lysis.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Blood Pressure; Child; Child, Preschool; Data Interpretation, Statistical; Erythrocytes, Abnormal; Female; Fetal Hemoglobin; Hematocrit; Humans; Male; Nigeria; Osmotic Fragility

Ascorbic acid can be important in sickle cell anemia (SCA) because significant oxidative stress occurs in the disease. Ascorbate could contribute to reduction of the increased oxygen free radicals generated in sickle red blood cells (SRBC) and to the recycling of vitamin E in the cells, while renal loss could contribute to the low plasma levels. Evaluation of red blood cell (RBC) and urine ascorbate in SCA has not been reported. Results showed (1) ascorbate levels in SRBC were similar to those in normals; (2) urine ascorbate excretion was increased in 36% of patients; (3) plasma levels of ascorbate were decreased.. (1) Ascorbate is present in SRBC, most likely due to ascorbate recycling, despite increased free-radical generation. (2) The increase in renal excretion may contribute to the low plasma levels of ascorbate. (3) The presence of ample ascorbate in SRBC and decreased plasma ascorbate suggests that ascorbate movement across the SRBC membrane may differ from normal RBC.

Topics: Adult; Anemia, Sickle Cell; Ascorbic Acid; Erythrocytes; Humans; Matched-Pair Analysis; Middle Aged; Osmolar Concentration; Sodium

Topics: Adult; Anemia, Sickle Cell; Ascorbic Acid; Coronary Vessel Anomalies; Female; Folic Acid; Free Radical Scavengers; Hematinics; Humans; Pentoxifylline

The plasma concentrations of the antioxidant vitamins A (retinol), C (ascorbic acid) and E (alpha-tocopherol) were determined in sickle cell anaemia (SCA). It was found that the concentrations of ascorbic acid and alpha-tocopherol were significantly depressed while that of retinol was only slightly reduced. The depletion in the levels of these antioxidant vitamins may account for some of the observed manifestations of SCA such as increased susceptibility to infection and haemolysis.

Topics: Adult; Anemia, Sickle Cell; Ascorbic Acid; Case-Control Studies; Humans; Vitamin A; Vitamin E

Topics: Anemia, Sickle Cell; Antimalarials; Ascorbic Acid; Blood Chemical Analysis; Child; Folic Acid; Humans; Injections, Intravenous; Lactates; Male; Penile Erection; Priapism; Vitamin B Complex

Normal and sickle cell erythrocyte membranes were examined for significant differences in their ATPase activities, thiobarbituric acid reactive products formed (measured relative to malondialdehyde), membrane protein polymerization, and number of protein-free sulfhydryl groups when treated with 0.5 mmol/L t-butylhydroperoxide (tBHP) for 30 minutes. Isolated sickle cell membranes treated with tBHP produced significantly greater inhibition in both their basal and calmodulin-stimulated Ca2+ + Mg(2+)-ATPase activities (75% inhibition in both cases) compared with that of control membranes. In addition, there was significantly more malondialdehyde formed from sickle cell membranes compared with control membranes. Oxidation caused greater protein polymerization in sickle cell membranes compared with normal membranes as demonstrated by the formation of high molecular weight polymers separated on sodium dodecyl sulfate polyacrylamide gels. The number of free sulfhydryl groups present in spectrin and actin decreased more in sickle cell membranes as measured by 3H-N-ethyl maleimide autoradiography and gel scanning. To prevent enzyme inhibition, erythrocyte membranes were treated with tBHP in the presence of 1 mmol/L ascorbate, a potential antioxidant, and 1 mmol/L desferal, an iron chelator. Both ascorbate and desferal added alone with tBHP were effective in preventing inhibition of the basal and calmodulin-stimulated Ca2+ + Mg(2+)-ATPase activities in normal membranes, but in sickle cell membranes only the addition of ascorbate and desferal together offered significant protection. The enhanced oxidation observed with sickle cell membranes can be mimicked in normal white membranes by adding hemoglobin, hemin, or ferrous chloride in the presence of tBHP. In contrast to hemoglobin, ferrous chloride has the ability to enhance membrane oxidation in the presence of ascorbate with or without tBHP. Furthermore, the addition of desferal to these membranes greatly decreased the iron-ascorbate-tBHP oxidation of erythrocyte membranes as determined by the sustained ATPase activities and the reduced formation of malondialdehyde. Maximal protection was provided by 1 mmol/L desferal in the presence of 1 mmol/L ascorbate, although some protection was observed even at 10 mumol/L, the lowest concentration tested. These results are discussed in light of the pro- and anti-oxidant effects of ascorbate in the absence and presence of iron and tBHP.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Ca(2+) Mg(2+)-ATPase; Calcium-Transporting ATPases; Calmodulin; Deferoxamine; Erythrocyte Membrane; Ethylmaleimide; Hemoglobins; Humans; Iron; Kinetics; Malondialdehyde; Membrane Proteins; Molecular Weight; Oxidation-Reduction; Peroxides; Polymers; tert-Butylhydroperoxide

Sickle erythrocyte (RBC) membranes were previously shown to manifest increased Fenton activity (iron-dependent, peroxide-driven formation of hydroxyl radical [.OH]) compared with normal RBC membranes, but the nature of the catalytic iron was not defined. We now find that sickle membranes exposed to superoxide (.O2-) and hydrogen peroxide (H2O2) have three distinct iron compartments able to act as Fenton catalysts: preexisting free iron, free iron released during oxidant stress, and a component that cannot be chelated with deferoxamine (DF). In a model system, addition of iron compounds to normal ghosts showed that free heme, hemoglobin, Fe/adenosine diphosphate (ADP), and ferritin all catalyze .OH production; concurrent inhibition studies using DF documented that the unchelatable Fenton component is free heme or hemoglobin. During exposure to peroxide only, the iron in sickle membranes was unable to act as a Fenton catalyst without addition of a reducing agent. At physiologic concentrations, both ascorbate and glutathione restored Fenton activity. Lipid peroxidation studies showed that at physiologic levels ascorbate acts primarily as an antioxidant; however, as pharmacologic levels are reached, its pro-oxidant effects predominate. This study elucidates the catalytic ability of the iron compartments in the sickle cell membrane, the importance of which relates to the potential role of .OH in membrane damage. It also illustrates the potential participation of cytoplasmic reducing agents in this process, which may be especially relevant in the context of administration of supraphysiologic doses of ascorbate to sickle cell patients.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Deferoxamine; Erythrocyte Membrane; Free Radicals; Glutathione; Heme; Humans; Hydrogen Peroxide; Hydroxides; Hydroxyl Radical; Iron; Kinetics; Lipid Peroxidation; NAD; NADP; Oxidation-Reduction; Reference Values

Thirteen patients (aged 0.7-17.9 y) with homozygous sickle cell disease were supplemented with alpha-tocopherol, vitamin C, zinc, and soybean oil (suppl 1; for 8 mo) and alpha-tocopherol, vitamin C, and fish oil (suppl 2; for 7 mo). Urinary zinc (suppl 1), plasma vitamin C, plasma cholesterol ester and erythrocyte (RBC) omega 3 fatty acids (suppl 2), and plasma and RBC alpha-tocopherol (suppl 1 and 2) increased. Suppl 1 decreased irreversibly sickled cells by 37.5%, decreased RBC protoporphyrin and urinary porphyrins, and increased the RBC total fatty acid-cholesterol ratio. Suppl 2 decreased plasma triglycerides, further increased the RBC alpha-tocopherol, moderately increased the RBC double-bond index, but decreased the RBC total fatty acid-cholesterol ratio. Zinc, copper, and porphyrins showed prolonged changes. The supplements did not change hemoglobin concentrations, RBC age (reticulocytes, polyamines), or number of aplastic and vasoocclusive crises. Zinc reduces irreversibly sickled cells. Augmentation of RBC antioxidant status by alpha-tocopherol and vitamin C and incorporation of omega 3 fatty acids into RBCs do not affect hemolytic component. Effects on vasoocclusive component are unclear.

Topics: Adolescent; Anemia, Sickle Cell; Ascorbic Acid; Child; Child, Preschool; Cholesterol Esters; Dietary Fats, Unsaturated; Erythrocyte Count; Erythrocytes; Fatty Acids; Female; Fetal Hemoglobin; Fish Oils; Hemoglobin, Sickle; Humans; Infant; Male; Soybean Oil; Vitamin E; Zinc

Because peroxidative damage to red cell membranes may contribute to the pathophysiology of sickle cell disease, deficiency of fat- and water-soluble antioxidants could be a determinant in the pathogenesis of this disease. We have previously reported a deficiency of vitamin E in sickle cell disease. The present study was undertaken to see if a deficiency in vitamin C might also be detected. Leukocyte vitamin C, which reflects total body vitamin C reserve, was measured by a modified 2,4-dinitrophenylhydrazine method. Sickle cell patients (N = 18) had lower leukocyte vitamin C levels (18.3 +/- 9.4 micrograms/10(8) cells) than normal controls (N = 12; 30.3 +/- 7.5 micrograms/10(8) cells; p less than 0.01). Furthermore, 50% of the patients had vitamin C levels below 15 micrograms/10(8) cells, a value consistent with vitamin C deficiency. A statistically significant correlation (r = -0.62 with 0.01 less than p less than or equal to 0.025) was found between leukocyte vitamin C levels and serum ferritin concentration. Because dietary vitamin C intake appeared to be adequate, increased vitamin C utilization may account for this deficiency. However, the mechanisms for this deficiency as well as its pathophysiologic consequences remain to be established.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Ascorbic Acid Deficiency; Ferritins; Humans; Leukocytes; Oxidation-Reduction

The sickled erythrocyte has been shown to be susceptible to lipid peroxidation and a role has been suggested for antioxidants in this process. The present study was undertaken in 22 children, aged 5-18 years with homozygous sickle cell disease (SS) and 9 HbAA controls (AA) of similar age. All the SS patients were in steady state ie, not in crisis or any acute illness at the time of the study. Levels of plasma tocopherol, retinol, carotenes and ascorbic acid (antioxidant vitamins of major nutritional importance) were measured. Plasma tocopherol carotenes and retinol were measured by HPLC after extraction into heptane. Total ascorbic acid (in trichloroacetic acid extracts of plasma) was measured colorimetrically following reaction with 2,4-dinitrophenylhydrazine. Riboflavin status was measured by the glutathione reductase activation test. Levels of all the measured antioxidants except ascorbate were reduced in SS patients compared with control children but only plasma alpha-tocopherol concentration was significantly different between the patients and controls. The median tocopherol level in SS patients (11.32 mumol/l) was significantly lower (P less than 0.02 Mann-Whitney) than that in control children (18.02 mumol/l) when measured directly or when calculated from tocopherol: cholesterol ratio, 4.55 mumol/mmol in SS patients and 7.50 mumol/mmol in control children. The median concentration of total plasma carotenes of SS patients (5.67 mumol/l) was lower than that of control children (12.14 mumol/l). Similarly, plasma beta-carotene concentration of SS patients was lower than that of control children but the difference in each case was not significant. Despite this, the vitamin A status (plasma retinol concentration) of SS patients was poorer than that of control children.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Anemia, Sickle Cell; Ascorbic Acid; Carotenoids; Child; Child, Preschool; Homozygote; Humans; Lipid Peroxidation; Nigeria; Vitamin A; Vitamin E

In 24 adults with hemoglobin SS followed at the Duke University Comprehensive Sickle Cell Center, we have studied the following nutritional parameters: reduced ascorbic acid; dehydroascorbic acid; alpha and beta carotenes; cryptoxanthin; and alpha and gamma tocopherols in whole blood, washed red blood cells, plasma, or serum. In the same population we also examined reduced glutathione (GSH) and oxidized glutathione (GSSG). Fifteen of these 24 patients also were interviewed for usual dietary intakes using a 28-day dietary history. Data obtained from patients with hemoglobin SS, sickle cell anemia (SCA) were compared to those found for seven healthy normal black adults of similar age. Plasma alpha tocopherol levels were significantly lower in SCA individuals than those of the controls (P less than 0.004). Alpha and gamma tocopherol levels in sickle RBCs were significantly higher than those from RBC suspensions of control subjects (P less than 0.007, and P less than 0.001, respectively). All serum values for carotenoids examined, specifically, beta carotene, alpha carotene, and cryptoxanthin were also markedly depressed when compared to those of healthy controls (P less than 0.001, P less than 0.002, and P less than 0.001, respectively). No other statistically significant differences were found between the two groups for any of the remaining variables, including dietary estimates. Dietary analyses suggest that dietary intakes of SCA individuals exceeded the recommended daily allowances (RDA) of all macro- and micronutrients measured, and intakes of most nutrients exceeded those of black controls interviewed. These results suggest that in individuals with SCA, several micronutrients vital to maintaining reducing capacity are present in diminished quantities in plasma/serum. These anomalies exist in SCA patients even though their intake of these micronutrients are similar to those of healthy black men and women.

Topics: Adult; Anemia, Sickle Cell; Ascorbic Acid; beta Carotene; Carotenoids; Cryptoxanthins; Diet; Female; Hemoglobins; Humans; Male; Middle Aged; Nutritional Status; Regression Analysis; Vitamin E; Xanthophylls

Sickle erythrocytes and their membranes are susceptible to endogenous free-radical-mediated oxidative damage which correlates with the proportion of irreversibly sickled cells. The suppression of incubation-induced oxidative stress by antioxidants, free radical scavengers and an iron chelator suggest that oxidation products of membrane-bound haemoglobin contribute towards the pathology of the disease.

Topics: Anemia, Sickle Cell; Antioxidants; Ascorbic Acid; Deferoxamine; Erythrocyte Membrane; Erythrocytes, Abnormal; Free Radicals; Humans; In Vitro Techniques; Iron; Oxidation-Reduction

The role of oxidant damage to red cells in sickle cell disease has been of interest in recent years. Ascorbic acid is a well known antioxidant. The present study found that sickle cell patients have low levels of plasma ascorbic acid. In addition, it was observed that the pretreatment of sickle cells with ascorbic acid protects their membranes against in vitro peroxidative lipid damage induced by their exposure to hydrogen peroxide. The data suggest that low plasma ascorbic acid levels in sickle cell patients may be a factor in the increased vulnerability of sickle cells to oxidant damage in vivo.

Topics: Anemia, Sickle Cell; Ascorbic Acid; Erythrocytes; Female; Humans; Male; Malondialdehyde; Peroxides

Topics: Anemia, Sickle Cell; Animals; Ascorbic Acid; Copper; Hemolysis; Humans; Rats; Risk; Sheep; Sickle Cell Trait

In vivo incubations of Hgb SC erythrocytes showed significantly more sickling in anterior chambers characterized by high concentrations of ascorbic acid than in anterior chambers with low concentrations of ascorbic acid (normal guinea pigs compared with scorbutic guinea pigs and normal guinea pigs compared with normal rats). Low concentrations of ascorbic acid, however, did not completely eliminate intracameral sickling. Because acetazolamide raises the concentration of aqueous humor ascorbate, it should be used with considerable discretion when treating hyphema and secondary glaucoma caused by sickle cells. Methazolamide may be more desirable.

Topics: Acetazolamide; Anemia, Sickle Cell; Animals; Anterior Chamber; Aqueous Humor; Ascorbic Acid; Erythrocytes, Abnormal; Glaucoma; Guinea Pigs; Hemoglobin, Sickle; Humans; Hyphema; Injections; Male; Rats; Sickle Cell Trait

Topics: Adolescent; Anemia, Sickle Cell; Ascorbic Acid; Blood Transfusion; Child; Deferoxamine; Erythrocyte Transfusion; Ferritins; Humans; Iron; Iron Chelating Agents; Liver Function Tests

Iron chelation with deferoxamine was studied in ten patients with sickle cell anemia who had received 2 to 37 liters of red blood cells. Urinary excretion of iron in response to 1.5 gm of deferoxamine administered intravenously ranged from 5.9 to 28.7 mg/24 hours and was closely related to the amount of iron acquired from transfusions. Administration of ascorbic acid did not improve deferoxamine-induced excretion of iron. Urinary excretion of iron in response to 0.75 gm of DFO intramuscularly was 4.7 to 6.9 mg/24 hours in three patients who had received 15 to 37 liters of red cells. The data indicate that measurement of DFO-induced excretion of iron is of value in detecting increased iron stores in children with sickle cell anemia who have received repeated transfusions and that chelation therapy will retard the accumulation of iron.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Ascorbic Acid; Blood Transfusion; Child; Deferoxamine; Erythrocyte Transfusion; Humans; Infusions, Parenteral; Iron

Topics: Anemia; Anemia, Hypochromic; Anemia, Sickle Cell; Anemia, Sideroblastic; Ascorbic Acid; Black People; Blood Proteins; Child Nutritional Physiological Phenomena; Child, Preschool; Diet; Diet Surveys; Dietary Proteins; Erythrocytes; Hematocrit; Hemoglobins; Humans; Iron; Mass Screening; Mississippi; Protein Binding; Transferrin

Topics: Anemia; Anemia, Sickle Cell; Ascorbic Acid; Counseling; Eugenics; Galactosemias; Genetics, Medical; Humans; Immunity; Malaria; Metabolism, Inborn Errors; Phenylketonurias; Preventive Medicine

Topics: Anemia; Anemia, Sickle Cell; Ascorbic Acid; Child; Erythrocytes, Abnormal; Erythropoiesis; Folic Acid; Humans; Infections; Pathology; Reticulocytes