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Phytocompounds Targeting for the Treatment of β-Thalassemia: A Review

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Submitted:

08 June 2024

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11 June 2024

Withdrawn:

13 August 2024

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Abstract
For treating β-thalassemia, increasing foetal haemoglobin (HbF) production with drugs shows promising result. Many studies have focused on finding new HbF-inducing phytocompounds and understanding how they work. This review compiles the identified agents so far. While these agents can stimulate HbF production, chemotherapy drugs cannot be practically used for treating β-haemoglobinopathies, like β-thalassemia, due to their toxicity and growth-inhibiting effects. To overcome this issue, researchers are exploring natural plant sources for effective, safe, and easy-to-use HbF-inducing agents. This review highlights summarizes the natural phytocompounds that stimulate HbF production, aiming to provide new insights into future treatments for β-thalassemia.
Keywords: 
Subject: Biology and Life Sciences  -   Plant Sciences

1. Introduction

Thalassemia, the most common form of hereditary anaemia [Cao & Galanello, 2010], is a genetic disorder that results from the impaired synthesis of one of the two globin chains in haemoglobin [Angastiniotis et al., 2019]. Haemoglobin, the protein in red blood cells responsible for carrying O2 throughout the body, is composed of two types of protein chains: α-globin and β-globin [Marengo-Rowe, 2006]. So, the thalassemia can be classified into two main types based on which globin chain is affected: α-thalassemia and β-thalassemia [Shafique et al., 2021]. Genetic disorders caused by mutations in the β-globin gene are widely known as the human β-haemoglobinopathies [Hariharan et al., 2021], in which β-thalassemia is the most prevalent ones, particularly in the Mediterranean, Africa, and Southeast Asia, leading to great mortality and morbidity [Ng et al., 2014; Weatherall & J, 2010]. The high occurrence of β-thalassemia mutations is due to the reason that causes a mild severity of malarial infection in the heterozygous state. However, in the homozygous state, these mutations shorten the lives of affected individuals [Flint et al., 1998].
β-thalassemia is caused by inherited mutations in the HBB gene complex [Higgs et al., 2012], resulting in a total absence or severe decrease in the production of β-globin chains. Completely absence of β-chain causes β0-thalassemia or thalassemia major. Reduced amounts of detectable beta globin cause β+thalassemia or thalassemia intermedia [Thein, 2013]. But in α-thalassemia, there resulting in the decreased production of α-globin chain. The lack of β-globin chain production leads to the accumulation and precipitation of free intracellular α-globin chains, which consequently result in premature haemolysis of red blood cells and apoptosis of erythroid precursors [El-Beshlawy et al., 2009; Schrier, 2002]. Ineffective erythropoiesis has also been known to be related to inefficient iron utilization [Rivella, 2009]. Therefore, the combined effects of ineffective erythropoiesis, haemolysis, and hypersplenism are the main culprits of severe anaemia in β-thalassemia patients [Mabaera et al., 2008].
The β-globin gene mutations can vary widely, leading to different forms and severities of β-thalassemia. The most severe form, β-thalassemia major, often requires regular blood transfusions and iron chelation therapy to manage iron overload due to transfusions [Ali et al., 2021]. Without treatment, patients with β-thalassemia major may suffer from severe anaemia, growth retardation, skeletal abnormalities, and other complications [Bajwa & Basit, 2023]. Intermediate forms, such as β-thalassemia intermedia, have a variable clinical presentation and may require intermittent transfusions and supportive care.
The clinical management of β-haemoglobinopathies involves various strategies to alleviate symptoms and prevent complications [Kohne, 2011]. The mainstay of treatment for β-thalassemia includes regular blood transfusions to maintain adequate haemoglobin levels and prevent severe anaemia. However, long-term transfusion therapy may cause iron overload from the gradual breakdown of transfused blood, potentially resulting in cardiac failure and/or death [Mabaera et al., 2008; Lal et al., 2021]. Advances in iron chelation therapy, which involves the use of medications to remove excess iron, have improved survival rates, but the effectiveness of treatment depends on adherence to iron chelation regimens [Mobarra et al., 2016].
Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the gene transfer therapies aimed at addressing the underlying molecular causes of β-haemoglobinopathies. Several hundred thalassemia patients have successfully undergone HSCT with promising results [Bhatia & Walters, 2008].
However, HSCT is limited to a small proportion of haemoglobinopathy patients due to the requirement for matched sibling donors and the risk of complications [Bhatia & Walters, 2008], such as graft-versus-host disease. Younger patients and those without significant disease complications tend to have the best outcomes following HSCT.
Transferring γ- or β-hematopoietic stem cells from patients can be another therapy option for β-thalassemia patients. Clinical gene transfer protocols have taken a long time to be approved, as the transduction of human hematopoietic stem cells and gene expression must reach high efficiency and levels [Srivastava & Shaji, 2017; Sadelain, 2006]. Although this approach has successfully passed initial human trials, issues such as low autoploidy recombination, insertional mutagenesis, and the effects of inserted vectors on the expression of nearby genes could potentially limit its application [Dunbar et al., 2007; Hargrove et al., 2008].
Apart from gene therapy, reactivating HbF through chemical agents also appears promising enough to develop into effective interventions to cure human β-haemoglobinopathies [El-Beshlawy et al., 2009]. Studies have revealed that homozygous β-thalassemia patients do not suffer severe anaemia until foetal γ-globin genes are silenced, and patients with hereditary persistence of foetal haemoglobin (HPFH), where HbF persists at high levels into adulthood, only suffer mild anaemia [Bianchi et al., 2009; Forget, 1998; Gallo et al., 1979]. Therefore, increasing the synthesis of HbF by reactivating foetal γ-globin genes is a potential therapy for patients suffering from β-thalassemia.
Pharmacological induction of HbF can correct the globin chain imbalance in β-thalassemia patients. Efforts have been made to identify naturally occurring inducers and drug treatments that can increase HbF synthesis and promote the expression of foetal γ-globin genes [Bou-Fakhredin et al., 2022; Olivieri et al., 1998]. Chemotherapeutic agents such as 5-azacytidine and hydroxyurea (HU) have been reported to enhance HbF production. However, these agents exhibit low efficacy and specificity, myelotoxicity, and carcinogenicity, as well as modest responses to treatment, greatly limiting their usefulness in clinical practice [Li et al., 2011; Watanapokasin et al., 2005; Heller et al., 1984]. The limitations of current treatments and the complex nature of β-haemoglobinopathies necessitate continued research and development of new therapeutic strategies [Frati & Miccio, 2021]. Discovering novel screening platforms for identifying potential HbF inducers with high efficiency and accuracy is essential.
Additionally, identifying new HbF-inducing agents from natural sources that combine efficacy, safety, and ease of use is a high priority [Mabaera et al., 2008]. Advances in genetic engineering and gene editing technologies, such as CRISPR-Cas9, offer new avenues for treating β-haemoglobinopathies by directly correcting the genetic mutations responsible for the diseases. These technologies have the potential to provide long-lasting and possibly curative treatments, but challenges such as delivery methods, off-target effects, and regulatory hurdles need to be addressed [Lu et al., 2023; Papizan et al., 2020].
Research into the molecular mechanisms regulating HbF expression and the development of more effective and safer HbF inducers is ongoing. Understanding the genetic and epigenetic factors (EF) involved in the switch from foetal to adult haemoglobin production can lead to new therapeutic targets. Combination therapies that include HbF inducers, gene editing, and supportive care may offer the best outcomes for patients with β-haemoglobinopathies [Sankaran, et al., 2013].

2. Epidemiology

From 2006 to 2018, the number of thalassemia patients increased from 354 to 1577, with the prevalence rate rising from 0.74 to 2.76 per 100,000 persons. Patients were categorized into α-thalassemia or β-thalassemia. Female prevalence consistently surpassed male prevalence [Lee et al., 2006-2018] (female-to-male ratio: 1.70–2.00).
Incidence rates decreased from 0.24 in 2006 to 0.15 per 100,000 persons in 2011 but rose to 0.41 by 2018, doubling in the last two years of the study [Lee et al., 2006-2018]. Incidence rates were higher in women and peaked in age groups 0–9, 30–39, and over 70 years. Blood transfusions were received by 27.7% of patients, with the annual rate decreasing from 34.7% in 2006 to 20.6% in 2018. Transfusion patients had higher incidences of comorbidities, significantly associated with transfusion events [Kadhim et al., 2017; Cunningham et al., 2004] (e.g., diabetes).
A total of 23 studies reported population-based estimates of β-thalassemia. The data came from several regions around the world (Figure 1):
North America: This included studies from the United States (US) and combined data from the US and Canada [Xie et al., 2018].
Europe: Countries included were Denmark, England, France, Germany, Greece, Italy, the Netherlands, Spain, and the United Kingdom (UK) [Hansen et al., 2020; Kleinman et al., 2018; Voskaridou et al., 2019].
Asia: Studies were conducted in Malaysia and Taiwan [Mohd Ibrahim et al., 2020; Tang et al., 2021].
Middle East: Countries included Oman, Iran, and Iraq [Rajab et al., 2000; Hadipour et al., 2019].
Algeria, was represented [Grifi et al., 2018].
Africa: Only one country, Algeria, was represented [Grifi et al., 2018]
For a few countries, multiple studies were found that reported β-thalassemia prevalence, showing moderate variations in estimates (as shown in Figure 2):
United States (US): The prevalence ranged from 0.2 per 100,000 people for the period 2004–2008 (using a stringent case definition) [Hulihanet al., 2015] to 0.8 per 100,000 people in 2016 (based on International Classification of Diseases, Ninth Revision [ICD-9] codes) [Paramore et al., 2017].
England: Estimates varied from 1.1 per 100,000 people for the period 2009–2018 (based on International Classification of Diseases, Tenth Revision [ICD-10] codes) [Jobanputra et al., 2020] to 2.3 per 100,000 people for the period 2019–2020 (based on the National Haemoglobinopathy Registry (NHR) Annual Data Report 2019/20).
France: The prevalence was reported as 0.6 per 100,000 people for the period 2005–2008 and 0.8 per 100,000 people in 2019 (based on the French National Registry (FNR) of thalassemia patients) [Thuret et al., 2010; Agouti et al., 2019].
Iran: Estimates ranged from 23.2 per 100,000 people in 2015 [Kadhim et al., 2017] to 32.6 per 100,000 people for the period 1955–2018 in the Fars Province [Haghpanah et al., 2021].

3. Inheritance Pattern

Thalassemia major and thalassemia intermedia are inherited in an autosomal recessive pattern [Angastiniotis et al., 2019]. This means that for an individual to be affected by these forms of thalassemia, they must inherit two altered copies of the HBB gene, one from each parent. So, when both copies of the HBB gene in each cell have variants, the production of haemoglobin is affected, leading to the severe symptoms observed in thalassemia major and intermedia [Gulani, & Weiler, 2023] (as shown in Figure 3).
The HBB gene provides instructions for making a part of haemoglobin [Morton et al., 1984], which is the protein in red blood cells that carries oxygen throughout the body [Gell, 2018].
Parents of a child with an autosomal recessive condition such as thalassemia major or intermedia typically carry one altered copy of the HBB gene and one normal copy (Figure 3). These carriers, also known as heterozygotes, do not usually show any signs and symptoms of thalassemia [Langer, 2024]. This is because the presence of one normal HBB gene is sufficient to produce enough haemoglobin for normal function.

4. Etiology

As mentioned above, β-thalassemia is an inherited blood disorder caused by various mutations-over 200 disease-causing mutations have been identified or, in rare cases, deletions of the beta-globin gene (HBB) located on chromosome 11 [Cao et al., 2010]. Most of these mutations are point mutations [Treisman et al., 1983] that disrupt the normal processes of transcriptional control, translation, and splicing of the HBB gene and its product (Figure 4).
The severity of the disease is influenced by the bi-allelic inheritance of two copies of the beta-globin gene, one on each chromosome 11, and by the diversity of the disease-causing mutations. The genotypic variability in beta-globin synthesis is categorized into two types: β+ for decreased production of beta-globin and β0 for complete absence of beta-globin production [Needs et al., 2023].
The phenotypic expression of β-thalassemia varies and is classified into three types based on the severity: minor, intermedia, and major [Langer, 2024]. Β-thalassemia minor occurs when an individual is heterozygous [Galanello & Origa, 2010], having one unaffected beta-globin gene and one affected gene, either β+ or β0. β-thalassemia intermedia and major occur in individuals who are either homozygous (having two affected β-globin genes) or compound heterozygous (having one β+ and one β0 gene) [Needs et al., 2023;].

5. Pathophysiology

Variation in the HBB gene cause beta thalassemia by affecting the production of beta-globin (as shown in Figure 5), a component of haemoglobin [Saad et al., 2023]. HbF is the primary haemoglobin until six months of age and consists of two alpha chains and two gamma chains [Kaufman et al., 2023]. Adult haemoglobin primarily consists of haemoglobin A (HbA), with two alpha chains and two beta chains, and a smaller amount of haemoglobin A2 (HbA2), with two alpha chains and two delta chains [Marengo-Rowe, 2006] (Figure 6).
β-thalassemia has two main pathological mechanisms: decreased haemoglobin synthesis leading to anaemia and increased HbF and HbA2 levels due to reduced beta chains for HbA formation, and excess α- chains forming insoluble inclusions [Needs et al., 2023] that cause significant intramedullary haemolysis (Figure 5).
This ineffective erythropoiesis results in severe anaemia, erythroid hyperplasia, bone marrow expansion, and extramedullary haematopoiesis, leading to bony deformities like frontal bossing and maxillary protrusion [Nienhuis et al.,2012].
Bone marrow expansion signals through the bone morphogenetic protein (BMP) pathway, inhibiting hepcidin production and causing iron hyperabsorption. Inadequately treated or transfusion-dependent patients risk iron overload, which can damage organs [Xiao et al., 2020; Nemeth et al., 2023]. Hepatosplenomegaly from extramedullary haematopoiesis and ongoing haemolysis can cause thrombocytopenia and hepatic dysfunction [Murakami et al., 2013].

6. Review of the Literature

Individuals with elevated HbF levels experience milder symptoms and have a normal life expectancy. Consequently, increasing HbF levels has proven to be a successful treatment strategy for β-thalassemia patients [Bianchi et al., 2009]. However, iron overload remains the primary cause of death in those with β-thalassemia [The Lancet, 2018; Taher et al., 2017]. In patients with β-thalassemia, the presence of faulty β-globin molecules can be counteracted by the production of γ-globin, a molecule similar to β-globin. γ-globin can pair with α-globin chains to create HbF [Ng et al., 2014]. By boosting γ-globin production, the imbalance between α and β chains is reduced, leading to less haemolysis, more effective red blood cell production, and an overall increase in total haemoglobin levels.
So according to Gambari et al., 2007 there are several HbF inducing agents such as Hydroxyurea (HU), 5-Azacytidine (5-Aza), Decitabine, Citarabine [Bianchi et al., 2009], Rapamycin, Thalidomide, Revlimid, Pomalidomide have been discovered that results in boosting γ-globin production [El-Beshlawy et al., 2009; Perrine et al., 2005; Fibach et al., 2006; Aerbajinai et al., 2007; Mabaera et al., 2008], that reduce the imbalance between α and β chains, leading to less haemolysis.

6.1. HbF Inducers act via P38 MAPK Signalling Pathway

From the above information, thalidomide, pomalidomide, hydroxyurea (HU), decitabine, show high potential in inducing HbF expression [Rahim et al., 2013]. Thalidomide, an immunomodulator, significantly increases HbF levels and erythroid precursor proliferation by activating the P38MAPK signalling pathway and Reactive Oxygen Species (ROS) [Aerbajinai et al., 2007]. Sodium butyrate, a histone deacetylase (HDAC) inhibitor, also activates the P38MAPK pathway and guanylate cyclase, leading to γ-globin gene induction and epigenetic changes [Dehghanifard et al., 2012; Fathallah et al., 2008; Kodeboyina et al., 2010]. It enhances acetylation of H4 histone and triggers pathways involving C-myc, C-myb, and boosting erythroid precursor proliferation [Boosalis et al., 2001]. Other HDAC inhibitors like trichostatin and apicidin similarly induce γ-globin gene expression through the P38MAPK pathway [Sangerman et al., 2006].
Decitabine and 5-azacitidine, acts as DNA methylation inhibitors, demethylate the γ-globin promoter, activating this gene in adult erythroid cells [Kiefer et al., 2008]. HU, a cytotoxic drug, increases HbF levels and promotes the production of foetal-like cells in β-thalassemia patients by inducing erythroid differentiation and activating the cGMP/soluble guanylate cyclase (sGC)/PKG pathway [Fathallah & Atweh, 2006; Ikuta et al., 2001]. HU and butyrate also stimulate HbF production via the cAMP pathway and small GTP-binding proteins [Keefer et al., 2006; Tang et al., 2005].

6.2. Phytocompounds as HbF Inducer

In recent years, scientists have undertaken extensive research to discover phytocompounds treatments that might be effective for β-haemoglobinopathies, such as β-thalassemia (listed in Table 1). An extract from the Aegle marmelos plant, which contains a compound called bergaptene, has been shown to trigger the differentiation of erythroid cells and stimulate the production of HbF in human leukemic K562 cells [Li et al., 2011; Guerrini et al., 2009; Lampronti et al., 2003].
Angelicin, a compound present in the fruit of Angelica archangelica, has been shown to be highly effective in promoting the differentiation of erythroid cells. Research indicates that angelicin significantly boosts the synthesis of HbF in erythroid progenitor cells and increases the accumulation of γ-globin mRNA in human leukemia K562 cells [El-Beshlawy et al., 2009; Lampronti et al., 2003].
Citropten found in bergamot juice, hold significant roles in the realm of human health. They possess the remarkable ability to stimulate the process of erythroid differentiation, the expression of the γ-globin gene, and the synthesis of HbF in human erythroid cells [Guerrini et al., 2009]. These actions are particularly noteworthy as they offer potential therapeutic avenues for addressing β-thalassemia.
Cucurbitacin D (CuD), a compound found in the Chinese medicinal herb Fructus trichosanthis, has been shown to be more effective than hydroxyurea in inducing HbF production. Research indicates that CuD not only increases the percentage of foetal cells but also enhances the HbF content in K562 cells, a type of human leukemia cell line, while exhibiting significantly lower cytotoxicity [Liu et al.,2010; Li et al., 2011].
This review highlights another natural compounds that derived from plants and show promise in the treatment of β-thalassemia. Specifically, these plant-based compounds have demonstrated the key therapeutic effects: it helps increase the levels of HbF through demethylate the γ-globin promoter and also activates the P38 MAPK pathway, leading to γ-globin gene induction and other epigenetic changes.
Nuamsee et al., 2021 on their “Trienone analogs of curcuminoids induce fetal hemoglobin synthesis via demethylation at Gγ-globin gene promoter” literature reported that natural “curcuminoids”—curcumin, demethoxycurcumin (DMC), and bis-demethoxycurcumin (BDMC)- induce HbF production in erythroid progenitors. This study explores whether trienone analogs of these curcuminoids can induce HbF in K562 erythroleukemic cell lines and primary human erythroid progenitor cells from β-thalassemia/HbE patients.
According to Zhu et al., 2020 it has been reported that “Sulforaphane”, found in cruciferous vegetables like broccoli, can activate the p38 MAPK pathway and has been shown to impact gene expression via epigenetic mechanisms.

7. Future Perspective

Given the lack of effective HbF-inducing agents for β-thalassemia treatment, researchers are exploring natural herbal medicines as potential alternatives. YiSui ShenXu Granule (YSSXG), a blend of 11 herbs, has been used for over 20 years to treat β-thalassemia [Zhang et al., 2008; et al., 2006]. A recent randomized single-blind trial confirmed its clinical efficacy, showing improvement in liver and spleen conditions without adverse reactions. The mechanism likely involves in demethylate the γ-globin gene to increase HbF production, compensating for the β-globin gene deficiency [Wu et al., 2007; Fang et al., 2007].
Additionally, Nuamsee et al., 2021 & Zhu et al., 2020 reported that curcuminoids (CUR) extract from Curcuma longa L and Sulforaphane from Brassica oleracea can induce HbF synthesis by activating p38 MAPK and gene expression via epigenetic changes. From the above information, CUR and Sulforaphane require further in vivo toxicity testing and clinical evaluation for therapeutic treatment of β- thalassemia in future.
Overall, natural herbal medicines show high potential for HbF induction with lower cytotoxicity compared to traditional chemotherapeutic agents, although further research is needed to ensure their safety and efficacy for clinical use.

8. Conclusion

β-thalassemia is a genetic blood disorder characterized by reduced production of haemoglobin. Current treatments for β-thalassemia have notable limitations. One promising approach is the induction of HbF using natural agents. Research indicates that various natural substances, such as angelicin, rapamycin, curcuminoid, citropten, and bergaptene, can increase HbF levels in β-thalassemia patients. Another critical goal in managing β-thalassemia is reducing iron overload.,
Due to their lack of side effects, natural agents warrant further investigation to understand their biological activity better. Identifying the most effective natural therapeutic agents to boost HbF production and decrease iron overload could significantly improve patient outcomes. Additionally, more research is needed to determine the bioavailability and impact of these natural compounds on humans. Traditional chemotherapeutic agents, including 5-azacytidine, hydroxyurea, rapamycin, thalidomide, revlimid, pomalidomide have been used to stimulate HbF synthesis in β-thalassemia patients. However, their use is limited by side effects such as cytotoxicity, growth inhibition, potential long-term carcinogenicity, and only moderate effectiveness in inducing HbF.
With advancements in biotechnology, more research is expected to optimize new treatments and natural remedies to reactivate HbF synthesis in β-thalassemia patients. Future studies should focus on discovering additional HbF-inducing agents from natural sources and traditional medicines worldwide. Extensive research is necessary to evaluate the efficacy and safety of these herbal medicines from laboratory studies to clinical application in individuals with beta-hemoglobinopathies.

Acknowledgments

I would like to express my sincere gratitude to all those who have contributed to the completion of my dissertation. Without the help of them it would be impossible to complete my work. First of all, I extend my heartfelt thanks to my dissertation guide Dr. Moutusi Mandi (Assistant Professor, Department of Zoology, The University of Burdwan) for invaluable guidance, expertise and continuous support throughout this work. Her mentorship greatly enriched the quality of my work. Last but not least, of course my deepest gratitude to my family for their continuous support and motivations to complete the paper.

Abbreviations

HbF- Foetal haemoglobin
O2- Oxygen
HBB- Haemoglobin beta
HSCT- Hematopoietic stem cell transplantation
HPFH- Hereditary persistence of foetal haemoglobin
HU- Hydroxyurea
EF- Epigenetic factors
US- United states
UK- United Kingdom
ICD- International Classification of Diseases
NHR- National Haemoglobinopathy Registry
FNR- French National Registry
HbA- Haemoglobin A
BMP- Bone morphogenetic protein
5-Aza - 5-Azacytidine
MAPK- Mitogen-activated protein kinase
ROS- Reactive Oxygen Species
HDAC- Histone deacetylase
cGMP- Cyclic guanosine monophosphate
PKG- Protein kinase G
cAMP- Cyclic adenosine 3,5-monophosphate
GTP- Guanosine triphosphate
CuD- Cucurbitacin D
sGC- Soluble guanylate cyclase
CUR- Curcuminoids
DMC- Demethoxycurcumin
BDMC- bis-demethoxycurcumin

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Figure 1. A) The bar plot showing the number of studies reporting population-based estimates of β-thalassemia by region. B) Pie chart presentation of the plot (Sporce- Lee et al., 2006-2018).
Figure 1. A) The bar plot showing the number of studies reporting population-based estimates of β-thalassemia by region. B) Pie chart presentation of the plot (Sporce- Lee et al., 2006-2018).
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Figure 2. This plot showing the prevalence of the condition in different countries over specified periods (Source- Hulihanet al., 2015; Kattamis et al., 2020).
Figure 2. This plot showing the prevalence of the condition in different countries over specified periods (Source- Hulihanet al., 2015; Kattamis et al., 2020).
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Figure 3. The autosomal recessive pattern of inheritance where both parents of an individual carry one altered copy of gene. (Source- https://app.biorender.com/ ; data from Angastiniotis et al., 2019).
Figure 3. The autosomal recessive pattern of inheritance where both parents of an individual carry one altered copy of gene. (Source- https://app.biorender.com/ ; data from Angastiniotis et al., 2019).
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Figure 4. Point mutations that disrupt the normal processes of transcriptional control, translation, and splicing of the HBB gene. (Source- https://app.biorender.com/ ; data from Thein, 2023).
Figure 4. Point mutations that disrupt the normal processes of transcriptional control, translation, and splicing of the HBB gene. (Source- https://app.biorender.com/ ; data from Thein, 2023).
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Figure 5. A) Comparison between haemoglobin formation in normal condition and in β-thalassemia with free α chain. B) Haemolysis of RBC. (Source- https://app.biorender.com/ ; data from Needs et al., 2023).
Figure 5. A) Comparison between haemoglobin formation in normal condition and in β-thalassemia with free α chain. B) Haemolysis of RBC. (Source- https://app.biorender.com/ ; data from Needs et al., 2023).
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Figure 6. A) Different types of haemoglobin. HbA, HbF, HbA2 with their globin chains. B) Schematic diagram of a-and b-globin gene clusters and the types of haemoglobin produced at each developmental stage. (Source- https://app.biorender.com/ ; data from Needs et al., 2023).
Figure 6. A) Different types of haemoglobin. HbA, HbF, HbA2 with their globin chains. B) Schematic diagram of a-and b-globin gene clusters and the types of haemoglobin produced at each developmental stage. (Source- https://app.biorender.com/ ; data from Needs et al., 2023).
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Figure 7. HbF Inducing drugs act via P38 MAPK Signalling Pathway that triggers the γ-globin gene expression. (Source- https://app.biorender.com/ ; data from Rahim et al., 2013).
Figure 7. HbF Inducing drugs act via P38 MAPK Signalling Pathway that triggers the γ-globin gene expression. (Source- https://app.biorender.com/ ; data from Rahim et al., 2013).
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Table 1. HbF inducing natural remedies or Phytocompounds.
Table 1. HbF inducing natural remedies or Phytocompounds.
Phytocompounds Plant Source Biological effect
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Bergaptene		 Aegle marmelos Erythroid differentiation of K562 cells, HbF induction [Li et al., 2011; Guerrini et al., 2009].
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Angelicin		 Angelica archangelica Erythroid differentiation,
HbF induction [El-Beshlawy et al., 2009; Lampronti et al., 2003].
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Citropten		 Bergamot orange Erythroid differentiation and HbF production [Guerrini et al., 2009].
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Cucurbitacin D		 Fructus trichosanthis Enhances the HbF content in K562 cells, a type of human leukemia cell line, while exhibiting significantly lower cytotoxicity [Liu et al.,2010; Li et al., 2011].
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