Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Background: The anti-sickling activity of Anogeissus leiocarpus, a plant used for managing sickle cell disease (SCD), has been previously proven. Objectives: This study investigated the anti-sickling mechanism of A. leiocarpus by probing its effects on Gardos channel (KCNN4), erythropoietin (EPO), erythropoietin receptor (EPOR), catalase (CAT), G6pD, D-type cyclins and cyclin-dependent kinase inhibitors (p21) gene expression as well as assessing in silico drug-likeness of reported compounds as EPOR agonist. Methods: A total of 18 rats (45-76 g) were selected and divided into 6 groups (n=3). The control group was given water ad libitum, standard group was given 0.1 mL/kg of Ciklavit® and experimental group was given daily oral doses of 50-100 mg/kg body weight of crude methanol extract or ethyl acetate fraction (EA-PF). Haematological parameters were analyzed while histopathological and molecular studies of kidney and bone marrow were carried out, followed by RT-PCR analysis of KCNN4, EPO, EPOR, CAT, G6pD, p21, and cyclin-dependent kinase inhibitors. Docking studies of the reported compounds were also done. Results: EA-PF had an insignificant (P>0.05) effect on haematological parameters compared to the basal group. While CAT and p21 acted in a positive feedback loop, G6pD was downregulated in the experimental groups. KCNN4 acted in a negative-feedback mechanism and the upregulation of EPO and EPOR was followed by increased reticulocytes. Kaempferol, quercetin, and catechin showed non-violation of Lipinski’s rule and high binding affinities of 6.5 kcal/mol, 6.7 kcal/mol, and 6.7 kcal/mol, respectively, for EPOR pocket compared to the co-crystallized ligand. Conclusion: Results suggest that ethyl acetate fraction of Anogeissus leiocarpus achieved a steady state level of the Gardos channel and stimulation of EPO expression via EPOR agonist.

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“…oxide and reduce iron overload (42). Others are stem cell transplantation, which is the only cure to date, and gene therapy (43).…”

Section: Discussionmentioning

confidence: 99%

Identification of the Anti-sickling Activity of Anogeissus leiocarpus and In Silico Investigation of Some of Its Phytochemicals

Elufioye

Williams

Cyrl-Olutayo

2020

Avicenna J Med Biochem

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Hyperuricemia, urine uric excretion, and associated complications in thalassemia patients

et al. 2019

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Genetic variants associated with the risk of stroke in sickle cell disease: a systematic review and meta-analysis

Kumari

Chauhan

Chaudhuri

et al. 2023

Preprint

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Background: Sickle cell disease (SCD) is the commonest cause of stroke in children. As it is a rare disease, studies investigating the association with complications like stroke in SCD have small sample sizes. Here, we performed a systematic review and meta-analysis of the studies exploring an association of genetic variants with stroke to get a better indication of their association with stroke. Methods: PubMed and Google Scholar were searched to identify studies that had performed an association analysis of genetic variants for the risk of stroke in SCD patients. After screening of eligible studies, summary statistics of association analysis with stroke and other general information were extracted. Meta-analysis was performed using the fixed effect method on the tool METAL and forest plots were plotted using the R program. The random effect model was performed as a sensitivity analysis for loci where significant heterogeneity was observed. Results: 407 studies were identified using the search term and after screening 39 studies that cumulatively analysed 11,780 SCD patients were included. These 39 studies included a total of 2,401 SCD patients with stroke, predominantly included individuals of African ancestry (N=16). Three of these studies performed whole exome sequencing while 35 performed single nucleotide-based genotyping. Though the studies reported association with 109 loci, meta-analyses could be performed only for 12 loci that had data from two or more studies. After meta-analysis we observed that four loci were significantly associated with risk for stroke: -α3.7kb Alpha-thalassemia deletion (P= 0.00000027), rs489347-TEK (P= 0.00081), rs2238432-ADCY9 (P= 0.00085) and rs11853426-ANXA2 (P= 0.0034). Conclusion: Ethnic representation of regions with a high prevalence of SCD like the Mediterranean basin and India needs to be improved for genetic studies on associated complications like stroke. Larger genome-wide collaborative studies on SCD and associated complications including stroke needs to be performed.

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Sickle Cell Disease – Current Treatment and New Therapeutical Approaches

Cited by 3 publications

References 114 publications

Identification of the Anti-sickling Activity of Anogeissus leiocarpus and In Silico Investigation of Some of Its Phytochemicals

Identification of the Anti-sickling Activity of Anogeissus leiocarpus and In Silico Investigation of Some of Its Phytochemicals

Hyperuricemia, urine uric excretion, and associated complications in thalassemia patients

Genetic variants associated with the risk of stroke in sickle cell disease: a systematic review and meta-analysis

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