scholarly journals Nicotinamide Improves Anemia and Decreases Reactive Oxygen Species in Sickle Cell Disease Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2019-2019
Author(s):  
Jagadeesh Ramasamy ◽  
Vinzon Ibanez ◽  
Vijaya Lakshmi Yalagala ◽  
Yogenthiran Saunthararajah ◽  
Robert E. Molokie ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Redox Potential ◽  
Sickle Cell ◽  
Therapeutic Option ◽  
Statistical Significance ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cell Disease ◽  
Nad Synthesis

Abstract The polymerization of deoxygenated HbS molecules in the red blood cells (RBCs) of patients with sickle cell disease (SCD) causes RBC destruction resulting in chronic pain, debilitating acute pain crises, strokes, multi-organ damage and a reduced life span. Therapeutic options remain limited. Bone marrow transplantation can be curative but is not an option for the majority of patients. Gene therapy interventions that also offer the promise of a cure are under investigation but are not likely to be available to the vast majority of patients in the near future. Hydroxyurea, the first drug approved for treatment of SCD, increases levels of Fetal Hemoglobin (HbF) that inhibit polymerization of HbS molecules but is not effective in all patients while a more powerful HbF-inducing drug, the DNA methyltransferase inhibitor decitabine has yet to be approved. L-glutamine, another approved therapeutic option, increases NAD redox potential and decreases reactive oxygen species (ROS) in the sickle RBCs to reduce symptoms. In our laboratory we have observed that increased ROS is associated with the retention of mitochondria in the SCD RBCs and have hypothesized that the abnormal presence of mitochondria in these cells is a major source of ROS (Jagadeeswaran et al Exp Hematol 50:46-52, 2017). In this investigation we have tested the hypothesis that chronic oral supplementation with nicotinamide, a direct precursor of NAD synthesis, would improve NAD redox potential, decrease mitochondrial retention and ROS in SCD RBCs, and reduce anemia in the SCD mouse model. The effect of nicotinamide was tested in SCD mice whose drinking water was supplemented for three months with 1% nicotinamide. The percentage of RBCs retaining mitochondria and the levels of ROS were determined by flow cytometric assays using the mitochondrial-specific dye TMRM and the ROS probe CM-H2DCFDA, respectively. In SCD mice receiving nicotinamide the fraction of RBCs retaining mitochondria was reduced 22.1% (p<0.05) and the level of ROS in RBCs was reduced 41% (p<0.01) compared to control SCD mice. The reticulocyte percentage was reduced 28% in nicotinamide-treated SCD mice compared to control SCD mice (p<0.01). The total RBC count was 30% higher (p<0.05) in nicotinamide-treated mice (6.61±0.76 X 10 6/μl) compared to control SCD mice (5.08±0.70 X 10 6/μl). Similar differences in hematocrit and total hemoglobin were also observed but failed to reach statistical significance. Total NAD levels were not significantly different in SCD mice receiving nicotinamide compared to control SCD mice (p<0.05), but the NADH/NAD total ratio was increased 2 fold (p<0.05). These results show that oral administration of high doses of nicotinamide decreases mitochondrial retention and ROS in SCD RBCs and improves NAD redox potential and anemia in SCD mice. These effects strongly suggest that additional studies be performed to investigate nicotinamide as a therapeutic option in SCD. Figure 1 Figure 1. Disclosures Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

2018 ◽  
Vol 315 (4) ◽  
pp. R840-R847 ◽  
Author(s):  
Angela Rivers ◽  
Ramasamy Jagadeeswaran ◽  
Donald Lavelle
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Reactive Oxygen ◽  
Organ Damage ◽  
The United States ◽  
Oxygen Species ◽  
Cell Disease ◽  
Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), 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 fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

Mitochondrial Uncoupling Protein 2 Is Present in Human Platelets and Regulates Platelet Activation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4147-4147 ◽  
Author(s):  
Sruti Shiva ◽  
Enrico M Novelli ◽  
Grant C Bullock ◽  
Elizabeth Kenny ◽  
Gabrielle Hill ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Mitochondrial Membrane ◽  
Reactive Oxygen ◽  
Human Platelets ◽  
Oxygen Species ◽  
Cell Disease ◽  
Superoxide Generation

Abstract It has long been recognized that platelets contain functional mitochondria and accumulating data suggest that several aspects of mitochondrial function, including reactive oxygen species production, modulate platelet thrombotic function. We have recently shown that platelet mitochondria isolated from patients with Sickle Cell Disease generate significantly greater concentrations of reactive oxygen species than healthy African American subjects and that this mitochondrial oxidant generation contributes to higher levels of basal platelet activation in these patients (Blood. 2014 May 1;123(18):2864-72). Based on these data, we have now investigated the factors that regulate platelet mitochondrial superoxide generation in healthy and Sickle Cell Disease platelets. Here we demonstrate that human platelets express mitochondrial uncoupling protein-2 (UCP2), a protein that is known to decrease the efficiency of oxidative phosphorylation and oxidant generation in other cell types but has previously not been identified in platelets. In this study we show that UCP2 protein is expressed in healthy human platelets and is fully functional as it facilitates proton leak across the inner mitochondrial membrane, leading to decreased mitochondrial membrane potential. Further, we demonstrate that the expression of this protein attenuates platelet mitochondrial superoxide generation, as treatment of platelets with Genipin (2-10µM), a pharmacological inhibitor of UCPs, concentration-dependently increases mitochondrial membrane potential and reactive oxygen species production. Further, an approximately 70% inhibition of UCP activity results in platelet activation demonstrated by increased membrane p-selectin expression (65±7% versus 6±3% in untreated controls) and augmented glycoprotein IIb/IIIa activation (57±9% versus 9±4% in untreated controls). The use of the mitochondrial-targeted antioxidant mitoTEMPO (10µM) decreases genipin-induced superoxide generation and significantly attenuates platelet activation. Notably, preliminary data presented here also suggest that UCP expression is decreased in platelets isolated from Sickle Cell Disease patients (3-fold) compared to healthy African American subjects. Additionally, ongoing studies are investigating platelet function in mice deficient in UCP2. Taken together, these data demonstrate a novel mechanism of regulation of platelet thrombotic function whose physiological relevance is apparent in the context of Sickle Cell Disease. More broadly this study advances the understanding of the role of the mitochondrion in platelet biology and thrombotic disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species

2015 ◽  
Vol 173 (2) ◽  
pp. 386-395 ◽  
Author(s):  
J Brett Heimlich ◽  
Joshua S Speed ◽  
Paul M O'Connor ◽  
Jennifer S Pollock ◽  
Tim M Townes ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Renal Injury ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cell Disease ◽  
Endothelin 1

scholarly journals Ginkgo biloba extract (EGb 761) attenuates oxidative stress induction in erythrocytes of sickle cell disease patients

2012 ◽  
Vol 48 (4) ◽  
pp. 659-665 ◽  
Author(s):  
Aline Emmer Ferreira Furman ◽  
Railson Henneberg ◽  
Priscila Bacarin Hermann ◽  
Maria Suely Soares Leonart ◽  
Aguinaldo José do Nascimento
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Sickle Cell ◽  
Reduced Glutathione ◽  
Reactive Oxygen ◽  
Intracellular Reactive Oxygen Species ◽  
Oxygen Species ◽  
Egb 761 ◽  
Cell Disease

Sickle cell disease promotes hemolytic anemia and occlusion of small blood vessels due to the presence of high concentrations of hemoglobin S, resulting in increased production of reactive oxygen species and decreased antioxidant defense capacity. The aim of this study was to evaluate the protective action of a standardized extract of Ginkgo biloba (EGb 761), selected due to its high content of flavonoids and terpenoids, in erythrocytes of patients with sickle cell anemia (HbSS, SS erythrocytes) subjected to oxidative stress using tert-butylhydroperoxide or 2,2-azobis-(amidinepropane)-dihydrochloride, in vitro. Hemolysis indexes, reduced glutathione, methemoglobin concentrations, lipid peroxidation, and intracellular reactive oxygen species were determined. SS erythrocytes displayed increased rates of oxidation of hemoglobin and membrane lipid peroxidation compared to normal erythrocytes (HbAA, AA erythrocytes), and the concentration of EGb 761 necessary to achieve the same antioxidant effect in SS erythrocytes was at least two times higher than in normal ones, inhibiting the formation of intracellular reactive oxygen species (IC50 of 13.6 µg/mL), partially preventing lipid peroxidation (IC50 of 242.5 µg/mL) and preventing hemolysis (IC50 of 10.5 µg/mL). Thus, EGb 761 has a beneficial effect on the oxidative status of SS erythrocytes. Moreover, EGb 761 failed to prevent oxidation of hemoglobin and reduced glutathione at the concentrations examined.

scholarly journals Utility of Procalcitonin in Differentiating Acute Chest Syndrome from Vaso-Occlusive Crisis in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Satish Maharaj ◽  
Simone Chang ◽  
Karan Seegobin ◽  
Marwan Shaikh ◽  
Kamila I. Cisak
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Acute Chest Syndrome ◽  
Adult Males ◽  
Cell Disease ◽  
Unequal Variances ◽  
Recorded Data

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014). Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance. Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT>0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample. Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding. Disclosures No relevant conflicts of interest to declare.

Decreased erythrocyte nicotinamide adenine dinucleotide redox potential and abnormal pyridine nucleotide content in sickle cell disease

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 512-515 ◽  
Author(s):  
CR Zerez ◽  
NA Lachant ◽  
SJ Lee ◽  
KR Tanaka
Keyword(s):  
Sickle Cell Disease ◽  
Redox Potential ◽  
Sickle Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Pyridine Nucleotide ◽  
Nicotinamide Adenine ◽  
Pyridine Nucleotides ◽  
Cell Disease ◽  
Sickle Erythrocyte

Abstract RBCs from individuals with sickle cell disease are more susceptible to oxidant damage. Because key antioxidant defense reactions are linked to the pyridine nucleotides nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), we tested the hypothesis that the RBC redox potential as manifested by the NADH/[NAD+ + NADH] and NADPH/[NADP+ + NADPH] ratios is decreased in sickle erythrocytes. Our data demonstrate that sickle RBCs have a significant decrease in the NADH/[NAD+ + NADH] ratio compared with normal RBCs (P less than .00005). Interestingly, sickle RBCs also had a significant increase in total NAD content compared with normal RBCs (P less than .00005). In contrast, although sickle RBCs had a significant increase in the total NADP content compared with normal RBCs (P less than .00005), sickle RBCs had no significant alteration in the NADPH/[NADP+ + NADPH] ratio. High reticulocyte controls demonstrated that these changes were not related to cell age. Thus, sickle RBCs have a decrease in NAD redox potential that may be a reflection of their increased oxidant sensitivity. The changes in these pyridine nucleotides may have further metabolic consequences for the sickle erythrocyte.

scholarly journals The Role of Reactive Oxygen Species in Myelofibrosis and Related Neoplasms

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Mads Emil Bjørn ◽  
Hans Carl Hasselbalch
Keyword(s):  
Reactive Oxygen Species ◽  
Lupus Erythematosus ◽  
Residual Disease ◽  
Myeloproliferative Neoplasms ◽  
Therapeutic Option ◽  
Reactive Oxygen ◽  
Chronic Obstructive ◽  
Oxygen Species ◽  
Obstructive Pulmonary Disease ◽  
Anticancer Properties

Reactive oxygen species (ROS) have been implicated in a wide variety of disorders ranging between traumatic, infectious, inflammatory, and malignant diseases. ROS are involved in inflammation-induced oxidative damage to cellular components including regulatory proteins and DNA. Furthermore, ROS have a major role in carcinogenesis and disease progression in the myeloproliferative neoplasms (MPNs), where the malignant clone itself produces excess of ROS thereby creating a vicious self-perpetuating circle in which ROS activate proinflammatory pathways (NF-κB) which in turn create more ROS. Targeting ROS may be a therapeutic option, which could possibly prevent genomic instability and ultimately myelofibrotic and leukemic transformation. In regard to the potent efficacy of the ROS-scavenger N-acetyl-cysteine (NAC) in decreasing ROS levels, it is intriguing to consider if NAC treatment might benefit patients with MPN. The encouraging results from studies in cystic fibrosis, systemic lupus erythematosus, and chronic obstructive pulmonary disease warrant such studies. In addition, the antioxidative potential of the widely used agents, interferon-alpha2, statins, and JAK inhibitors, should be investigated as well. A combinatorial approach using old agents with anticancer properties together with novel JAK1/2 inhibitors may open a new era for patients with MPNs, the outlook not only being “minimal residual disease” and potential cure but also a marked improvement in inflammation-mediated comorbidities.

scholarly journals TheCCR5Δ32Polymorphism in Brazilian Patients with Sickle Cell Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Mariana Pezzute Lopes ◽  
Magnun Nueldo Nunes Santos ◽  
Eliel Wagner Faber ◽  
Marcos André Cavalcanti Bezerra ◽  
Betânia Lucena Domingues Hatzlhofer ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Statistical Significance ◽  
Population Sample ◽  
Selective Advantage ◽  
Northeastern Brazil ◽  
Control Group ◽  
Cell Disease ◽  
Specific Pcr

Background. Previous studies on the role of inflammation in the pathophysiology of sickle cell disease (SCD) suggested that theCCR5Δ32allele, which is responsible for the production of truncated C-C chemokine receptor type 5 (CCR5), could confer a selective advantage on patients with SCD because it leads to a less efficient Th1 response. We determined the frequency of theCCR5Δ32polymorphism in 795 Afro-Brazilian SCD patients followed up at the Pernambuco Hematology and Hemotherapy Center, in Northeastern Brazil, divided into a pediatric group (3 months–17 years,n=483) and an adult group (18–70 years,n=312). The adult patients were also compared to a healthy control group (blood donors, 18–61 years,n=247).Methods. TheCCR5/CCR5Δ32polymorphism was determined by allele-specific PCR.Results. No homozygous patient for theCCR5Δ32allele was detected. The frequency of heterozygotes in the study population (patients and controls) was 5.8%, in the total SCD patients 5.1%, in the children 5.4%, in the adults with SCD 4.8%, and in the adult controls 8.1%. These differences did not reach statistical significance.Conclusions. Our findings failed to demonstrate an important role of theCCR5Δ32allele in the population sample studied here.

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