Piceatannol: A Potential Futuristic Natural Stilbene as Fetal Haemoglobin Inducer

Beta thalassaemia is an autosomal recessive inherited blood disorder which results in abnormal formation of Haemoglobin molecule and ineffective erythropoiesis. Patients need to be dependent on habitual blood transfusion and on unaffordable exorbitant therapies for continued existence. It has been hypothesized that if the level of foetal Haemoglobin increases, it compensates the need of adult Haemoglobin and hence, ameliorates clinical symptoms associated with beta thalassaemia major. Illation from previous studies has proved that reactivation of foetal Haemoglobin with the aid of natural compounds is a better alternative therapy for patients of beta thalassaemia because of its cost effectiveness and occurrence in natural eatables. Piceatannol, a naturally occurring stilbene, is less studied compound in comparison to resveratrol, but it shows a wide range of biological activities. This article has mainly focused on piceatannol and its application as a foetal Haemoglobin inducer in future.

Haemoglobinopathies, beta thalassaemia and sickle cell anaemia are genetic disorders that arise due to absence of globin gene or improper synthesis of Haemoglobin molecules in humans. These genetic diseases are a considerable cause of mortality around the world. Advancement in research methodologies is providing a novel approach for treatment of these disorders. Medical heterogeneity is observed among the patients of beta thalassaemia and sickle cell anaemia due to altered foetal Haemoglobin levels in erythrocytes [1]. Foetal blood comprises of foetal Haemoglobin, that is 70% of total Haemoglobin during birth. Foetal Haemoglobin (HbF) is a mixture of two molecular species i.e., α₂Gγ₂ and α₂Aγ₂. The globin ratio of these molecules is 70:30 in non-affected newborns, whereas in adults, it is 40:60 because of genetic switch [2].

The process of switching of HbA (adult Haemoglobin) to HbF represents important remedial implication in patients suffering from beta thalassaemia. Hydroxyurea is used to increase the level of HbF in patients with beta thalassaemia, but it is toxic in nature. The other drawback associated with hydroxyurea is that it augments the γ globin gene reactivation moderately. Therefore, it is necessary to find out agents having good properties and which could induce higher HbF levels in individuals [3].

Though gene therapy and stem cell transplantation therapies possess potential to treat or cure beta thalassaemia, neither of them is currently applicable to patients of beta thalassaemia, because of the high cost of treatment, varied patients’ response, technological issues and absence of sophisticated medical care, which are required to supply these therapies in areas where patients reside. In spite of the advancements in iron chelating therapy, the life expectancies of beta thalassaemia patients have not achieved great success rates. No drugs are known to be safe or effective for the treatment of beta-thalassaemia [4].

Many agents have been depicted, that boost up γ globin gene expression as well as HbF levels in human erythroid culture or in humans, but majority of agents are cytotoxic in nature, damage DNA and have other lethal effects. Hydroxyurea, which is the only approved metabolite used in HbF induction, has been found to be less effective. Natural products like resveratrol and rapamycin are devoid of cytotoxicity or growth inhibitory activity. Theses agents elevate HbF levels in human erythroid precursor cells [4,5].

This review has mainly dealt with the basics of foetal Haemoglobin (HbF) induction and the compounds used for HbF induction.

Haemoglobin is a tetramer containing two different polypeptide chains i.e., alpha and beta polypeptide chains [6]. The alpha globin chains are encoded by alpha globin genes which are found in duplication and are confined in the telomeric region on the short arm of chromosome 16. The length of the cluster of alpha globin genes is 26 kB and it includes embryonic zeta (ζ) gene, adult alpha1 and alpha2 genes [7,8]. Globin genes encoding beta globin chains are localized on chromosome 11 and they contain embryonic, foetal (Gγ, Aγ), adult δ and β genes [9,10]. Combination of different globin chains results in the formation of a functional Haemoglobin molecule.

The composition of Haemoglobin molecule varies during the gestation and developmental stages of an embryo. During the early stages of gestation, erythropoiesis takes place in the yolk sac. After the first trimester of gestation, first switch accompanied in beta globin cluster, results in transitioning of the process of erythropoiesis, which has to take place in foetal liver. As the time of birth approaches, the outcome of second switch is shifting of erythropoiesis to bone marrow. HbF (α₂γ₂) is the main Haemoglobin over the phase of gestation and it is progressively substituted by HbA (α₂β₂) at the stage of infancy [10].

Improper Haemoglobin switch results in higher expression of foetal Haemoglobin, with effective erythropoiesis. This condition is called Hereditary Persistence of Foetal Haemoglobin (HPFH). It has been observed that patients suffering from sickle cell disease and beta thalassaemia, having an improper Haemoglobin switch in their genes, lead normal and healthy lives. So, it can be concluded that induction of foetal Haemoglobin level in thalassaemia patients will help in ameliorate the severities of sickle cell anaemia and beta thalassaemia [11].

Literature review has stated that the potential use of medicinal plant extracts, mention curative purposes, have been published together with sanative strategies, for restoring healthy state in a number of diseases. Dyslipidaemia, atherosclerosis, hepatitis, bacterial and virus infections are the names of few of such common diseases [12].

In case of beta thalassaemia, few numbers of products from natural world have capability to induce foetal Haemoglobin and to alleviate the pain of disease. Data stating sources and biological effects of these natural compounds have been listed in [Table/Fig-1].

Piceatannol, known as 3, 3’, 4’, 5-transtrihydroxystilbene, is a powder which has an off white colour. It is not soluble in water but it is soluble in ethanol and dimethyl sulphoxide. Piceatannol contains two phenolic rings which are joined together by a styrene double bond. Cis and trans are the two isomeric forms of piceatannol. Trans isomeric form is sterically more stable in comparison to cis isomeric form [25]. The presence of piceatannol has been confirmed in different fruits and plants such as Vaccinium berries, Vitis amurensi, grapes, Arachis hypogaea, Polygonum cuspidatum [26–29]. The concentration of this compound was found to vary in different sources and it was characterized by different analytical techniques.

Piceatannol possess various health benefits. It possesses anti-adipogenic property, due to which it can modulate the development of adipose tissue [30]. It may be helpful in stimulating the osteoblastic activity, leading to the formation of bone [31]. It is also known to possess antimelanogenic activity [32]. It may also prevent Type 2 diabetes [33].

Piceatannol is a natural polyphenol and a structural analogue of resveratrol [34]. It contains one extra-hydroxyl group in its structure [35]. Synthesis of both the compounds takes place in plants against fungal or in environmentally stressed conditions. Therefore, these are classified as phytoalexins [34]. Chemical structures of both the compounds have been shown below [Table/Fig-2].

[Table/Fig-2]:

Chemical structures of piceatannol and resveratrol

Chemical structures of piceatannol and resveratrol [36,37]. Both, piceatannol and resveratrol share almost similar properties. Few of these similar properties have been mentioned below [Table/Fig-3].

Data mentioned in literature and research work have stated that piceatannol is a better Anti-oxidant than resveratrol. It has been proved that piceatannol has better activities than resveratrol. Piceatannol is required in very less amounts as compared to resveratrol, for testing of its biological activities [25].

Though evidence shows that resveratrol plays an important role in the prevention of chronic diseases, its meagre bioavailability and fast metabolism limits its use in the prevention of chronic diseases. Analogues of resveratrol, such as piceatannol, overcome the problem of meagre bioavailability and fast metabolism. Therefore, it is more beneficial than resveratrol for improving health and related benefits [42].

Most of the well described signal pathways in mammals are mitogen-activated protein kinase pathways. They include different subtypes: c-Jun N terminal protein kinase (JNK), p38 and Extra-cellular Signal Regulated Kinase (ERK). Mitogen activated protein kinases activate each other by phosphorylation in the cytoplasm of the cell and this results in the activation of kinases and various transcription factors. The p38 and JNK pathways are connected to the mechanism of apoptosis in cells and ERK pathway is associated with proliferation and differentiation in cells [38].

The level of activation of mitogen activated protein kinases was observed after the treatment of cells with different concentration of piceatannol. It was observed that the expression of p38 mitogen activated protein kinase was increased and that phospho-ERK expression was decreased in cells treated with piceatannol for 24 hours. Observations of both the pathways were made by comparing the treated cells with control cells (cells not treated with piceatannol) [43].

Piceatannol has shown strong Anti-oxidant activity and it has been observed that piceatannol treatment increased the concentration of intracellular Ca₂+ ions and reactive oxygen species, which are known to be the responsible factors of p38 mitogen activated protein kinase activation and ERK inactivation [43].

The mechanism of action of piceatannol has been hypothetically stated in [Table/Fig-4]. Natural stilbene piceatannol is applied on cultured cells, as shown in [Table/Fig-4]. A magnified view of the cell has been displayed beside that of a treated cell, which shows sequences of events that take place in treated cells.

[Table/Fig-4]:

Comparison of similar properties of resveratrol and piceatannol

[Table/Fig-4] A hypothetical illustration of action of piceatannol on mitogen activated protein kinase and that of extra-cellular signal regulated kinase on induction of foetal Haemoglobin. After piceatannol treatment, p38 Mitogen activated protein kinase activation and extra-cellular signal regulated kinase deactivation result in foetal Haemoglobin production and boosting of total Haemoglobin level in U937 cells.

Earlier studies have confirmed that the application of piceatannol on cells increased the expression of p38 Mitogen Activated Protein Kinase (MAPK) and that it inhibited Extra-cellular Signal Regulated Kinase (ERK) [43]. The expected outcome of these pathways may be the highest expression of gamma globin genes in cells. Because of this, there will be more production of foetal Haemoglobin and an eventual increase in total Haemoglobin levels in cells.

Till date, various reviews, literatures and research works have been published, which have stated the mechanism of action of different naturally occurring compounds and their involvement in reactivation of HbF in patients of beta thalassaemia. All the natural compounds, when they were tested on cells, showed the activation of p38 MAPK (mitogen activated protein kinase) pathway and deactivation of ERK (extra-cellular signal regulated kinase) pathway. It was observed that activation of p38 MAPK (mitogen activated protein kinase) pathway and deactivation of ERK (extra-cellular signal regulated kinase) pathway led to an increase in higher expression of gamma globin gene and an increase in the level of HbF in treated cells.

Increase in gamma globin gene expression and level of foetal Haemoglobin by activation of p38 MAPK pathway and deactivation of ERK pathway, has been observed in cells treated with different naturally occurring pharmacological and chemical compounds, such as cucurbitacin D, hydroxy urea, butyrate, an ethanol extract of Fructus trichosanthis, resveratrol [18,24,44,45].

On the basis of available literature, it may be concluded piceatannol treatment may increase the expression of gamma globin gene and result in increase in foetal Haemoglobin production in beta thalassaemia patients, because activation of p38 MAPK pathway and deactivation of ERK pathway have been confirmed in piceatannol treated cells [46].

Augmentation of level of foetal Haemoglobin in patients suffering from beta thalassaemia is an alternative and a promising approach for curing the disease. Various compounds from the natural world and medicinal plants have been identified, which possess the capacity to augment the foetal Haemoglobin levels. Piceatannol, a natural stilbene, possesses a broad range of biological activities which are comparable and similar to activities possessed by compound, resveratrol. Although it is an analogue of resveratrol, it is a less studied compound and its semiquinone radical has a greater stability.

It can be concluded that possession of wide varieties of pharmacological properties, such as Anti-oxidant activity, anti inflammatory activity and anti-tumour activity, strengthen the use of this compound as a pharmacological molecule. However, there is a need to generate further data on the bioavailability and toxicity of piceatannol in humans. Research work needs to be done and data on its capacity to increase foetal Haemoglobin levels and effective doses required to augment the levels of foetal Haemoglobin, needs to be generated.

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