Abstract
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.
Highlights
The anti-sickling activity of Anogeissus leiocarpus, a plant used for managing sickle cell disease (SCD), has been previously proven
The disease is characterized by chronic intravascular haemolysis due to abnormal red blood cells (RBCs) shape that leads to vaso-occlusive crises which is the hallmark of sickle cell disease (SCD) that creates economic burden and makes management difficult in developing countries [3, 4]
A scanty cellular population with serrated edges was observed in 50 mg/kg crude extract (CE) extract group (Figure 3E) compared to 100 mg/kg CE group, in which cell clumping, small-sized cells and a few abnormally shaped cells were observed (Figure 3F) whereas normally shaped nucleated cells and erythrocytes at the background were seen in Ciklavit® group (Figure 3B)
Summary
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. 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. 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. The resulting net loss of KCl and KHCO3 is linked to osmotic-driven water loss that causes cell dehydration referred to as Gardos effect
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