In Vitro and In Vivo Studies for the Investigation of γ-Globin Gene Induction by Adhatoda vasica : A Pre-Clinical Study of HbF Inducers for β-Thalassemia

Fetal hemoglobin (HbF) is a potent genetic modifier, and the γ-globin gene induction has proven to be a sustainable therapeutic approach for the management of β-thalassemia. In this study, we have evaluated the HbF induction ability of and , and the identification of potential therapeutic compounds...

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Published in:Frontiers in pharmacology 2022-03, Vol.13, p.797853
Main Authors: Iftikhar, Fizza, Rahman, Saeedur, Khan, Muhammad Behroz Naeem, Khan, Kanwal, Khan, Muhammad Noman, Uddin, Reaz, Musharraf, Syed Ghulam
Format: Article
Language:English
Subjects:
Adhatoda vasica
bioassay-guided isolation
erythroid differentiation
HbF induction
hematological indices
Pharmacology
pyrroquinazoline alkaloids
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Summary:Fetal hemoglobin (HbF) is a potent genetic modifier, and the γ-globin gene induction has proven to be a sustainable therapeutic approach for the management of β-thalassemia. In this study, we have evaluated the HbF induction ability of and , and the identification of potential therapeutic compounds through a bioassay-guided approach. benzidine-Hb assay demonstrated strong erythroid differentiation of K562 cells by extracts. Subsequently, an study with an aqueous extract of (100 mg/kg) showed significant induction of the γ-globin gene and HbF production. While in the acute study, the hematological and biochemical indices were found to be unaltered at the lower dose of . Following the bioassay-guided approach, two isolated compounds, vasicinol ( ) and vasicine ( ) strongly enhanced HbF levels and showed prominent cellular growth kinetics with ample accumulation of total hemoglobin in K562 cultures. High HbF levels were examined by immunofluorescence and flow cytometry analysis, concomitant with the overexpression in the γ-globin gene level. Compound (0.1 µM) and compound (1 µM) resulted in a greater increase in F-cells (90 and 83%) with marked up (8-fold and 5.1-fold) expression of the γ-globin gene, respectively. Molecular docking studies indicated strong binding affinities of ( ) and ( ) with HDAC2 and KDM1 protein that predict the possible mechanism of compounds in inhibition of these epigenetic regulators in the γ-globin gene reactivation. Altogether, these observations demonstrated the therapeutic usefulness of for fostering HbF production in clinical implications for blood disorders.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.797853