Oxidative status in the β-thalassemia syndromes in Sri Lanka; a cross-sectional survey

Allen, Angela; Perera, Shiromi; Mettananda, Sachith; Rodrigo, Rexan; Perera, Lasantha B.; Darshana, Thamal; Stefanowicz, Fiona; Jackson-Crawford, Anthony; Heirene, Lesley; Fisher, Christopher A.; Olivieri, Nancy F.; Rees, David C.; Premawardhena, Anuja; Allen, Stephen

doi:10.1016/j.freeradbiomed.2021.02.028

Cited by 10 publications

(17 citation statements)

References 51 publications

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“…Disease severity is another challenging issue that seems to be in uential on oxidative biomarkers of thalassemia patients. This hypothesis is supported by substantial variability in biomarkers of oxidative damage which are observed both within and between different types of thalassemia syndromes 12 . However, Mana khiet al 13 reported no signi cant association between disease severity and oxidative status of thalassemia patients.…”

Section: Discussionmentioning

confidence: 90%

“…Another concern is the controversial ndings regarding the effect of splenectomy on oxidative biomarkers in thalassemia patients. Splenectomized patients experience more severe oxidative stress and damage compared to non-splenectomized patients 12 . The suggested mechanism is that the circulating abnormal red cells enhance the potential for free radical production and deplete antioxidants, which result in considerable oxidative damage compared to the patients with an intact spleen.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, reduced antioxidant capacity, reduction in Vitamin E, and decreased superoxide dismutase and glutathione peroxidase activity or level were reported inchildren with thalassemia major 14 anda group of patients with β thalassemia major with unknown age range 15 . Furthermore, the antioxidant de ciency was reported in patients affected by thalassemia syndrome (thalassemia major, intermedia, HbE, and sickle thalassemia) with median age 26.0 years (IQR 15.3-38.80) 12 .…”

Section: Discussionmentioning

confidence: 99%

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The Effect of N-Acetyl Cysteine and Vitamin E on Oxidative Status and Hemoglobin Level in Transfusion-Dependent Thalassemia Patients: A Systematic Review and Meta-Analysis

Haghpanah¹,

Hosseini-Bensenjan²,

Zekavat³

et al. 2021

Preprint

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This meta-analysis was conducted to summarize the comparative effect of NAC and Vitamin E on oxidative status, including total antioxidant capacity (TAC), total oxidative stress (TOS), oxidative stress index (OSI), and hemoglobin (Hb) in patients with TDT.All methods were performed in accordance with the PRISMA checklist. We searched databases including Web of Science (ISI), Scopus, PubMed, and Embase. Meta-analysis was done using Stata statistical software version 16.0.Finally,four randomized-controlled trials (RCT)for NAC and four RCTs for Vitamin E were included.Our meta-analyses showed a significant increase in the weighted mean differences (WMD) of Hband a significant decrease in the WMD of OSI in the NAC group.In subgroup analysis based on age: in the NAC group, a significant increase in the WMD of TAC andHband a significant decrease in the WMD of TOS were detectedonly in children. In theVitamin E group, a significant increase in Hb and a significantdecrease in TOS and OSI were determined in the children subgroup as well.NAC can be used as an effective antioxidant supplementparticularlyin children with TDT. Also, Vitamin Eshowed a beneficial antioxidant effect in TDT children. So, more well-designed randomized, controlled trials for the effect of NAC in adult TDT andthe effect of vitamin E both in adults and children are recommended with more focus on theessential influencing factors on the oxidative status in TDT patients.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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The Effect of N-Acetyl Cysteine and Vitamin E on Oxidative Status and Hemoglobin Level in Transfusion-Dependent Thalassemia Patients: A Systematic Review and Meta-Analysis

Haghpanah¹,

Hosseini-Bensenjan²,

Zekavat³

et al. 2021

Preprint

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“…Another important finding of this study is the demonstration of a reduction in erythropoietic stress following hydroxyurea treatment. Erythropoietic stress in patients with β-thalassaemia is primarily due to ineffective erythropoiesis, which plays a significant role in disease pathogenesis 32 – 34 . Hence, reducing erythropoietic stress would be expected to ameliorate the symptoms and signs of β-thalassaemia and improve the quality of life.…”

Section: Discussionmentioning

confidence: 99%

A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

Yasara

Wickramarathne

Mettananda

et al. 2022

Sci Rep

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Hydroxyurea is an antimetabolite drug that induces fetal haemoglobin in sickle cell disease. However, its clinical usefulness in β-thalassaemia is unproven. We conducted a randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of hydroxyurea in transfusion-dependent β-thalassaemia. Sixty patients were assigned 1:1 to oral hydroxyurea 10–20 mg/kg/day or placebo for 6 months by stratified block randomisation. Hydroxyurea treatment did not alter the blood transfusion volume overall. However, a significantly higher proportion of patients on hydroxyurea showed increases in fetal haemoglobin percentage (89% vs. 59%; p < 0.05) and reductions in erythropoietic stress as measured by soluble transferrin receptor concentration (79% vs. 40%; p < 0.05). Based on fetal haemoglobin induction (> 1.5%), 44% of patients were identified as hydroxyurea-responders. Hydroxyurea-responders, required significantly lower blood volume (77 ± SD27ml/kg) compared to hydroxyurea-non-responders (108 ± SD24ml/kg; p < 0.01) and placebo-receivers (102 ± 28ml/kg; p < 0.05). Response to hydroxyurea was significantly higher in patients with HbE β-thalassaemia genotype (50% vs. 0%; p < 0.01) and Xmn1 polymorphism of the γ-globin gene (67% vs. 27%; p < 0.05). We conclude that oral hydroxyurea increased fetal haemoglobin percentage and reduced erythropoietic stress of ineffective erythropoiesis in patients with transfusion-dependent β-thalassaemia. Hydroxyurea reduced the transfusion burden in approximately 40% of patients. Response to hydroxyurea was higher in patients with HbE β-thalassaemia genotype and Xmn1 polymorphism of the γ-globin gene.

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“…Consequently, free α-globin chains that do not have adequate β-like globin chains to pair with, form insoluble α-hemichromes that trigger a cascade of events through the generation of reactive oxygen species leading to premature destruction of erythroid cells ( Figure 1 ); ( Schrier et al, 2003 ). Thus, excess free α-globin chains are the main mediators of ineffective erythropoiesis and haemolysis in β-thalassaemia ( Allen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic and Epigenetic Therapies for β-Thalassaemia by Altering the Expression of α-Globin Gene

Mettananda

2021

Front. Genome Ed.

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β-Thalassaemia is caused by over 300 mutations in and around the β-globin gene that lead to impaired synthesis of β-globin. The expression of α-globin continues normally, resulting in an excess of α-globin chains within red blood cells and their precursors. These unpaired α-globin chains form unstable α-hemichromes that trigger cascades of events to generate reactive oxygen species, leading to ineffective erythropoiesis and haemolysis in patients with β-thalassaemia. The clinical genetic data reported over several decades have demonstrated how the coinheritance of α-thalassaemia ameliorates the disease phenotype of β-thalassaemia. Thus, it is evident that down-regulation of the α-globin gene expression in patients with β-thalassaemia could ameliorate or even cure β-thalassaemia. Over the last few years, significant progress has been made in utilising this pathway to devise a cure for β-thalassaemia. Most research has been done to alter the epigenetic landscape of the α-globin locus or the well-characterised distant enhancers of α-globin. In vitro, pre-clinical studies on primary human erythroid cells have unveiled inhibition of histone lysine demethylation and histone deacetylation as potential targets to achieve selective downregulation of α-globin through epigenetic drug targeting. CRISPR based genome editing has been successfully used in vitro to mutate α-globin genes or enhancers of α-goblin to achieve clinically significant knockdowns of α-globin to the levels beneficial for patients with β-thalassaemia. This review summarises the current knowledge on the regulation of human α-globin genes and the clinical genetic data supporting the pathway of targeting α-globin as a treatment for β-thalassaemia. It also presents the progress of epigenetic drug and genome editing approaches currently in development to treat β-thalassaemia.

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Oxidative status in the β-thalassemia syndromes in Sri Lanka; a cross-sectional survey

Cited by 10 publications

References 51 publications

The Effect of N-Acetyl Cysteine and Vitamin E on Oxidative Status and Hemoglobin Level in Transfusion-Dependent Thalassemia Patients: A Systematic Review and Meta-Analysis

The Effect of N-Acetyl Cysteine and Vitamin E on Oxidative Status and Hemoglobin Level in Transfusion-Dependent Thalassemia Patients: A Systematic Review and Meta-Analysis

A randomised double-blind placebo-controlled clinical trial of oral hydroxyurea for transfusion-dependent β-thalassaemia

Genetic and Epigenetic Therapies for β-Thalassaemia by Altering the Expression of α-Globin Gene

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