Mangiferin is a xanthone and xanthones are some of the most potent antioxidants known; they are thought to be more potent than both vitamin C or vitamin E and are sometimes unofficially referred to as “super antioxidants.” Xanthones are heat-stable molecules. Mangiferin, generally called C-glucosyl xanthone, is widely distributed in higher plants (Sanchez and others 2000) where it provides protection to producer plants against different forms of static and dynamic stresses including ingress of pathogenic microorganisms (Muruganandan and others 2002). It is a pharmacologically active phytochemical and a natural polyphenolic antioxidant present in the bark, fruits, roots, and leaves of Mangifera indica Linn, and a few other medicinal plants recommended in the Indian system of medicine for treatment of a number of immunodeficiency diseases (Scartezzini and Speroni 2000).
Mangiferin (C 2- β–D –glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone) (Figure 1) was first isolated from Mangifera indica leaves, while from the bark homomangiferin (1,6,7-trihydroxy-3-methoxy-2-C- β -D-glucopyranosyl-xanthone) was isolated. A quantitative estimation on the dried leaf and bark material revealed that the mangiferin content was higher in the mango bark (Sissi and Saleh 1965) than in the leaf. Saleh and El-Ansari (1975) reported on the co-occurrence of the 3 xanthones (mangiferin, isomangiferin, and homomangiferin). They isolated 2 xanthones in the leaves along with a 3rd xanthone, isomangiferin (1-, 3-, 6-, 7-tetrahydroxy-4-C-β-D-glucopyranosyl-xanthone), which had been first identified in Anemarrhena asphodeloides. Mangiferin content of mango pulp was found to be about 4.4 mg/kg (Schieber and others 2000), seed kernel 42 mg/kg (Ahmed and others 2007), whereas in dried mango peel it was 1690 mg/kg (Table 1). In the mango stem bark, mangiferin was the most abundant phenolic compound, estimated at about 71.4 g/kg (Rastraelli and others 2002). From a global point of view, xanthones are only known to have restricted distribution (about 5 families). On the other hand, mangiferin has a wider distribution (recorded within 12 families), and within the anacardiacae, besides Mangifera indica only Mangifera zeylanica is recorded as containing mangiferin.
Bioactivity of mango mangiferin
Many researchers have established mangiferin as the possible active principle of mango (Mangifera indica L.) stem bark and leaf extract and attributed most of the biological activities of the extracts to it (Sanchez and others 2000). From the various studies done on mangiferin and the extracts from mango leaves, bark, and flowers, it has been found to exhibit a wide range of pharmacological effects: antioxidant, anticancer, antimicrobial, antiatherosclerotic, antiallergenic, anti-inflammatory, analgesic, and immunomodulatory among many others. Mangiferin has been investigated in vitro for its antioxidant (Rouillard and others 1998), immuno-stimulating, and antiviral properties (Zheng and Lu 1990), and it was found to protect hepatocytes, lymphocytes, neutrophils, and macrophages from oxidative stress; reduce atherogenicity in streptozotocin diabetic rats; and to reduce the streptozotocin-induced oxidative damage to cardiac and renal tissues in rats (Muruganandan and others 2002).
The iron-complexing ability of mangiferin was reported as a primary mechanism for protection of liver mitochondria against Fe2+ citrate-induced lipid peroxidation (Halliwell and Gutteridge 1986). They also showed that in vitro antioxidant activity of mangiferin is related to its iron-chelating properties and not merely due to the scavenging activity of free radicals. Iron chelators such as mangiferin could be an important approach to reduce iron-induced oxidative damage in pathologies related to abnormal intracellular iron distribution and/or iron overload, such as hereditary hemochromatosis, h-thalassemia, Friedreich's ataxia, and sideroblastic anemia (Britton and others 2002). The metabolism of mangiferin yields noranthyriol after cleavage of the C–C linkage of the glucose moiety, which exhibits a potent iron chelating effect, and an inhibitory effect of the induced respiratory burst in rat neutrophyls (Andreu and others 2005b). Those effects were thought to have originated from the high scavenger capacity of mangiferin by singlet oxygen.
Mangiferin (MF) was found to protect mitochondrial membrane against lipid peroxidation hence preserving its integrity. From their study, Halliwell and Gutteridge (1986) suggested that mangiferin removes iron from the Fe2+ citrate complex and forms an unstable complex with it, favoring Fe2+ oxidation to Fe3+ with subsequent formation of a more stable complex with Fe3+, which is not able to initiate and/or propagate mitochondrial lipid peroxidation. This Fe3+ mangiferin complex impairs ferric iron reduction to ferrous iron by endogenous reducers like ascorbate, sparing them and also preventing Fe2+ reloading of the biological system, which can readily participate in reactions involved in OH formation.
It has been suggested that oxidation derivatives of mangiferin may sensitize mitochondria to calcium-induced permeability transition (Andreu and others 2005c), a process often related to apoptotic/necrotic cell death. In this regard, it was proposed that the accumulation of such oxidation products would take place in such cells exposed to an overproduction of reactive oxygen species, such as cancer cells, where the occurrence of apoptosis induced by mitochondria permeability transition may be a cellular defense mechanism against excessive reactive oxygen species formation (Nunez-Selles 2005).
Mangiferin has been found to inhibit colon tumorigenesis in rats. Bhattacharya and others (1972) reported that the mechanism of this compound in the central nervous system is related to its ability to inhibit monoamine oxidase activity. Malignant cell proliferation in the colonic mucosa of male F344 rats was reduced by 75% after addition of MF to the diet (0.1%) in a long-term study which suggested that MF may act as a naturally occurring chemopreventive agent in colon cancer (Yoshimia and others 2001). Chemoprevention effect of MF has also been tested on other tumors like the ascitic fibrisarcoma (AFS) in Swiss mice where significant inhibition levels were recorded coupled with increased survival rates (Guha and Chattopadhyav 1996). Alongside the tumor studies on rats treated with mangiferin, Yoshimia and others (2001) found that mangiferin also inhibited body weight gain in experimental rats. This points at the possible utilization of mangiferin in food products for special dietary needs like with obese people.
1-Methyl-4-phenyl-pyridine ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1-, 2-, 3-, 6-tetrahydropyridine (MPTP) has been found to induce a Parkinsonian syndrome in humans and animals, a neurotoxic effect postulated to derive from oxidative stress (Amazzal and others 2007). Mangiferin has been found to protect neuroblastoma cells line N2A against MPP+ induced cytotoxicity, to restore the glutathione (GSH) content, and to downregulate both superoxide dismutase 1 (SOD1) and catalase (cat mRNA) expression all being mediated by oxidative stress (Amazzal and others 2007). In Parkinson's disease, the nigral level of iron is increased and may contribute to the hyper-production of reactive oxygen species, leading to oxidation and nitration of proteins, lipids, and DNA, as was observed in postmortem brains (Halliwell 2006). Therefore, mangiferin could be a useful compound in therapies for degenerative diseases, including Parkinson's disease, in which oxidative stress plays a crucial role.
Mangiferin, being able to traverse the blood–brain barrier as demonstrated by Martınez and others (2001) in gerbils, has been found to have real potential to ameliorate the oxidative stress observed in neurodegenerative disorders. Mangiferin has been shown to reduce the intracellular Ca2+ concentration, an activity that may contribute to its protective effects and reduce iron neurotoxicity in cells. For the immune system, lymphocyte apoptosis maintains the normal physiology and self-tolerance of the system. For peripheral T cells, apoptosis induced by repeated T-cell receptor (TCR) stimulation, known as activation-induced cell death (AICD), may be responsible for the peripheral deletion of autoreactive T cells (Green and Ware 1997) and is involved in terminating the immune response through elimination of activated lymphocytes. The imbalance in this apoptotic process is dangerous and leads to severe diseases associated with autoimmune phenomena (Rieux-Lancat and others 1995) and immunodeficiencies (Alimonti and others 2003). CD95 and its ligand (CD95L) play a crucial role in this type of cell death (Devadas and others 2002). Activation of T cells via T-cell receptor signaling increases intracellular reactive oxygen species and Ca2+, leading to CD95L expression and, consequently, activation-induced cell death (Gulow and others 2005). Activation-induced cell death plays an important role in the maintenance of peripheral lymphocyte homeostasis. Reactive oxygen species combined with simultaneous calcium (Ca2+) influx into the cytosol are required for induction of activation-induced cell death. Mango stem bark extract, whose main active ingredient is mangiferin has been shown to protect T cells from in vitro activation-induced cell death due to its richness in polyphenols which diminished the increase of intracellular reactive oxygen species and free Ca2+ induced by T-cell receptor triggering (Hernandez and others 2007).
Reduction of the reactive oxygen species has been found to consume ATP, thus progressively reducing the energy charge of the system. Mangiferin has been shown to be able to scavenge reactive oxygen species, thus inhibiting all those processes leading to energy charge decrease, red blood cell damage, and membrane destabilization. Erythrocytes and erythrocyte membrane have a high ratio of polyunsaturated fatty acids to total lipids, indicating susceptibility to lipid peroxidation. Red blood cells are highly vulnerable to lipid peroxidation due to constant exposure to high oxygen tension and the presence of large iron ion concentrations (Pawlak and others 1998). After human cell studies, Rodriguez and others (2006) suggested that Mangiferin protects erythrocytes and red blood cells from reactive oxygen species production thus contributing to integrity and functionality of these cells.
The use of dietary ingredients to protect against radiation-induced damage is an attractive proposition, because they are part of the daily human diet, do not have side effects, will have wide acceptability, and can be safely manipulated for human use. The mango fruit is commonly used by humans in various forms and the principal compound mangiferin has been isolated. From their study on cultured human peripheral blood lymphocytes (HPBLs), Jagetia and Baliga (2005) found that mangiferin provided protection against radiation-induced sickness and mortality. A similar effect of mangiferin was observed for radiation-induced bone marrow deaths (Jagetia and Baliga 2005).
It has been suggested that mangiferin reduces blood glucose levels by inhibiting the glucose absorption from the intestine. This hypothesis could be supported by the recent findings that mangiferin inhibits the glucosidase enzymes sucrase, isomaltase, and maltase from rats (Yoshikawa and others 2001) which are involved in the digestion of carbohydrates into simple sugars in the gut leading to delay or inhibition of carbohydrate breakdown and subsequent slower glucose absorption from the intestine (Aderibigbe and others 2001). Mangiferin has been suggested to possess both pancreatic and extrapancreatic mechanisms in its antidiabetic action and such apparent dual actions of mangiferin enhance its efficiency.
Mangiferin was found to significantly reduce plasma total cholesterol, triglycerides, and LDL-C associated with a concomitant increase in HDL-C levels and a decrease in atherogenic index in diabetic rats indicating its potential antihyperlipidemic and antiatherogenic activity (Muruganandan and others 2005). The triglyceride-lowering property of mangiferin could indirectly contribute to the overall antihyperglycemic activity through the glucose–fatty acid cycle mechanism (Randle and others 1963). According to the Randle glucose–fatty acid cycle, an increased supply of plasma triglycerides could constitute a source of increased free fatty acid availability and oxidation that can impair insulin action and glucose metabolism and utilization leading to development of hyperglycemia. Therefore, the reduction of triglycerides following administration with mangiferin would also facilitate glucose oxidation and utilization and, subsequently, reduction of hyperglycemia (Muruganandan and others 2005).
It has been demonstrated elsewhere that mangiferin possesses a wide range of antibacterial effects, both with regard to Gram-positive and Gram-negative bacteria. The species most sensitive to mangiferin among the Gram-positive microorganisms was Bacillus pumilus, whereas among the Gram-negative species the most sensitive to mangiferin was Salmonella agona, though it has to be noted that higher concentrations of mangiferin were necessary (30% to 35%) to achieve the desired effect with regard to the Gram-negative microorganisms (Stoilova and others 2005). Antifungal effect of mangiferin has also been shown with regard to Thermoascus aurantiacus, Saccharomyces cerevisiae, Trichoderma reesei, and Aspergillus flavus (Lova and others 2005). Chakrabarti and Ghosal (1985) found that the fungus Fusarium moniliforme var. subglutinans transforms mangiferin into polymerous quinone, possibly due to the phenoloxidase it releases. It is possible that the resistance to mangiferin by various other mycelial fungi is due to this mechanism.
At this point, it is worth mentioning that Mangiferin alone did not show higher biological activity than the whole extract of either the leaf or bark raw material, and it has been hypothesized that the total antioxidant effect of any mango extract is due to the presence of a combination of several polyphenolic compounds and their derivatives and not only the single, though potent, compound mangiferin (Arts and others 2000).
Mechanism of mangiferin bioactivity
The chemical structure of mangiferin fulfills the 4 requisites that have been reported to have high bioavailability by oral administration: molecular weight below 500 Dalton (C19H18O12); fewer than 5 donor functions for hydrogen bonds; fewer than 10 acceptor functions for hydrogen bonds; and potential log P (calculated) less than + 5 (log Pmangiferin : + 2.73). These similar properties are shared by most of the other mango polyphenols.
The mechanism of bioactivities of mangiferin is mainly centered on its capacity to provide cellular protection as an antioxidant and radical captodative agent. A biologically active antioxidant is a substance that, when present even at low concentration, compared to those of an oxidizable substrate such as membrane lipid or DNA, significantly delays or inhibits oxidation of that substrate. Mangiferin performs its antioxidant function at different levels of the oxidative sequence. As far as membrane lipid peroxidation is concerned, it acts by (a) decreasing the localized O2 concentration and generating mangiferin phenoxy radicals (2) (Figure 2) in concert, (b) binding metal ions (Fe 2+/3+) in the form of a mangiferin–iron complex also called metal ligand complex (3) (Figure 2), which is a stable complex structure that will not allow the generation of such tissue damaging ·OH radicals and/or oxo-ferryl groups; (c) regulating polymer chain initiation by interaction with the reactive oxygen species to produce feebly-reactive oxo-ferryl radical (caged oxygen radical) (4) (Figure 2). This radical acts as a soft inducer of polymerization of the vinylic monomer methylmethacrylate (MMA). The generated radical complex containing a polar end group (mangiferin –Fe3+-O-) acts as a chain terminator by oxidizing the other end group carbon radical of the polymer resulting in a low-molecular-weight mangiferin–Fe–PMMA (polymethylmethacrylate)–polymer (5) (Figure 2), (d) scavenging lipid peroxy/alkoxy radicals and thereby preventing continued abstraction of hydrogen from cellular lipids, and (e) maintaining a cellular oxidation–antioxidant balance (via 12) (Figure 2) (Ghosal and Rao 1996).
The deficiency in the body's functioning has for long been associated with free radicals, and thus one tends to view oxidants as bad and antioxidants as good. The actual situation is rarely so simple; an oxidant–antioxidant balance is a realistic depiction of the normal state. Mangiferin (1) (Figure 2) and the resonance-stabilized phenoxy radicals (2) (Figure 2) in conjugated forms would assist to maintain the desired oxidantantioxidant balance in vivo via such systems as 3 and 4 (Figure 2). These 2 systems were found to contribute to the formation of the complex system mangiferin–Fe–PMMA–polymer (5) (Figure 2) (Ghosal and Ran 1996). Also formed during the activity of mangiferin are low-molecular-weight mangiferin complexes as shown by 6 and 7 in Figure 2 (Ghosal and Rao 1996).