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Pathophysiology and recent therapeutic insights of sickle cell disease

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Abstract

Sickle cell disease (SCD) is an autosomal recessive blood disorder which occurs due to point mutation in the β-globin chain of hemoglobin. Since the past decades, various therapies have been put forth, which are based on obstructing pathophysiological mechanisms of SCD including inhibition of Gardos channel and cation fluxes which in turn prevents sickle erythrocyte destruction and dehydration. The pharmacological approaches are based on the mechanism of reactivating γ-globin expression by utilizing fetal hemoglobin (HbF)-inducing drugs such as hydroxyurea. In SCD, gene therapy could be considered as a promising tool which involves modifying mutation at the gene-specific target by either promoting insertion or deletion of globins. Although there are various therapies emerged so far in the treatment of SCD, many of them have faced a major setback in most of developing countries in terms of cost, unavailability of expertise, and suitable donor. Therefore, in addition to pathophysiological aspects, this review will discuss new advancements and approaches made in the therapeutic domain of SCD including a viewpoint of modulating hemoglobin in SCD by the intervention of probiotics.

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Abbreviations

SCD:

Sickle cell disease

HbF:

Fetal hemoglobin

HbS:

Sickle hemoglobin

RBCs:

Red blood cells

SCFAs:

Short-chain fatty acids

VOC:

Vao-occlusive crisis

NO:

Nitric oxide

GM-CSF:

Granulocyte macrophage colony-stimulating factor

G-CSF:

Granulocyte colony-stimulating factor

NuRD:

Nucleosome remodeling deacetylase complex

sGC:

Soluble guanylate cyclase

MAPKs:

Mitogen-activated protein kinases

ERK:

Extracellular signal-regulated protein kinase

JNK:

c-Jun N-terminal kinase

ROS:

Reactive oxygen species

H2O2 :

Hydrogen peroxide

elF2α:

Eukaryotic initiation factor 2α

HDAC:

Histone deacetylase

HDR:

Homology-directed repair

cGMP:

Cyclic guanosine monophosphate pathway

GCPRs:

G-coupled protein receptors

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Acknowledgments

We are thankful to Uka Tarsadia University, Bardoli, Gujarat, India, for providing necessary research facilities to conduct the study.

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The presented work was not supported by any funding.

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FS and MD conceptualized the study and prepared the manuscript draft. MD reviewed, edited and submitted the manuscript.

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Correspondence to Mitesh Dwivedi.

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Shah, F., Dwivedi, M. Pathophysiology and recent therapeutic insights of sickle cell disease. Ann Hematol 99, 925–935 (2020). https://doi.org/10.1007/s00277-020-03977-9

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