Oxidative stress in β-thalassaemia and sickle cell disease

Voskou, Stella; Aslan, Mutay; Fanis, Pavlos; Phylactides, Marios; Kleanthous, Marina

doi:10.1016/j.redox.2015.07.018

Cited by 135 publications

(122 citation statements)

References 220 publications

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“…The decrease in PS exposure in the presence of these oxidants was unexpected as oxidants are generally thought to increase PS exposure in a number of cell types, including red cells from normal individuals and SCA patients (Cimen, 2008; Mohanty et al , 2014; Voskou et al , 2015). A possible explanation lies in the ability of red cells to shed PS into the incubation media either as the free lipid or in microvesicles (Piccin et al , 2015b), which may reduce the remaining PS present on the outside of the red cell membrane despite an increase in scrambling.…”

Section: Resultsmentioning

confidence: 99%

“…SCA is associated with increased oxidative stress, neutrophil leucocytosis and vascular endothelial dysfunction, all of which are also associated with increased PS exposure (Jain, 1985; Hebbel, 1991; Kuypers, 1998; Mutze et al , 2003; Banerjee & Kuypers, 2004; Zhang et al , 2013). Recent reviews have reinforced the view that ROS are actively involved in lipid scrambling in SCA (Cimen, 2008; Mohanty et al , 2014; Voskou et al , 2015), with limited experimental evidence supporting this assumption. Aside from thiol modification with NEM (de Jong & Kuypers, 2006), however, definitive evidence for stimulation of PS exposure by oxidant challenge is scant.…”

Section: Discussionmentioning

confidence: 98%

“…This is particularly significant in diseases such as SCA in which vascular oxidative stress is increased (Rice‐Evans et al , 1986) with accumulations of highly reactive oxygen species (ROS) including the superoxide anion, hydrogen peroxide and the hydroxyl radical (Sies, 1997; Chirico & Pialoux, 2012; Voskou et al , 2015). Myeloperoxidase released from activated neutrophils may also add to oxidant challenge in SCA, through production of hypochlorous acid (HOCl) from hydrogen peroxide (Vissers et al , 1994; Mutze et al , 2003; Zhang et al , 2013).…”

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confidence: 99%

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Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

et al. 2018

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SummaryPhosphatidylserine (PS) exposure increases as red cells age, and is an important signal for the removal of senescent cells from the circulation. PS exposure is elevated in red cells from sickle cell anaemia (SCA) patients and is thought to enhance haemolysis and vaso‐occlusion. Although precise conditions leading to its externalisation are unclear, high intracellular Ca2+ has been implicated. Red cells from SCA patients are also exposed to an increased oxidative challenge, and we postulated that this stimulates PS exposure, through increased Ca2+ levels. We tested four different ways of generating oxidative stress: hypoxanthine and xanthine oxidase, phenazine methosulphate, nitrite and tert‐butyl hydroperoxide, together with thiol modification with N‐ethylmaleimide (NEM), dithiothreitol and hypochlorous acid (HOCl), in red cells permeabilised to Ca2+ using bromo‐A23187. Unexpectedly, our findings showed that the four oxidants significantly reduced Ca2+‐induced PS exposure (by 40–60%) with no appreciable effect on Ca2+ affinity. By contrast, NEM markedly increased PS exposure (by about 400%) and slightly but significantly increased the affinity for Ca2+. Dithiothreitol modestly reduced PS exposure (by 25%) and HOCl had no effect. These findings emphasise the importance of thiol modification for PS exposure in sickle cells but suggest that increased oxidant stress alone is not important.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

et al. 2018

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“…Increased inflammatory cytokines in hemolytic RBC diseases may arise from endothelial activation, from oxidized hemoglobin and free hemin, reduction in NO, and/or other mechanisms (7,17,92,144). The release into the circulation of free hemin and ROS upon RBC hemolysis activates NF-jB and AP-1, which in turn increase the expression of proinflammatory cytokines (IL1, IL6, TNFa) and endothelial adhesion molecules (L-selectin, P-selectin, VCAM-1, ICAM-1) (200)(201)(202). A spiraling inflammatory process occurs as these cytokines trigger leukocyte infiltration that releases more ROS.…”

Section: Fig 2 Hbe Acts As a Bmentioning

confidence: 99%

“…O xidative stress and the generation of free radicals are fundamental initiating mechanisms within the red blood cell (RBC) ultimately leading to morbidity and death from many inherited hemoglobinopathies, including sickle-cell anemia, SC disease, b-thalassemia, and HbE/b-thalassemia (HbE/b-thal) (114,200) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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Combination of a TGF‐β ligand trap (RAP‐GRL) and TMPRSS6‐ASO is superior for correcting β‐thalassemia

Guerra,

Hamilton,

Rivera

et al. 2024

American J Hematol

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A recently approved drug that induces erythroid cell maturation (luspatercept) has been shown to improve anemia and reduce the need for blood transfusion in non‐transfusion‐dependent as well as transfusion‐dependent β‐thalassemia (BT) patients. Although these results were predominantly positive, not all the patients showed the expected increase in hemoglobin (Hb) levels or transfusion burden reduction. Additional studies indicated that administration of luspatercept in transfusion‐dependent BT was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content. Altogether, these studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management. As luspatercept does not appear to directly affect iron metabolism, we hypothesized that TMPRSS6‐ASO could improve iron parameters and iron overload when co‐administered with luspatercept. We used an agent analogous to murine luspatercept (RAP‐GRL) and another novel therapeutic, IONIS TMPRSS6‐LRx (TMPRSS6‐ASO), a hepcidin inducer, to treat non‐transfusion‐dependent BT‐intermedia mice. Our study shows that RAP‐GRL alone improved red blood cell (RBC) production, with no or limited effect on splenomegaly and iron parameters. In contrast, TMPRSS6‐ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre‐clinical support for combining TMPRSS6‐ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients.

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Oxidative stress in β-thalassaemia and sickle cell disease

Cited by 135 publications

References 220 publications

Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

Oxidative stress and phosphatidylserine exposure in red cells from patients with sickle cell anaemia

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Combination of a TGF‐β ligand trap (RAP‐GRL) and TMPRSS6‐ASO is superior for correcting β‐thalassemia

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