Monoterpenes as therapeutic candidates to induce fetal hemoglobin synthesis and up-regulation of gamma-globin gene: An in vitro and in vivo investigation

Iftikhar, Fizza; Khan, Muhammad Behroz Naeem; Musharraf, Syed Ghulam

doi:10.1016/j.ejphar.2020.173700

Cited by 9 publications

(5 citation statements)

References 43 publications

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“…Apart from the sugars, monoterpenes also play a significant role in the γ-globin gene expression and HbF induction [ 23 ]. Geraniol is a monoterpenoid, found in various aromatic plants as essential oils.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Study of Serum Samples of β-YAC Transgenic Mice Treated with Tenofovir Disoproxil Fumarate

Kumari

Khan

Siddiqui

et al. 2022

IJMS

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β-thalassemia is one of the most common monogenic disorders and a life-threatening health issue in children. A cost-effective and safe therapeutic approach to treat this disease is to reactivate the γ-globin gene for fetal hemoglobin (HbF) production that has been silenced during infancy. Hydroxyurea (HU) is the only FDA approved HbF inducer. However, its cytotoxicity and inability to respond significantly in all patients pose a need for an HbF inducer with better efficacy. The study describes the serum metabolic alteration in β-YAC transgenic mice treated with Tenofovir disoproxil fumarate (TDF) (n = 5), a newly identified HbF inducer, and compared to the mice groups treated with HU (n = 5) and untreated control (n = 5) using gas chromatography-mass spectrometry. Various univariate and multivariate statistical analyses were performed to identify discriminant metabolites that altered the biological pathways encompassing galactose metabolism, lactose degradation, and inositol. Furthermore, the decreased concentrations of L-fucose and geraniol in TDF-treated mice help in recovering towards normal, decreasing oxidative stress even much better than the HU-treated mice. The proposed study suggested that TDF can reduce the deficiency of blood required for β-thalassemia and can be used for the preclinical study at phase I/II for fetal hemoglobin production.

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Section: Discussionmentioning

confidence: 99%

Metabolomics Study of Serum Samples of β-YAC Transgenic Mice Treated with Tenofovir Disoproxil Fumarate

Kumari

Khan

Siddiqui

et al. 2022

IJMS

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“…The in vitro erythroid differentiation ability of A. vasica was further validated by using β-YAC transgenic mice to assess induction and γ-globin gene expression. The transgenic mice containing the human β-globin gene locus including the locus control region (LCR) in a yeast artificial chromosome (YAC) was used with the approval of the Institutional Animal Care and Use Committee of the Animal Research Facility (Animal Safety Protocol number 2017-0003) ( Boosalis et al, 2015 ; Iftikhar et al, 2020 ). These β-YAC mice were already characterized previously ( Costa et al, 2012 ) and bought from the University of Kansas Medical Center.…”

Section: Methodsmentioning

confidence: 99%

“…The quantitative amount of total hemoglobin synthesized after treating the cells with lead compounds was assessed using the plasma hemoglobin kit (Sigma, United States), as reported previously ( Iftikhar et al, 2020 ). K562 cell lysate was obtained by using lysis buffer containing 0.2% Triton X-100 in 100 mM potassium phosphate (pH 7.8).…”

Section: Methodsmentioning

confidence: 99%

“…For Flow analysis, a previously described method was followed on differentiated K562 cells and mice whole blood ( Iftikhar et al, 2020 ). Briefly, treated cells were fixed and permeabilized with 0.05% glutaraldehyde and 0.1% Triton X-100, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, the utilization of natural HbF inducers in countries with a high prevalence rate of disease is more affordable as compared to other ways of treatment. Some reported HbF inducers from natural sources are resveratrol, mithramycin, rapamycin, curcuminoid, cucurbitacin D, cinchonidine, and quinidine ( Liu et al, 2010 ; Ng and Ko, 2014 ; Iftikhar et al, 2019 ; Iftikhar et al, 2020 ; Zuccato et al, 2021 ). Yet, many of these are recently identified HbF inducing agents, and their therapeutic applications are restricted due to their carcinogenic and cytotoxic properties and require further clinical trials ( de Dreuzy et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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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

Iftikhar¹,

Rahman

Khan³

et al. 2022

Front. Pharmacol.

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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 A. vasica in vitro and in vivo, and the identification of potential therapeutic compounds through a bioassay-guided approach. In vitro benzidine-Hb assay demonstrated strong erythroid differentiation of K562 cells by A. vasica extracts. Subsequently, an in vivo study with an aqueous extract of A. vasica (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 A. vasica. Following the bioassay-guided approach, two isolated compounds, vasicinol (1) and vasicine (2) 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 1 (0.1 µM) and compound 2 (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 (1) and (2) 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 A. vasica for fostering HbF production in clinical implications for blood disorders.

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Biopolymers in Aromatherapeutic Textiles

Danila

2024

Biopolymers in the Textile Industry

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Monoterpenes as therapeutic candidates to induce fetal hemoglobin synthesis and up-regulation of gamma-globin gene: An in vitro and in vivo investigation

Cited by 9 publications

References 43 publications

Metabolomics Study of Serum Samples of β-YAC Transgenic Mice Treated with Tenofovir Disoproxil Fumarate

Metabolomics Study of Serum Samples of β-YAC Transgenic Mice Treated with Tenofovir Disoproxil Fumarate

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

Biopolymers in Aromatherapeutic Textiles

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