scholarly journals The Role of miRNAs as Therapeutic Tools in Sickle Cell Disease

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1106
Author(s):  
Cyril Cyrus
Keyword(s):  
Sickle Cell ◽  
Cell Cycle Progression ◽  
Globin Gene ◽  
Erythroid Differentiation ◽  
Clinical Severity ◽  
Functional Studies ◽  
Abnormal Hemoglobin ◽  
Therapeutic Tools ◽  
Targeted Medicine

Background and Objectives: Sickle cell disorder (SCD) is a paradigmatic example of a complex monogenic disorder. SCD is characterized by the production of abnormal hemoglobin, primarily in the deoxygenated state, which makes erythrocytes susceptible to intracellular hemoglobin polymerization. Functional studies have affirmed that the dysregulation of miRNAs enhances clinical severity or has an ameliorating effect in SCD. miRNAs can be effectively regulated to reduce the pace of cell cycle progression, to reduce iron levels, to influence hemolysis and oxidative stress, and most importantly, to increase γ-globin gene expression and enhance the effectiveness of hydroxyurea. Results: This review highlights the roles played by some key miRNAs in hemoglobinopathies, especially in hematopoiesis, erythroid differentiation, and severity of anemia, which make miRNAs attractive molecular tools for innovative therapeutic approaches. Conclusion: In this era of targeted medicine, miRNAs mimics and antagomirs may be promising inducers of HbF synthesis which could ameliorate the clinical severity of SCD.

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 Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management

2012 ◽  
Vol 2012 ◽  
pp. 1-55 ◽  
Author(s):  
Samir K. Ballas ◽  
Muge R. Kesen ◽  
Morton F. Goldberg ◽  
Gerard A. Lutty ◽  
Carlton Dampier ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Point Mutation ◽  
Sickle Cell ◽  
Globin Gene ◽  
Single Point ◽  
Acute Chest Syndrome ◽  
Single Point Mutation ◽  
Cell Disease ◽  
Exon 1 ◽  
Abnormal Hemoglobin

The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of theβglobin gene resulting in the substitution of glutamic acid by valine at position 6 of theβglobin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

scholarly journals Dissecting the role of genetic modifiers of hemoglobinopathies: A futuristic approach towards precision medicine

2021 ◽  
Author(s):  
Priya Hariharan ◽  
Manju Gorivale ◽  
Pratibha Sawant ◽  
Pallavi Mehta ◽  
Anita Nadkarni
Keyword(s):  
Disease Severity ◽  
Phenotypic Variability ◽  
Globin Gene ◽  
Gene Promoter ◽  
Clinical Severity ◽  
Genetic Modifiers ◽  
Promoter Polymorphisms ◽  
Cumulative Impact ◽  
Remarkable Result

Abstract Introduction: Hemoglobinopathies though a monogenic disorder, show phenotypic variability. Hence, understanding the genetics underlying the heritable sub-phenotypes of hemoglobinopathies, specific to each population, would be prognostically useful and could inform personalized therapeutics. This study aimed to evaluate the role of genetic modifiers leading to higher HbF production with cumulative impact of the modifiers on disease severity. Materials and methods:200 patients [100 β-thalassemia homozygotes,100 Sickle Cell Anemia], and 50 healthy controls were recruited. Primary screening followed with molecular analysis for confirming the β-hemoglobinopathy was performed. Co-existing α-thalassemia and the polymorphisms located in 3 genetic loci linked to HbF regulation were screened.Results: The most remarkable result was the association of SNPs with clinically relevant phenotypic groups. The γ-globin gene promoter polymorphisms [-158 C→T,+25 G→A],BCL11A rs1427407 G→T,-3 bp HBS1L-MYB rs66650371 and rs9399137 T→C polymorphisms were correlated with higher HbF, in group that has lower disease severity score (P<0.00001), milder clinical presentation, and a significant delay in the age of the first transfusion.Conclusion:Our study emphasizes the complex genetic interactions underlying the disease phenotype that may be a prognostic marker for predicting the clinical severity and assist in disease management.

Prevention of Stroke in Sickle Cell Anemia

2014 ◽  
Vol 42 (2) ◽  
pp. 135-138 ◽  
Author(s):  
Robert J. Adams
Keyword(s):  
High Risk ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Preventive Treatment ◽  
High Risk Group ◽  
Large Artery ◽  
Rbc Membrane ◽  
Abnormal Hemoglobin ◽  
The Brain

Sickle cell anemia (SCD) is a disease characterized by abnormal hemoglobin (Hb) structure. There is a mutation in the beta-globin gene that changes the sixth amino acid from glutamic acid to valine causing the mutated hemoglobin (HbS) to polymerize reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen and distort the red blood cell (RBC) membrane. This leads to episodes of microvascular vasoocclusion and premature RBC destruction leading to hemolytic anemia. For reasons that are unclear, some children develop a large artery vasculopathy (gradual narrowing and ultimate occlusion causing deprivation of blood to the brain — a stroke in other words) involving the intracranial arteries supplying the brain.The risk of stroke for a child with SCD is many times greater than that of a healthy child without SCD or heart disease. There is a technique that allows the identification of the children with SCD who have high risk even within this relatively high-risk group. And there is a highly effective preventive treatment.

scholarly journals The Role of RBC Oxidative Stress in Sickle Cell Disease: From the Molecular Basis to Pathologic Implications

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1608
Author(s):  
Qinhong Wang ◽  
Rahima Zennadi
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Redox State ◽  
Continuous Production ◽  
Globin Gene ◽  
Critical Role ◽  
Cell Disease ◽  
Membrane Structure And Function

Sickle cell disease (SCD) is an inherited monogenic disorder and the most common severe hemoglobinopathy in the world. SCD is characterized by a point mutation in the β-globin gene, which results in hemoglobin (Hb) S production, leading to a variety of mechanistic and phenotypic changes within the sickle red blood cell (RBC). In SCD, the sickle RBCs are the root cause of the disease and they are a primary source of oxidative stress since sickle RBC redox state is compromised due to an imbalance between prooxidants and antioxidants. This imbalance in redox state is a result of a continuous production of reactive oxygen species (ROS) within the sickle RBC caused by the constant endogenous Hb autoxidation and NADPH oxidase activation, as well as by a deficiency in the antioxidant defense system. Accumulation of non-neutralized ROS within the sickle RBCs affects RBC membrane structure and function, leading to membrane integrity deficiency, low deformability, phosphatidylserine exposure, and release of micro-vesicles. These oxidative stress-associated RBC phenotypic modifications consequently evoke a myriad of physiological changes involved in multi-system manifestations. Thus, RBC oxidative stress in SCD can ultimately instigate major processes involved in organ damage. The critical role of the sickle RBC ROS production and its regulation in SCD pathophysiology are discussed here.

scholarly journals <i>ß</i>-Globin Gene Cluster Haplotypes and Clinical Severity in Sickle Cell Anemia Patients in Southern Brazil

2014 ◽  
Vol 04 (02) ◽  
pp. 16-23 ◽  
Author(s):  
Maria A. L. da Silva ◽  
João R. Friedrisch ◽  
Christina M. Bittar ◽  
Meide Urnau ◽  
Jóice Merzoni ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Clinical Severity ◽  
Southern Brazil ◽  
Globin Gene Cluster

scholarly journals Immunological Hallmarks of Inflammatory Status in Vaso-Occlusive Crisis of Sickle Cell Anemia Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander Leonardo Silva-Junior ◽  
Nadja Pinto Garcia ◽  
Evilázio Cunha Cardoso ◽  
Stephanny Dias ◽  
Andrea Monteiro Tarragô ◽  
...  
Keyword(s):  
Growth Factors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Gm Csf ◽  
Inflammatory Status ◽  
Ifn Γ

Sickle Cell Anemia (SCA) is the most common genetic disorder around the world. The mutation in the β-globin gene is responsible for a higher hemolysis rate, with further involvement of immunological molecules, especially cytokines, chemokines, growth factors, and anaphylatoxins. These molecules are responsible for inducing and attracting immune cells into circulation, thus contributing to increases in leukocytes and other pro-inflammatory mediators, and can culminate in a vaso-occlusive crisis (VOC). This study aimed to characterize the levels of these molecules in SCA patients in different clinical conditions in order to identify potential hallmarks of inflammation in these patients. An analytical prospective study was conducted using the serum of SCA patients in steady-state (StSt; n = 27) and VOC (n = 22), along with 53 healthy donors (HD). Samples from the VOC group were obtained on admission and on discharge, in the convalescent phase (CV). Levels of chemokines (CXCL8, CXCL10, CL2, CLL3, CCL4, CL5, and CCL11), cytokines (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-17A, TNF-α, and IFN-γ) and growth factors (VEGF, FGFb, PDGF-BB, GM-CSF, and G-CSF) were measured using a Luminex assay, and anaphylatoxins (C3a, C4a, and C5a) were measured using Cytometric Bead Array. SCA patients in StSt showed a pro-inflammatory profile, and were indicated as being higher producers of CCL2, IL-1β, IL-12p70, IFN-γ, IL-17A, and GM-CSF, while VOC is highlighted by molecules IL-4 and IL-5, but also IL-2, IL-7, PDGF-BB, and G-CSF. PDGF-BB and IL-1ra seemed to be two important hallmarks for the acute-to-chronic stage, due to their significant decrease after crisis inflammation and statistical difference in VOC and CV groups. These molecules show higher levels and a strong correlation with other molecules in VOC. Furthermore, they remain at higher levels even after crisis recovery, which suggest their importance in the role of inflammation during crisis and participation in immune cell adhesion and activation. These results support a relevant role of cytokines, neutrophil and monocytes, since these may act as markers of VOC inflammation in SCA patients.

scholarly journals MicroRNA Regulation of Brain Tumour Initiating Cells in Central Nervous System Tumours

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Neha Garg ◽  
Thusyanth Vijayakumar ◽  
David Bakhshinyan ◽  
Chitra Venugopal ◽  
Sheila K. Singh
Keyword(s):  
Brain Tumour ◽  
Small Population ◽  
Poor Clinical Outcome ◽  
Microrna Regulation ◽  
Functional Studies ◽  
Central Nervous System Tumours ◽  
Cancer Initiation ◽  
Cns Tumours ◽  
Therapeutic Tools

CNS tumours occur in both pediatric and adult patients and many of these tumours are associated with poor clinical outcome. Due to a paradigm shift in thinking for the last several years, these tumours are now considered to originate from a small population of stem-like cells within the bulk tumour tissue. These cells, termed as brain tumour initiating cells (BTICs), are perceived to be regulated by microRNAs at the posttranscriptional/translational levels. Proliferation, stemness, differentiation, invasion, angiogenesis, metastasis, apoptosis, and cell cycle constitute some of the significant processes modulated by microRNAs in cancer initiation and progression. Characterization and functional studies on oncogenic or tumour suppressive microRNAs are made possible because of developments in sequencing and microarray techniques. In the current review, we bring recent knowledge of the role of microRNAs in BTIC formation and therapy. Special attention is paid to two highly aggressive and well-characterized brain tumours: gliomas and medulloblastoma. As microRNA seems to be altered in the pathogenesis of many human diseases, “microRNA therapy” may now have potential to improve outcomes for brain tumour patients. In this rapidly evolving field, further understanding of miRNA biology and its contribution towards cancer can be mined for new therapeutic tools.

scholarly journals MiR-27a Promotes Hemin-Induced Erythroid Differentiation of K562 Cells by Targeting CDC25B

2018 ◽  
Vol 46 (1) ◽  
pp. 365-374 ◽  
Author(s):  
Dongsheng Wang ◽  
Si Si ◽  
Qiang Wang ◽  
Guangcheng Luo ◽  
Qin Du ◽  
...  
Keyword(s):  
Cell Division ◽  
Potential Role ◽  
Globin Gene ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Dual Luciferase Reporter Assay ◽  
Cell Division Control

Background/Aims: MicroRNAs (miRNAs) play a crucial role in erythropoiesis. MiR-23a∼27a∼24-2 clusters have been proven to take part in erythropoiesis via some proteins. CDC25B (cell division control Cdc2 phosphostase B) is also the target of mir-27a; whether it regulates erythropoiesis and its mechanism are unknown. Methods: To evaluate the potential role of miR-27a during erythroid differentiation, we performed miR-27a gain- and loss-of-function experiments on hemin-induced K562 cells. We detected miR-27a expression after hemin stimulation at different time points. At the same time, the γ-globin gene also was measured via real-time PCR. According to the results of the chips, we screened the target protein of miR-27a through a dual-luciferase reporter assay and identified it via Western blot analyses. To evaluate the function of CDC25B, benzidine staining and flow cytometry were employed to detect the cell differentiation and cell cycle. Results: We found that miR-27a promotes hemin-induced erythroid differentiation of human K562 cells by targeting cell division cycle 25 B (CDC25B). Overexpression of miR-27a promotes the differentiation of hemin-induced K562 cells, as demonstrated by γ-globin overexpression. The inhibition of miR-27a expression suppresses erythroid differentiation, thus leading to a reduction in the γ-globin gene. CDC25B was identified as a new target of miR-27a during erythroid differentiation. Overexpression of miR-27a led to decreased CDC25B expression after hemin treatment, and CDC25B was up-regulated when miR-27a expression was inhibited. Moreover, the inhibition of CDC25B affected erythroid differentiation, as assessed by γ-globin expression. Conclusion: This study is the first report of the interaction between miR-27a and CDC25B, and it improves the understanding of miRNA functions during erythroid differentiation.

scholarly journals Frequency of beta S globin gene haplotypes among sickle cell patients in Nigeria

2021 ◽  
Vol 49 (6) ◽  
pp. 030006052110199
Author(s):  
Abosede Adabale ◽  
Samira Batista Lobo Makanjuola ◽  
Akinsegun Akinbami ◽  
Adedoyin Dosunmu ◽  
Alani Akanmu ◽  
...  
Keyword(s):  
Blood Cell ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Clinical Severity ◽  
Polymorphism Analysis ◽  
Cell Width ◽  
Cell Counts ◽  
Haematological Profile

Objective To determine the frequency of beta s globin gene haplotypes in Nigerian patients with sickle cell disease (SCD) and to measure their correlation with clinical and haematological characteristics. Methods This study enrolled patients with SCD and collected their peripheral blood for restriction fragment length polymorphism analysis in order to identify five polymorphic sites in the β-globin gene cluster. Results A total of 245 homozygous SCD patients (490 alleles) were included in the study. Among the analysed alleles, 426 (86.9%) had the Benin (BEN) haplotype; 19 (3.9%) had the Senegal (SEN) haplotype; 31 (6.3%) had the Cameroon haplotype; five (1.0%) had the Bantu/Central African Republic haplotype; and nine 9 (1.8%) had atypical haplotypes. No significant association was observed between the haplotypes and haematological events, although patients with the BEN/SEN haplotype showed improved red blood cell counts, haemoglobin levels and red blood cell width index. No significant association was observed between the haplotypes and the three clinical manifestations, although patients with the BEN/SEN haplotype showed a four-fold lower frequency of painful episodes. Conclusion These findings suggest that the SEN haplotype combined with the BEN haplotype might contribute toward a better haematological profile and milder clinical severity in SCD.

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