scholarly journals Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease

2019 ◽  
Vol 244 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Xingguo Zhu ◽  
Aluya R Oseghale ◽  
Lopez H Nicole ◽  
Biaoru Li ◽  
Betty S Pace
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Hemoglobin S ◽  
Nrf2 Activation ◽  
Chronic Hemolysis ◽  
Abnormal Hemoglobin ◽  
Small Chemical

Individuals with sickle cell disease have severe anemia due to the production of abnormal hemoglobin S, chronic red blood cell hemolysis, and increased oxidative stress leading to endothelial cell dysfunction, vasculopathy, and progressive organ damage. The transcription factor NRF2 (erythroid-derived 2)-like 2) is a master regulator of antioxidant proteins; under low oxidative stress, NRF2 is sequestered in the cytoplasm by Kelch-like ECH-associated protein 1, β-transducin repeat-containing protein or HRD1, and directed to the proteasome for degradation. When cells are exposed to oxidative stress, NRF2 is released from these repressor proteins, translocates to the nucleus, and activates antioxidant genes to suppress cellular reactive oxidant species and inflammation. In erythroid progenitors, NRF2 also modulates fetal hemoglobin expression through direct binding in the γ-globin promoter and modification of chromatin structure in the β-globin locus. In sickle erythroid cells, NRF2 provides unique benefits through fetal hemoglobin induction to inhibit hemoglobin S polymerization and protection against oxidative stress due to chronic hemolysis. Thus, development of small chemical molecules that activate NRF2 has the potential to ameliorate the clinical severity of sickle cell disease. In this review, we discuss progress towards understanding NRF2 regulation and strategies to develop agents for the treatment of sickle cell disease. Impact statement Sickle cell disease (SCD) is a group of inherited blood disorders caused by mutations in the human β-globin gene, leading to the synthesis of abnormal hemoglobin S, chronic hemolysis, and oxidative stress. Inhibition of hemoglobin S polymerization by fetal hemoglobin holds the greatest promise for treating SCD. The transcription factor NRF2, is the master regulator of the cellular oxidative stress response and activator of fetal hemoglobin expression. In animal models, various small chemical molecules activate NRF2 and ameliorate the pathophysiology of SCD. This review discusses the mechanisms of NRF2 regulation and therapeutic strategies of NRF2 activation to design the treatment options for individuals with SCD.

scholarly journals Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3182-3188 ◽  
Author(s):  
M Maier-Redelsperger ◽  
CT Noguchi ◽  
M de Montalembert ◽  
GP Rodgers ◽  
AN Schechter ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Oxygen Saturation ◽  
Cell Population ◽  
Sickle Cell ◽  
Clinical Manifestations ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Normal Children ◽  
Hemoglobin S ◽  
F Cells

Abstract Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

Reduced Oxidative Stress and Enhanced Nitric Oxide (NO) Bioavailability in Transgenic-Knockout Sickle Mice Expressing Fetal Hemoglobin (HbF) Is Mediated by Decreased Sickling and Hemolysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 842-842
Author(s):  
Trisha Dasgupta ◽  
Mary E. Fabry ◽  
Dhananjay K. Kaul
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Manipulation ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Multiple Organ ◽  
Protective Effects ◽  
Cell Disease ◽  
No Bioavailability

Abstract The primary event in the vaso-occlusive pathophysiology of sickle cell disease (SCD) is polymerization of hemoglobin S under deoxygenated conditions. In SCD, sub-clinical transient vaso-occlusive events caused by red cell sickling are likely to be more frequent resulting in “reperfusion injury” that generates reactive oxygen species and results in chronic oxidative stress that will contribute to multiple organ damage. In fact, previous studies have suggested that sickling is etiologic to repefusion injury and oxidative stress (Kaul and Hebbel, JCI, 2000), although the effect of antisickling therapy on oxidative stress has not been evaluated. Increasing the levels of antisickling fetal hemoglobin (HbF) by hydroxyurea therapy markedly reduces polymer formation. HbF exerts an ameliorating effect in sickle cell disease patients both on red cells and in the prevention of multiple organ damage. Here, we hypothesize that induction of HbF by genetic manipulation (in the absence of pharmacological manipulation) will reduce organ oxidative stress by reducing sickling and hemolysis, and thereby increase NO bioavailability. To test our hypothesis, we measured activity of selected antioxidants and lipid peroxidation (LPO) in BERK mice expressing exclusively human α- and βS-globins and varying levels of HbF, i.e., BERK (<1% HbF), BERKγM (20% HbF) and BERKγH (40% HbF). Percent sickled cells in venous samples (drawn in 2.5% glutaraldehyde solution in 0.1M cacodylate buffer) showed a distinct decrease with increased %HbF (P<0.05, multiple comparisons). Consistent with maximal sickling, BERK mice showed 5.4–6.9-fold increase in LPO in various tissues (muscle, kidney and liver) compared with C57BL controls (P<0.001). In contrast, BERKγM and BERKγH mice showed a marked decrease (73% and 80%, respectively) in LPO compared with BERK mice (P<0.001). Also, activity/levels of antioxidants (superoxide dismutase [SOD], catalase, glutathione peroxidase [GPx] and reduced glutathione [GSH]) showed significant decreases in BERK mice (P<0.001–0.00001). On the other hand, BERKγM and BERKγH mice showed significant increases in antioxidant activity (P<0.05–0.0001). Induction of HbF was associated with increased levels of NO metabolites (NOx) and reduced hemolysis; the latter is in agreement with our previous observations in BERKγM mice (Kaul et al. JCI, 2004). These results strongly suggest that reduced sickling and hemolysis in the presence of HbF cause increased NO bioavailability. NO is well known to exert antioxidative effects. Thus, we show for the first time that the induction of antisickling HbF leads to an increase in NO bioavailability and a decrease in oxidative stress, and that these protective effects are mediated primarily by reduced intravascular sickling.

scholarly journals Chronic osteo-articular changes in patients with sickle cell disease

2021 ◽  
Vol 61 (1) ◽  
Author(s):  
Taciana Fernandes Araújo Ferreira ◽  
Ana Paula Teixeira dos Santos ◽  
Alexandra Silva Leal ◽  
Gilberto de Araújo Pereira ◽  
Sheila Soares Silva ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Chain Gene ◽  
Cell Disease ◽  
Locomotor System ◽  
High Prevalence ◽  
Significant Impairment ◽  
Chronic Hemolysis ◽  
Abnormal Hemoglobin ◽  
The Mean

Abstract Background Sickle cell disease (SCD) is an autosomal recessive genetic disease in which a mutation occurs in the β-globin chain gene, resulting in abnormal hemoglobin levels. In an environment with reduced oxygen concentration, red blood cells change their conformation, resulting in chronic hemolysis and consequent anemia and vaso-occlusive crises with injuries to several organs, with a significant impairment of the osteoarticular system. This study aimed to verify the chronic osteoarticular alterations and their association with clinical and laboratory characteristics of patients with SCD with a more severe phenotype (SS and Sβ0), on a steady-state fasis. Methods Fifty-five patients were referred to a medical consultation with a specialized assessment of the locomotor system, followed by laboratory tests and radiographic examinations. Results In total, 74.5% patients had hemoglobinopathy SS; 67.3% were female; and 78.2% were non-whites. The mean patient age was 30.5 years. Most patients (61.8%) reported up to three crises per year, with a predominance of high-intensity pain (65.5%). Radiographic alterations were present in 80% patients. A total of 140 lesions were identified, most which were located in the spine, femur, and shoulders. Most lesions were osteonecrosis and osteoarthritis and were statistically associated with the non-use of hydroxyurea. Conclusions There was a high prevalence of chronic osteoarticular alterations, which was statistically associated only with the non-regular use of hydroxyurea.

scholarly journals Effects of Sulforaphane Obtained from Broccoli Sprout Homogenate in Patients with Sickle Cell Disease (SCD)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4931-4931
Author(s):  
Jennifer Doss ◽  
Jude Jonassaint ◽  
Nirmish Shah ◽  
Marilyn J. Telen ◽  
Jen-Tsan A. Chi
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Red Cells ◽  
Physiological Effects ◽  
Cell Disease ◽  
Safety Concerns ◽  
Nrf2 Activation ◽  
Broccoli Sprout ◽  
Nrf2 Expression

Abstract BACKGROUND Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, characterized by chronic complications due to ongoing vaso-occlusion and hemolysis. Previous studies have shown that red cells from individuals with sickle cell disease (HbSS) have reduced NRF2 expression levels, which contribute to decreased oxidative stress capacity and increased hemolysis (Sangokoya, et al. 2010 Blood). Additionally, Macari and Lowry have shown that in vitro NRF2 activation of erythroid progenitors results in induction of anti-oxidant stress response genes, as well as increased percent fetal hemoglobin (HbF), which is known to prevent sickling (2011 Blood). Therefore, we hypothesize that NRF2 activation in SCD patients has potential therapeutic benefits by simultaneously inducing HbF and increasing the anti-oxidative stress capacity of red cells. We proposed to activate NRF2 by using sulforaphane (SFN), a well-known natural product enriched in broccoli sprouts. We conducted an open-label, dose-escalation clinical trial for SCD patients to investigate the safety and physiological effects of NRF2 activation by SFN through ingestion of a broccoli sprout homogenate (BSH). METHODS Male and female adult patients (> 18 years) with either HbSS or HbSߺ thalassemia were enrolled at the Duke Comprehensive Sickle Cell Center adult clinic. Exclusion criteria: RBC transfusion or a change in hydroxyurea dose in the last three months, ongoing pregnancy, diabetes, or renal insufficiency (BUN >21 mg/dL and/or creatinine >1.4 mg/dL). Inclusion criteria: Hematocrit (Hct) ≥ 20% and Hb > 6.0 g/dL. Recruited subjects were instructed to avoid additional SFN-containing foods before and during the study period. Subjects ingested a thawed preparation of BSH once daily for 21 days to allow for repopulation of red cells during therapy. Tolerability, toxicity, and physiological effects of NRF2 activation were determined at pre-treatment baseline (day 0), on the last day of ingestion (day 21), and after a wash-out period (day 49). Five patients were recruited for each dose (50g, 100g), with the smaller dose having elicited no safety concerns. RESULTS No safety concerns were noted among the subjects at either dose. In both cohorts, there were no significant differences in the adverse events, pain scores, complete blood counts, complete metabolic profile, reticulocyte count, and LDH levels when comparing days 0 and 21. In the 50g cohort, there was an overall but not statistically significant increase of average HbF from 14.5% to 14.9% (p=0.0786) in all five patients from Day 0 to Day 21; analyses are incomplete for the higher dose. We also observed a trend of NRF2 mRNA target gene induction, including heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase (quinone 1, NQO1), and globin mRNAs, at day 21 vs day 0, which returned to baseline levels at day 49. In the 50g cohort, we observed a 66% increase of ho-1 and 44% increase of nqo1 mRNA levels at day 21 vs. baseline. In the 100g cohort, we observed a 14% increase of ho-1 and 42% increase of nqo1mRNA levels at day 21 vs. baseline. CONCLUSION Our pilot trial suggests that NRF2 activation by BSH may increase NRF2 expression programs and induce fetal hemoglobin. We aim to enroll more patients at escalating doses, as participants present a wide range of clinical variability and may show variable response. Additionally, the lack of statistical significance at the lowest doses along with a lack of safety concerns strongly compel us to pursue more potent NRF2 inducers to elicit more robust physiological changes for additional clinical trials. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comparison of oxidative stress and the frequency of polymorphisms in the HFE gene between hemoglobin S trait blood donors and sickle cell disease patients

2011 ◽  
Vol 10 (4) ◽  
pp. 3446-3454 ◽  
Author(s):  
L.M.S. Viana-Baracioli ◽  
N.C. Tukamoto Junior ◽  
O. Ricci Júnior ◽  
L.C. Mattos ◽  
I.L. Ângulo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Donors ◽  
Hfe Gene ◽  
Cell Disease ◽  
Hemoglobin S

scholarly journals Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3182-3188 ◽  
Author(s):  
M Maier-Redelsperger ◽  
CT Noguchi ◽  
M de Montalembert ◽  
GP Rodgers ◽  
AN Schechter ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Oxygen Saturation ◽  
Cell Population ◽  
Sickle Cell ◽  
Clinical Manifestations ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
Normal Children ◽  
Hemoglobin S ◽  
F Cells

Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.

scholarly journals To Give or Not to Give: RhD Immunoglobulin for an RHD*39 Pregnant Woman with Sickle Cell Disease

2021 ◽  
pp. 1-5
Author(s):  
Justin E. Juskewitch ◽  
Craig D. Tauscher ◽  
Sheila K. Moldenhauer ◽  
Jennifer E. Schieber ◽  
Eapen K. Jacob ◽  
...  
Keyword(s):  
Pregnant Woman ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Pregnancy Termination ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Childbearing Age ◽  
Procedural Complications ◽  
History Of ◽  
Chronic Hemolysis

Introduction: Patients with sickle cell disease (SCD) have repeated episodes of red blood cell (RBC) sickling and microvascular occlusion that manifest as pain crises, acute chest syndrome, and chronic hemolysis. These clinical sequelae usually increase during pregnancy. Given the racial distribution of SCD, patients with SCD are also more likely to have rarer RBC antigen genotypes than RBC donor populations. We present the management and clinical outcome of a 21-year-old pregnant woman with SCD and an RHD*39 (RhD[S103P], G-negative) variant. Case Presentation: Ms. S is B positive with a reported history of anti-D, anti-C, and anti-E alloantibodies (anti-G testing unknown). Genetic testing revealed both an RHD*39 and homozygous partial RHCE*ceVS.02 genotype. Absorption/elution testing confirmed the presence of anti-G, anti-C, and anti-E alloantibodies but could not definitively determine the presence/absence of an anti-D alloantibody. Ms. S desired to undergo elective pregnancy termination and the need for postprocedural RhD immunoglobulin (RhIG) was posed. Given that only the G antigen site is changed in an RHD*39 genotype and the potential risk of RhIG triggering a hyperhemolytic episode in an SCD patient, RhIG was not administered. There were no procedural complications. Follow-up testing at 10 weeks showed no increase in RBC alloantibody strength. Discussion/Conclusion: Ms. S represents a rare RHD*39 and partial RHCE*ceVS.02 genotype which did not further alloimmunize in the absence of RhIG administration. Her case also highlights the importance of routine anti-G alloantibody testing in women of childbearing age with apparent anti-D and anti-C alloantibodies.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

scholarly journals Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management

2011 ◽  
Vol 86 (6) ◽  
pp. 484-489 ◽  
Author(s):  
Erfan Nur ◽  
Bart J. Biemond ◽  
Hans-Martin Otten ◽  
Dees P. Brandjes ◽  
John-John B. Schnog ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Disease Management ◽  
Sickle Cell ◽  
Cell Disease
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