Natural Antioxidants in Anemia Treatment

Anemia, characterized by a decrease of the hemoglobin level in the blood and a reduction in carrying capacity of oxygen, is a major public health problem which affects people of all ages. The methods used to treat anemia are blood transfusion and oral administration of iron-based supplements, but these treatments are associated with a number of side effects, such as nausea, vomiting, constipation, and stomach pain, which limit its long-term use. In addition, oral iron supplements are poorly absorbed in the intestinal tract, due to overexpression of hepcidin, a peptide hormone that plays a central role in iron homeostasis. In this review, we conducted an analysis of the literature on biologically active compounds and plant extracts used in the treatment of various types of anemia. The purpose of this review is to provide up-to-date information on the use of these compounds and plant extracts, in order to explore their therapeutic potential. The advantage of using them is that they are available from natural resources and can be used as main, alternative, or adjuvant therapies in many diseases, such as various types of anemia.


Introduction
Anemia is defined as a reduction in the number of circulating RBCs [1] or as a condition in which the number of erythrocytes (and subsequently their ability to carry oxygen) is insufficient to meet physiological needs [2]. Anemia is characterized by a decrease of the hemoglobin (Hb) level in the blood (generally less than 13.5 g/dL in men and 12.5 g/dL in women), which results in a reduction in carrying capacity of oxygen. Diseases that decrease Hb production (e.g., iron deficiency, B12, or folate deficiencies) or accelerate its destruction are often the result of a defect in the structure of Hb [3]. Although anemia is frequently diagnosed by a low level of Hb or hematocrit (Htc), it can also be diagnosed by using the number of RBCs, the average mean erythrocyte volume, the number of reticulocytes in the blood, the examination of the blood smear or Hb electrophoresis [4].
Anemia is a major public health problem. It affects people of all ages, especially pregnant women and children. According to statistics, globally, anemia affects 41.8% of pregnant women and 47.4% of preschool children [5]. Moreover, it has negative effects on health and development, including neonatal and perinatal mortality, low birth weight [6], premature birth [7,8], and developmental delays of the children [9]. Clinically, it is characterized by pallor, fatigue, dizziness, difficulty breathing dyspneea, and weakness [10]. In the absence of effective management, anemia can promote decreased cognitive ability, weakened immune system, and increased mortality [11].
Anemia can be classified in terms of pathogenesis and erythrocyte morphology [12]. The pathogenic mechanisms involved in the onset of anemia are inadequate production and loss of erythrocytes as a result of bleeding or hemolysis. Depending on these pathogenic The most effective method used to treat anemia is blood transfusion [27]. Oral administration of iron-based supplements is an effective and, at the same time, inexpensive method used to treat patients with iron deficiency anemia. Moreover, this method of treatment is associated with a number of side effects, such as nausea, vomiting, constipation, and stomach pain, which limits its long-term use. In addition, oral iron supplements are poorly absorbed in the intestinal tract, due to overexpression of hepcidin, a peptide hormone that plays a central role in iron homeostasis [28]. If iron supplements are not effectively assimilated by the body, or if their absorption is inhibited, parenteral administration is recommended. Long-term parenteral administration of iron supplements can lead to hyperpigmentation of the skin. Moreover, one of the side effects of taking iron-based supplements is increased free radical production [27]. The use of inappropriate doses of iron-based supplements can induce oxidative stress [29,30], with the formation of oxidation products, and can lead to cardiovascular, neurological, or cancer conditions [31][32][33]. The presence of an excess of free iron initiates the Fenton reaction, which leads to oxidative damage to cell membranes, proteins, lipids, and nucleic acids, as well as the stimulation of inflammatory mediators [34,35].
Therefore, in the case of patients with anemia, the aim is to reduce the dose of iron and replace it with other complementary treatments.
The therapeutic use of herbal products in common clinical practice is not yet regulated for several reasons, such as the lack of efficacy and toxicity data that are required for their approval by health authorities. To these are added the competition of large pharmaceutical companies that make remarkable profits from the sale of synthetic drugs [36]. Currently, there is an increase in the number of clinical trials with herbal therapeutic products used in various diseases, in order to confirm their therapeutic value and receive the necessary approvals for their marketing [37]. Some phytochemicals or herbs act directly to induce the resolution of anemia, and others act pleiotropically through their antioxidant activity, by increasing oxidative stress resistance or by triggering cellular mechanisms, such as autophagy [38], or, for example, by targeting inflammation in the elderly population and subsequently reducing the anemia associated with chronic inflammation [39].
In this review, we conducted an analysis of the literature on biologically active compounds and plant extracts used in the treatment of various types of anemia. The purpose of this review is to provide up-to-date information on the use of these compounds and plant extracts, in order to explore their therapeutic potential. The advantage of using them is that they are available from natural resources and can be used as main, alternative, or adjuvant therapies in many diseases, such as various types of anemia.

Natural Antioxidants in Iron Deficiency Treatment
Iron is essential for the production of Hb. Depletion of iron deposits can be caused by blood loss, decreased iron intake, impaired absorption, or increased demand. Iron deficiency anemia can be caused by occult gastrointestinal bleeding [40] or decreased iron in the diet, or reduced iron absorption [26], accounting for more than half of all types of anemia [11] and require iron supplementation.
Due to the fact that oral iron supplements are associated with side effects, such as gastrointestinal irritations, reduced bioavailability, and lipid peroxidation [41], it is necessary to develop new iron-based supplements without or with minimal side effects. Polysaccharide chelated iron is characterized by high stability, water solubility, and fewer side effects [42]. Other polysaccharide-iron complexes have been used in the treatment of IDA, such as iron-dextran, iron-starch, and Niferex (a combination of ascorbic acid and iron-polysaccharide complex) [43,44].
Ulva prolifera is one of the most widespread species of green macroalgae [45]. The sulfate polysaccharides from Ulva prolifera (SUE) are a group of sulfated heteropolysaccharides with unique structural features in the form of rhamnose and uronic acid linkages of (1 → 4) -linked β-L-arabinopyranose residues [46]. In the case of rat-induced IDA, the SUE-iron (III) complex induced an increase in the number of RBCs and serum iron levels and contributed to the restoration of normal Hb levels [47].
Angelica sinensis has been shown to improve hematopoiesis by increasing the secretion of hematopoietic growth factors, such as erythropoietin, by stimulating hematopoietic cells and muscle tissue [48]. Polysaccharides from A. sinensis (ASP) improved serum iron levels and participated in the regulation of iron homeostasis [49]. Moreover, Liu et al. (2012) obtained ASP from the root powder of A. sinensis riched in arabinose, glucose, and galactose, with a molar ratio of 1: 5.68: 3.91 [50]. ASP has been shown to decrease hepcidin expression by inhibiting SMAD 4 expression in the liver and stimulating erythropoietin secretion, while other results showed that the decreased hepatic hepcidin expression is due to inhibition of the expression of JAK1/2, phospho-JAK1/2, phospho-SMAD1/5/8, phospho-ERK1/2, and stimulating SMAD7 [51]. Previously, ASPs have been shown to activate erythropoiesis [52,53].
Beetroot (Beta vulgaris) contains iron, nitrates, sodium, potassium, and betalaine [54]. Among the benefits of beetroot juice are the treatment of anemia by improving the ability of erythrocytes to carry oxygen, lowering blood pressure by dilating blood vessels and relaxing smooth muscles, preventing birth defects by increasing folate levels, etc. [55]. Compared to other vegetables with a high iron content, beets have a low price and are easy to store [56]. Consumption of 8 g of beets for 20 days induced an increase in Hb, ferritin, and serum iron levels, as well as a decrease in transferrin and total iron-binding capacity levels in seven women aged 22-24 years [57]. Consumption of beetroot in the form of juice (100-200 mL) increased the level of Hb [58,59]. Moreover, administration of 200 mL of beet juice for six weeks induced the increase of HTC, RBC, iron, and ferritin levels [58]. The administration of beetroot in the form of powder and iron-based supplements for 14 days in women with anemia led to increased levels of Hb, HTC, and erythrocyte counts [60].
Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload, as the body cannot eliminate excess iron. If not treated properly, the cumulative effects of iron overload led to morbidity and mortality [73]. One unit of transfused RBCs contains about 250 mg of iron [74], while the body cannot excrete more than 1 mg of iron per day. A patient who receives 25 units per year accumulates 5 g of iron per year in the absence of chelation [75].
Chelation therapy is used in binding the iron excess and removing it from the body. Synthetic iron chelators are toxic in high doses. Due to the high costs, toxicity and side effects of treatment with synthetic iron chelators, a large number of patients are currently not receiving any iron chelation treatment. There are a number of orally active antioxidants that have the ability to chelate iron and eliminate free radicals. They also have a lower cost and toxicity compared to synthetic drugs. These natural chelators form complexes with metals and could be used in the treatment of iron overload without inducing another micromineral deficiency, being an advantage that synthetic drugs do not have [76].
The natural iron chelators contain a catechol or gallate fragment that acts as a binding site for metals and further is eliminated from the body. In addition to the ability to chelate iron and eliminate free radicals, these antioxidants can be effective in iron overload by reducing the iron load in the liver, increasing iron excretion in feces and urine, reducing serum ferritin, removing iron from ferritin and transferrin, increasing hepcidin expression, reducing iron absorption in the intestine, increasing iron absorption and incorporation into the heme, and inducting osteo-and cardio-protective effects [76].
Flavonoids and polyphenolic compounds with at least two iron binding sites have iron chelating properties. These flavonoids fall into two categories: lipophilic and hydrophilic chelators. Lipophilic chelators increase iron absorption, reduce iron excretion, and increase the deposition of excess iron in tissues. Therefore, they are a possible treatment for irondeficiency anemia. Hydrophilic chelators, on the other hand, favor the elimination of excess iron, reduce iron absorption, and exert antioxidant and anti-inflammatory activity, without having other side effects [36]. Combining synthetic iron chelators with these antioxidants, or even replacing them with chelators from natural sources, would be a possible treatment for iron overload [76]. By chelating iron, flavonoids decrease high oxygen toxicity, for example, by inhibiting HO • production from the Fenton reaction [77]. The mechanism by which certain flavonoids reduce the bioavailability of non-hemic iron is not fully understood, but it is assumed that flavonoids have the ability to chelate non-hemic iron [78][79][80][81][82].
Curcumin, the main curcuminoid in Curcuma longa L. (turmeric), is a low-molecularweight polyphenol, widely used in Ayurveda and Chinese medicine [87]. Turmeric type 97 (77% curcumin, 17% dexethoxycurcumin, and 3% bisdemethoxy curcumin) induced an increase in the level of transferrin receptor 1 (TfR1) and the induction of activated iron-regulatory proteins (IRPs), a decrease of the hepatic ferritin level and its H and L subunits [88]. Other results show that 1000 mg iron/kg body weight and curcumin increased TfR1 and iron-responsive element-binding protein (IRP), favored the appearance of hypochromic RBCs, and decreased the levels of Hb, HTC, serum iron, ferritin, hepcidin, and transferrin saturation, as well as iron levels in the spleen and bone marrow [89].
Quercetin is a flavonol found in onions, broccoli, garlic, tomatoes, black tea, spinach, and apples [90][91][92], recognized for their antioxidant and anti-inflammatory activity [93]. Quercetin increased the expression of hepcidin, one of the main hormones involved in intestinal absorption of iron, which could involve the Nrf2 pathway [94]. Granado-Serrano et al. (2012) demonstrated that quercetin can activate the Nrf2 pathway by supporting nuclear translocation and its transcriptional activity [95]. Given that the levels of ferroportin (FPN) and ferritin are overexpressed transcriptionally by the Nrf2 pathway, quercetin could affect iron homeostasis and help cells to fight against oxidative stress [96]. Prenatal exposure of mice to quercetin resulted in increased hepatic iron deposits and induced overexpression of hepcidin to adults [77].
Quercetin chelates metal ions in a stable complex, thus preventing the Fenton reaction [97], and protects human erythrocytes from iron-induced oxidative damage [98,99]. Quercetin can also act as a siderophore through glucose transporters [100]. Similar to other flavonoids, it is thought to form a complex with Fe 3+ that has greater stability than Fe 2+ . Even if quercetin initially forms a complex with Fe 2+ , it will be further self-oxidized, resulting in Fe 3+ [101]. Iron chelation by the 3-hydroxyl group of quercetin is an important factor in iron absorption in the duodenum [79]. The decrease in duodenal iron transfer is due to the chelation of iron by quercetin, which increases the apical absorption of iron, but prevents basolateral transport. However, the precise site of iron chelation by quercetin is unknown. It is not known whether chelation occurs in the duodenal lumen or in the cytosol of duodenal enterocytes [96].
Myricetin (3,5,7,3 ,4 ,5 -hexahydroxyflavonol) is a flavonoid initially isolated from the bark of the Myrica rubra that has been shown to have iron-chelating properties [80,102]. Administration of myricetin to C57BL/6 mice favored an increase in RBCs, Hb levels, and serum iron and decrease in the hepatic expression of hepcidin and splenic iron levels [103].
Silibin is a biologically active compound from silymarin [104], a flavonolignan raported to have iron chelating effect [105], while other studies reported a high affinity for Fe (III) iron-silibin complex in acidic pH [104,106]. Bares et al. (2008) observed that oral administration of silibin for 12 weeks reduced iron deposits in patients with chronic hepatitis C [107].
The main pharmacological effects of the natural antioxidants in iron chelation activities are summarised in Table 2.

Natural Antioxidants in the Treatment of Hemolytic Anemia
Hemolytic anemia is a normocytic anemia characterized by low Hb levels due to the destruction of RBCs and increased hemoglobin catabolism. Depending on where the hemolysis occurs, it can be intravascular or extravascular [126]. Destruction can also occur in the case of inherited protein deficiencies (membranopathies, i.e., hereditary spherocytosis), fragmentation (i.e., microangiopathic hemolytic anemia, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation), antibodies that bind to RBC resulting in phagocytosis (immune-mediated), drug-induced hemolysis, infections, or direct trauma [127].

Natural Antioxidants in the Treatment of Thalassemia
Thalassemias are a group of inherited diseases that lead to a defective hemoglobin production. Patients with thalassemia have a mutation that affects the production of the hemoglobin globin polypeptide chain and is associated with inefficient erythropoiesis. It is characterized by decreased HbA production secondary to low beta-globin chain production and stopping maturation due to apoptosis of erythroid precursors induced by excess alpha chain precipitates [150].
Iron overload is a common complication of thalassemia syndromes, which can lead to organ damage and increased mortality [151,152]. Iron-induced toxicity in β-thalassemia is the leading cause of oxidative stress. Oxidative stress, associated with the formation of reactive oxygen species (ROS), plays an important role in the development of inflammation, decreased plasma antioxidant levels, depletion of erythrocyte glutathione (GSH), increased lipid peroxidation of RBCs membranes and immunosuppression in the affected patients [153,154]. Moreover, iron overload in patients with β-thalassemia decreases T cell proliferative activity [155,156].
Flavonoids and phenolic compounds have antioxidant properties, ability to neutralize free radicals [157][158][159][160] and metal chelation, suggesting that they may have a protective effect under oxidative stress-based pathological conditions caused by iron overload [161]. Therefore, the use of polyphenols as iron chelators has been proposed in clinical practice [162].
Silymarin, isolated from Silybum marianum, is a powerful antioxidant and has hepatoprotective and iron chelating activities [163], being introduced as an adjuvant without side effects in numerous clinical trials [164]. Gharagozloo et al. (2013) recommended the use of silymarin as a possible herbal immunomodulatory drug in the treatment of patients with β-thalassemia due to its antioxidant, cytoprotective and iron chelating activity. The study included 59 β-thalassemia patients who received 140 mg of silymarin and desferioxamine (DFO) three times daily for 3 months. Combination therapy has been well tolerated and more effective in reducing serum ferritin levels than administering DFO alone, in increasing GSH level of RBCs and promoting a decrease in serum iron and ferritin [165]. In another clinical study, patients were treated with a combination of DFO and silymarin (420 mg/day) or DFO for 9 months. Silymarin treatment significantly reduced serum iron, ferritin, serum hepcidin, and soluble transferrin receptor (sTfR), demonstrating the beneficial potential of silymarin as an iron chelating agent in reducing the serum ferritin and iron level in β-thalassemia [166]. Similar results were obtained by Hagag et al. (2015) in a clinical study for silymarin in combination with deferiprone (DFP) [167], as well by the combination of deferasirox (DFX) and silymarin [168]. Serum iron levels decreased significantly [168]. Therefore, the effects of iron chelating silymarin are related to its Fe (III) binding capacity.
Beta-thalassemia major is a hereditary haemolytic anemia in the treatment of which multiple blood transfusions are used [177]. Patients with major thalassemia, also known as Cooley's anemia, have severe and hypochromic microcytic anemia, associated with an increased number of RBCs and a low level of mean corpuscular volume (MCV) and mean corpuscular Hb (MCH). Peripheral blood smear highlights microcytosis and hypochromia, anisocytosis, poikilocytosis, and nucleated RBCs (e.g., erythroblasts). The number of erythroblasts correlates with the degree of anemia and is significantly increased after splenectomy [178].
Finding natural iron chelators of plant origin that also act as a hepcidin agonist may be useful in the management of excess iron in patients with β-thalassemia major [179].

Natural Antioxidants in the Treatment of Sickle Cell Anemia
Sickle cell anemia is inherited as an autosomal recessive condition [185]. Sickle cell disease is one of the most notable impairments in the structure of hemoglobin. While the amount of hemoglobin produced may be normal, the substitution of the amino acid valine with glutamic acid results in a structural defect that favors the polymerization of deoxygenated hemoglobin [186]. It is characterized by the presence of sickle-shaped cells that block blood flow through the spleen, causing splenic sequestration [185]. When deoxyhemoglobin polymerizes, it forms fibers that alter the shape of erythrocytes [186]. Repeated stress caused by sickle cell disease will damage circulating erythrocyte membranes, leading to premature cell death. While sickle cell anemia may remain asymptomatic for a significant period of time, severe hypoxia may cause a seizure, with symptoms of generalized pain, fatigue, headache, jaundice, and repeated vascular occlusion (stroke, etc.) [3].
Given the increasing mortality rate of patients with sickle cell disease, especially in children, and the side effects of chemotherapy, the addition of natural products (phytomedicines/herbal drugs) in the treatment is beneficial [187]. Several herbal extracts have properties in sickle cell anemia treatment, but there is still no promising drug on the market for the treatment of this condition [188][189][190][191]. The active constituents of medicinal plants and natural compounds, known as antisickling agents, are rich in aromatic amino acids, phenolic compounds, and antioxidants [192] and acts as antioxidant therapy to ameliorate the complications of sickle cell anemia [193]. Antioxidants have many beneficial effects, protect against RBC lipid peroxidation, increased glutathione levels (GSH), and reduce ROS levels [194].
Rutin (quercetin-3-rhamnosyl glucoside) is a flavone intentive studied for its antioxidant properties [195][196][197]. Rutin has antiplatelet and protective effects of the vascular endothelium against oxidative stress in sickle cell anemia [198,199]. Moreover, it restored the integrity of the erythrocyte membrane, prevented and reversed lipid peroxidation, induced increased GSH and CAT levels, and decreased SOD activity. The beneficial effects of rutin in sickle cell anemia may be associated with modulation of deoxy-hemoglobin and alteration of redox homeostasis. Similar results were obtained fot chrysin [199].
The main pharmacological effects of the phytochemicals/herbs in sickle cell anemia treatment are summarized in Table 6.  [194] Rutin in silico in vitro sickle erythrocytes induced with 2% metabisulphite -restored the integrity of erythrocytes membrane -prevented and reversed lipid peroxidation ↑ GSH and CAT levels ↓ SOD activity [199] Chrysin in silico in vitro sickling was induced with 2% metabisulphite at 3 h.
-prevented sickling -re-established the integrity of erythrocytes membrane -prevented and reversed lipid peroxidation ↑ GSH, CAT ↓ SOD [200] Pfaffia paniculata extract 0.0, 0.2, or 0.5 mg/mL in vitro RBCs from patients with sickle cell disease -improvement of RBC deformability in patients with SCD -the fragility of RBCs of patients with sickle cell disease was not affected [201] Aqueous extracts of Dennettia tripetala and Physalis angulata leaf extract in vitro homozygous sickle cell erythrocyte ↑ GSH, SOD ↓ catalase ↓ ROS ↓ % of sickled cells ↓ haemoglobin polymerization rate ↓ osmotic fragility of human sickle RBCs [202] Ethanol extract of Terminalia catappa L. (Combretaceae) leaves in vitro metabisulphite-induced sickling -inhibited osmotically-induced hemolysis of human erythrocytes -prevented and reversed the sickling of human 'SS' erythrocythes [203] Extracts of the roots of Cissus populnea L. in vitro sodium metabisulphite induced sickling of the HbSS red blood cells -anti-sickling activity [204] Methanolic leaf extracts of Carica papaya L. (Caricaceae) in vitro Hbss red blood cells obtained from non-crisis state sickle cell patients ↓ hemolysis and protected erythrocyte membrane integrity under osmotic stress conditions -inhibited formation of sickle cells under severe hypoxia [205] Leaves and stem of Parquetina nigrescens L.
in vitro pre-sickled HbSS blood cell suspensions blood samples of noncrisis sickle cell individuals -antisickling activity -protected the integrity of the erythrocyte membrane by the reduction in hemolysis of the Hbss cells -inhibited formation of sickle cells under severe hypoxia [206] Aqueous extract of Carica papaya leaf 2, 4, 6, 8, and 10 mg/mL -prevented sickling -membrane stabilizing effect on HbSS red blood cells ↓ osmotic fragility of HbSS red blood cells [207] Divanilloylquinic acids isolated from Fagara zanthoxyloides Lam.
patients with severe sickle cell anemia antisickling properties [208]   Leaf and gel extracts of the Aloe vera (Aloe barbadensis) in vitro sickle erythrocytes -inhibited sickle cell polymerization -improved of the Fe 2+ /Fe 3+ ratio of HbSS [223] Aged garlic extract 5 mL daily clinical study for 4 weeks five patients with sickle-cell anemia ↓ number of Heinz bodies -antioxidant activity on sickle RBCs [224] of Moringa Oleifera Seeds and leaves extracts in vitro erythrocyte cells deoxygenated with 2% sodium metabisulphite -antisickling activity in deoxygenated erythrocytes [225] Amphimas pterocarpoides in vitro the sickling of RBCs was induced using sodium metabisulfite (2%) -anti-sickling effects ↑ the solubility of the deoxy-haemoglobin S -allowed the rehydration of SS cells by reinforcing their capacity to resist against osmotic fragility [226] Isoquercitrin in vitro sickle erythrocytes ↓ % sickle cells ↓poimerization ↑ the oxygen affinity ↑ osmotic fragility of the sickle RBCs [227] Hyphaene Thebaica (Doum) fruit extract 1000, 500, and 250 µg/mL in vitro incubation of RBCs with 2% sodium metabisulte ↑ in the percentage of unsickled RBCs [228] Genistein in vitro sickle erythrocytes ↓ polymerization of Hb S ↓ % sickle cells ↑ the osmotic fragility of the erythrocyte cell [229] Methanol seed extract of Buchholzia coriacea and Mucuna pruriens seed extract 50%, 25%, 12.5%, and 6.25% seed extracts in vitro sickle cell blood from sickle cell disease patients with subsequent addition of 2% sodium metabisulphite to cause more sickling.

Natural Antioxidants in the Treatment of Aplastic Anemia
Aplastic anemia is a condition in which the bone marrow is destroyed and blood cell production is diminished [231]. This usually correlates with a deficiency of erythrocytes (anemia), leukocytes (leukopenia), and platelets (thrombocytopenia) [232,233]. Aplastic anemia refers to the syndrome of chronic primary hematopoietic insufficiency due to lesions, leading to diminution or absence of hematopoietic precursors in the bone marrow [234,235].
Aplastic anemia can be caused either by extrinsic suppression mediated by hematopoietic stem cell immunity or by intrinsic bone marrow progenitor abnormality [236,237]. Damaged hematopoietic stem cells mature into self-reactive T-helper (T1) cells that release cytokines: interferon (IFN) and tumor necrosis factor (TNF) to develop a cytotoxic cascade to kill and suppress other hematopoietic stem cells. The exact antigens of T1 target cells are unclear, but one appears to be one of the glucose inositol phosphate-bound (GPI) proteins on cell membranes. Moreover, genes involved in apoptosis are overexpressed [238].
Strategies recently applied in the treatment of aplastic anemia include immunosuppression and/or hematopoietic stem cell transplantation [239,240]. Numerous lymphocytotoxic agents have been widely used, but some of them have various adverse effects, such as anaphylaxis fever, chest pain, and diarrhea [241].
In recent years, natural herbal products have attracted much attention, being used as an effective and safe alternative treatment for bone marrow failure [242].

Conflicts of Interest:
The authors declare no conflict of interest.