Mangiferin: a natural miracle bioactive compound against lifestyle related disorders

The current review article is an attempt to explain the therapeutic potential of mangiferin, a bioactive compound of the mango, against lifestyle-related disorders. Mangiferin (2-β-D-glucopyranosyl-1,3,6,7-tetrahydroxy-9H-xanthen-9-one) can be isolated from higher plants as well as the mango fruit and their byproducts (i.e. peel, seed, and kernel). It possesses several health endorsing properties such as antioxidant, antimicrobial, antidiabetic, antiallergic, anticancer, hypocholesterolemic, and immunomodulatory. It suppresses the activation of peroxisome proliferator activated receptor isoforms by changing the transcription process. Mangiferin protects against different human cancers, including lung, colon, breast, and neuronal cancers, through the suppression of tumor necrosis factor α expression, inducible nitric oxide synthase potential, and proliferation and induction of apoptosis. It also protects against neural and breast cancers by suppressing the expression of matrix metalloproteinase (MMP)-9 and MMP-7 and inhibiting enzymatic activity, metastatic potential, and activation of the β-catenin pathway. It has the capacity to block lipid peroxidation, in order to provide a shielding effect against physiological threats. Additionally, mangiferin enhances the capacity of the monocyte-macrophage system and possesses antibacterial activity against gram-positive and gram-negative bacteria. This review summarizes the literature pertaining to mangiferin and its associated health claims.


Background
Mangiferin is a xanthone present in significant levels in higher plants and in different parts of the mango fruit, such as the peel, stalks, leaves, barks, kernel, and stone. It is a promising antioxidant with tremendous health-related properties such as antiviral, anticancer, antidiabetic, antioxidative, antiaging, immunomodulatory, hepatoprotective and analgesic effects [1]. Isomangiferin and homomangiferin, which constitute 10% of the total phenolics, are also present in different parts of the mango tree, such as leaves, mango peel, and twigs, [2,3]. They prevent the production of hydroxyl radicals due to their iron chelating ability in Fenton-type reactions [4]. The chemical structure of mangiferin is shown in Fig. 1.
Methanolic mangiferin extracts are potent antioxidants (EC 50 : 5.8 ± 0.96 μg/ml), and have demonstrated hepatoprotective actions against carbon tetrachloride-induced liver damage, further supporting the performance of their in vivo radical scavenging system [1]. Mangiferin also lowered hydrogen peroxide-induced lipid peroxidation in human peripheral blood lymphocytes in a dose-dependent manner [5]. A study conducted by [6] determined that the administration of mangiferin (1, 10, 100 μg/ml) significantly increased the resistance of erythrocyte cells to hydrogen peroxide-induced reactive oxygen species (ROS). It also prevented the depletion of GTP and total nucleotides (NT), as well as ATP damage, and restored energy charge potential in H 2 O 2 -treated erythrocytes in a dose-dependent manner. Mangiferin protects hepatocytes from free radical-mediated hypoxia/reoxygenation injury by forming mangiferin: Fe 3+ complexes and neutralizing free radicals [7]. This iron-complexing ability of mangiferin has been shown to provide protection from lipid peroxidation induced by Fe 2+ -citrate in rat liver mitochondria. Ten micromolar mangiferin was able to protect against the loss of mitochondrial trans-membrane potential (ΔΨ) and the swelling of mitochondria in livers treated with 50 μM Fe 2+ -citrate. It also suppressed iron citrate-induced mitochondrial antimycin A-insensitive oxygen consumption, stimulated oxygen consumption, and prevented Fe 3+ reduction of ascorbate due to Fe 2+ auto-oxidation. Mangiferin is unable to participate in Fenton-type reactions and lipid peroxidation, as the absorption spectra of mangiferin: Fe 2+ /Fe 3+ complexes indicates that the more stable Fe 3+ complex is formed preferentially, and this compound cannot participate in the aforementioned mechanisms [8].
Nevertheless, the C-glucosyl bonds of several C-glucosides interact with the intestinal microflora, facilitating molecule metabolism and transformation into corresponding aglycones. Mangiferin can be used at low concentrations prevent cell damage through reducing localized oxygen concentrations, removing hydroxyl radicals and oxo-ferryl groups, producing mangiferin metal complexes, and initiating the reaction by which free radicals and polymer chain modulation are neutralized [13].
The chemical configuration of mangiferin is influenced by the antioxidant activity of phenolic compounds. Mangiferin showed higher iron chelating ability because of its great antioxidant potential, and its antioxidant potential mainly depends upon the type of compounds, purity of active compounds, applied methods, and higher degree of polymerization [10]. Flavonoids have lower IC 50 values because of a 2-3 double bond conjugated with a 4-carbonyl group present in its microsomal system, which improved the phenoxyl radical-stabilizing effect of 3,4-catechol [14,15]. Moreover, flavonol glycosides exhibit antioxidant activities due to the presence of glycosidic moieties [16]. Other chemical modifications like O-glycosylation and methylationin the flavonoids thereby changing the entire structure of the biomolecules [17]. The activity levels of tricarboxylic acid (TCA), as well as key enzymes in the electron transport chain, such as malate dehydrogenase, isocitrate dehydrogenase, succinate dehydrogenase, and α-ketoglutarate dehydrogenase, are decreased by mangiferin in rats with lung cancer [18]. Mangiferin was also shown to be effective in vitro against glycated protein/chelate ironinduced toxicity in human umbilical vein endothelial cells, as it decreased lipid peroxidase and increased antioxidant enzymes levels [19].
Mangiferin has also been shown to exert a prohypoglycemic role by modulating glucose metabolism, ameliorating insulin resistance, lowering cholesterol synthesis, and inhibiting the expression of the tumor necrosis factor α and inducible nitric oxide synthase [20]. It also induces apoptosis and inhibits the progression and promotion of cell proliferation by interfering with cell cycle regulation, the signaling of several cancer transduction pathways in tumor cells [21].
Jutiviboonsuk and Sardsaengjun [22] estimated the mangiferin content in the methanolic extract of the Nam Doc Mai variety to be 2.80 g/100 g, followed by the Keow Savoey variety at 2.40 g/100 g, and Gaew variety at 1.30 g/100 g.

Mangiferin synthesis and metabolism
Synthesis of mangiferin is accomplished by the friedel-Craft reactions, wherein the glycosyl donor and the electron rich aromatic compound are linked by glycosidic linkage [23]. In this case, aryl C-glycosylation of nonfunctional C-9 carbonyl groups is necessary because of the lack of electrons [10,11]. In the presence of sodium methoxide (NaOMe), mangiferin gives 0.1% yield Fig. 1 Chemical structure of mangiferin followed by the formation of an O-glycosidic bond through hydrolysis by treatment of the aglycone 1,3,6,7tetrahydroxyxanthone with R-acetobromoglucose [12,24]. Mangiferin is synthesized by the reaction of aglycone 1,3,6,7-tetrahydroxyxanthone with R-acetobromoglucose followed by hydrolysis of the formed O-glycosidic linkage [12]. Aglycone compounds have higher antioxidant potential compared to their corresponding glycosides [25].
In C-glucosides, the anomeric oxygen atoms present in glucose are substituted with carbon atoms, making this family significantly dissimilar from the O-glycosides [26]. They are stable against enzymatic and acid degradation [27]. In humans, the intestinal flora plays many important roles in the metabolism of various substances. Many C-glucosides contain C-glucosyl bonds, including abrusin 2-O-β-D-apioside, mangiferin, aloesin, aloeresin A, bergenin, barbaloin, puerarin, safflor yellow B, and homoorientin, and are also transformed by human intestinal bacteria into the corresponding aglycones [28]. Importantly, the glycosyl substituent has antioxidant advantages, owing to its structure and position, over the aglycone substituent [17]. The bioavailability of glycosides is enhanced through the glucose moiety [29].

Pharmacokinetic role
Mangiferin is obtained from the mango with many other active ingredients but poor lipophilicity and hydrophilicity. Mangiferin concentrations were measured using RP-HPLC in rats orally dosed with crude mangiferin and a mangiferin-phospholipid complex. The results showed that mangiferin-phospholipid complex solubility in water and n-octanol was improved, and the complex oil-water partition coefficient was improved by 6.2 times. Furthermore, significantly enhanced intestinal permeability was observed in the rats. AUC and peak plasma concentration in rats treated with crude mangiferin were lower than those treated with the mangiferin-phospholipid complex [30].
Hepatoprotective activity was increased by mangiferin complex administration in rats treated with carbon tetrachloride through restoration of liver antioxidant and serum hepatic marker enzymes. The bioavailability of mangiferin in rats increased 9.75-fold when using the mangiferin complex compared to pure mangiferin. Moreover, hepatoprotection in rats was increased via administration of a mangiferin-soya phospholipid complex due to improved bioavailability [31]. Zhang et al [32] determined that mangiferin recovery ranged from 80.0 to 85.6% in the eye and from 82.0 to 88.0% in the plasma. Mangiferin can pass through the blood-ocular barrier and has been shown to be effective in curtailing various eye diseases [32]. Similarly, [33] investigated the concentration of mangiferin in plasma (0.6 to 24 μg/mL) and urine (0.48 to 24 μg/mL) through HPLC.
Likewise, mangiferin concentration in feces and urine were 1.4 and 1.6% for 9 and 11 days respectively after the administration of 74 mg mangiferin/kg body weight [34]. Using high-speed countercurrent chromatography via a HPLC-diode array detector, mangiferin and neomangiferin were quantified as 292.8 mg and 165.6 mg from an n-butanol:water (1:1, v/v) extract of the Chinese medicinal plant Anemarrhena asphodeloides Bunge [35].
Furthermore, researchers have quantified the mangiferin, neomangiferin and 5-hydroxymethyl furancarboxaldehyde (5-HMF) content from the Chinese medicinal plant Anemarrhena asphodeloides. They quantified 166.0 mg and 293.0 mg of the neomangiferin and mangiferin respectively with 99.0 and 99.6% purity through on-line high-speed countercurrent chromatography and HPLC-diode array detection coupling [35]. In another study, [36] determined that the mangiferin concentration in the retina 0.45 h after intravenous administration of a 50 mg/kg dose was 6.00 ± 1.50 μg/ml, which gradually decreased to 0.30 ± 0.02 μg/ml at 5 h.

Health perspectives
Anticancer Taking precautions against carcinogens has become a very effective anticancer preventive measure. Fruits and vegetables have been shown to have anticancer potential owing to the presence of bioactive compounds. Mangiferin shows antileukemic and preventive effects in HL-60 leukemia cells. After treatment, mangiferin caused cell cycle arrest in the G2/M phase. It accomplished this in a dose-dependent manner at higher concentrations, and further induced Wee1 mRNA expression while significantly suppressing mRNA expression of Chk1 and cdc25C. It also significantly inhibited ATR, Chk1, Wee1, Akt, and Erk1/2 phosphorylation. In addition, mangiferintreatment also decreased activation of cyclin B1 and cdc25C, as well as protein expression levels of Akt and Wee1. It also inhibited cell cycle progression via ATR-Chk1 DNA damage stress-response pathways, leading to cell cycle-arrest in leukemia cells at the G2/M phase [37]. Mangiferin targets several proinflammatory transcription factors, growth factors, cell-cycle proteins, cytokines, kinases, adhesion molecules, chemokines, and inflammatory enzymes by inhibiting the initiation, promotion, and metastasis stages of cancer [38]. Estrogen receptor alpha (ERα) and beta (ERβ) are two regulators of gene transcription responsible for breast cancer. Mangiferin activates the estrogen receptor alpha (ERα) [39].
In U87 glioma cells, miR-15b regulates the expression of matrix metalloproteinase (MMP)-9. Mangiferin significantly restrained proliferation and increased apoptosis through promotion of miR-15b and inhibition of MMP-9. Addition of an MMP-9 agonist antibody in U87 glioma cells reduces the efficacy of mangiferin [40].
Lung carcinoma was induced by benzo(a)pyrene (BaP) (50 mg/kg body weight (BW)) in healthy male Swiss albino mice, resulting in a decrease in body weight, lung weight, and enhanced liver marker enzymes. However, administration of mangiferin (100 mg/kg BW) dissolved in corn oil in these animals lowered the activity of lysosomal enzymes such as β-glucuronidase, acidphosphatase, β-galactosidase and N-acetyl glucosaminidase [42]. Mangiferin significantly lowered DNA damage in etoposide-treated mononuclear cells (MNCs), promoted Nrf2 translocation into the nucleus, enhanced nuclear Nrf2 expression, upregulated NAD(P)H dehydrogenase [quinone] 1 (NQO1), an Nrf2 signaling target, and increased Nrf2 binding with NQO1-antioxidant response element (ARE) sequences in human umbilical cord mononuclear blood cells [43]. In the human cell line nasopharyngeal carcinoma (CNE2 cells), mangiferin different concentrations are (12.5, 25, 50, 100, 150 and 200 μM) suppressed CNE2 cell proliferation via G2/M phase cell cycle arrest, induced early apoptosis, downregulated the mRNA and protein levels of Bcl-2, and upregulated Bax [44]. It also has been shown to inhibit NF-κB (p65 subunit) and IκBα expression in peripheral blood mononuclear cells (PBMCs) in rats with cigarette smokeinduced chronic bronchitis. It considerably lowers the serum high-sensitivity C-reactive proteins (Hs-CRP) and TNFα levels, and reduced chronic inflammatory damage to the bronchioles in PBMCs [45].
The higher concentrations of mangiferin (10, 25 or 50 μM) with doxorubicin for 96 h have the ability to resensitize MCF-7 breast cancer cellsthrough reducing cell viability and inhibiting P-glycoprotein (P-gp) expression [46]. Mangiferin increases Nrf2 expression and protein stability in human HL60 myeloid leukemia cells in vitro in a dose-and time-dependent manner. Moreover, it also inhibits the ubiquitination and degradation of blood cells through increased stability of the Nrf2 protein [47].
In HL-60 cells, mangiferin (50 μM) enhanced Nrf2 protein accumulation, increased Nrf2 binding of ARE, regulated NQO1 expression, and decreased intracellular ROS levels. It also relieved oxidative stress and attenuated etoposide-induced cytotoxicity in mononuclear human umbilical cord blood cells [48].
Finally, mangiferin has been shown to lower cell viability, suppress metastatic potential, decrease MMP-7 and -9 expression, reverse epithelial-mesenchymal transition (EMT), and inhibit the β-catenin pathway in breast cancer cell lines. Mangiferin considerably decreased tumor proliferation, weight, and volume, and enhanced apoptosis, as well as also decreased the expression levels of MMP-7, MMP-9, active β-catenin, vimentin, while increasing the expression of E-cadherin in in vitro MDA-MB-231 xenograft mice [49].
In another study, [50] determined that different concentrations of mangiferin (25-200 μM) exhibited antiproliferation effects on K562 cells in a dose-dependent manner through downregulating expression of the BCR and ABL genes. Likewise, mangiferin (80 μM) also showed inhibitory effects on HL-60 cells by stopping the progression of cell cycle at the phase of G2/M, and enhancing the expression of CDC2 and CCNB1 mRNA [51]. Mangiferin has an antiproliferative role on the telomerase activity of K562 cells by inducing apoptosis and upregulating Fas levels [52].
Oral administration of mangiferin (100 miligram/kilogram BW) through the diet for 18 weeks significantly ameliorated the elevated levels of glycoprotein components, membrane lipid peroxidation, and ATPases in lung carcinoma-induced animals. Mangiferin increased the concentration of glutathione, catalase (CAT), superoxide dismutase, glutathione reductase, glutathione peroxidase, vitamin E, and vitamin C [53]. Similarly, in the breast cancer cell line MDA-MB231, mangiferin also suppressed classical NFκB activation by IκB kinases (IKK) α/β in impairing IκB degradation, NFκB translocation, and NFκB/DNA binding. Furthermore, mangiferin inhibits additional NFκB pathways which participated in cancer cell survival and therapy resistance such as c-Jun N-terminal kinases (JNK) 1/2, MEK1, p90 ribosomal s6 kinase, and mitogen-and stress-activated protein kinase 1 [54]. Mangiferin has the potential for antigenic toxicity of neurotoxicity against methylmercury (MeHg) -induced IMR-32 (human neuroblastoma) cell lines. It considerably suppresses MeHg-induced DNA damage, lowers MeHg-induced oxidative stress, intracellular Ca 2+ influx, and inhibits depolarization of the mitochondrial membrane. It also enhances glutathione (GSH) and glutathione S-transferases (GST) levels, leading to significantly decreased malondialdehyde (MDA) formation [55]. It also induced apoptosis in the human acute myeloid leukemia cell line HL-60 through comcomitant enhancement of caspase-3 activity and DNA fragmentation, significantly decreasing the nuclear entry of NF-κB p65, suppressing NF-κB activation, and inhibiting the expression of Bcl-xL and X-linked inhibitor of apoptosis protein (XIAP) [56]. The inhibition of NFκB via the (A) classical and (B) alternative pathways by mangiferin is shown in Fig. 2.

Antinflammatory activity
Acute nociceptive, neuropathic pain and inflammatory responses depend on the peripheral activation of primary sensory afferent neurons, which show several inhibitory neuro-receptors such as opioid, alpha-adrenergic, cholinergic, cannabinoid receptors, and adenosine and these receptor agonists represent possible targets for drugs [57,58].
Mangiferin also attenuates mortality and acute lung injury (ALI) induced by cecal ligation and puncture. It also inhibited NF-κB signaling and sepsis activated-MAPKs, suppressing the production of proinflammatory  [11, 45, 55, 123, 124]) mediators. It also upregulated the expression and activity of heme oxygenase (HO)-1 in the lung of septic mice in a dose-dependent fashion [63]. Bhatia et al. [64] determined that mangiferin (1-50 μM) reduced 8-isoPGF2α and PGE2 production induced by LPS in a dosedependent manner in rat primary microglia. It also lowered COX-2 protein synthesis induced by LPS without modifying the transcription of COX-2.
Mangiferin also ameliorates intestinal inflammation and impairs the gastrointestinal transit postoperative ileus (POI) of rats. It recovers delayed intestinal transit induced by intestinal manipulation. Furthermore, mangiferin considerably suppressed myeloperoxidase activity (a marker of neutrophil infiltration) and nitrate/nitrite ratio, as well as lowered the plasma levels of IL-1β, TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1) in rats [65].
Mangiferin also downregulates the mRNA expression of pro-inflammatory mediators such as induced nitric oxide synthase (iNOS), TNF-α, IL-1β, and IL-6, phosphorylation of NF-κB p65, and intercellular adhesion molecule-1 (ICAM-1), in the colon of a dextran sulfate sodium (DSS)-induced colitis model in mice. It also inhibited DSS-induced MAPK protein phosphorylation/ activation and also blocked TNF-α stimulated RAW 264.7 mouse macrophage cell nuclear translocation of NF-κB. It also suppressed NF-κB transcriptional activity in HT-29 human colorectal adenocarcinoma cells in a dose-dependent manner [66]. Furthermore, mangiferin shows a gastroprotective effect in mice. Administration of mangiferin (3, 10 and 30 mg/kg) decreased ethanolinduced gastric damage by 30, 35, & 63% respectively, and reduced indomethacin-induced gastric damage by 22, 23, and 57% respectively. In pylorus-ligated rats, gastric secretion and total acidity significantly decreased by mangiferin, and effectively prevents the depletion of the ethanol-related protein from the gastric mucosa of the non-protein sulfhydryl content [67].

Diabetes treatment
Diabetes is becoming a major health disorder among the population, and more than 80% of diabetic patients suffer from type 2 diabetes. This type of diabetes is associated with a reduced ability to increase the glucose utilization in its major target tissues: skeletal muscle and adipose tissue. These increases in blood glucose and insulin levels are linked with cardiovascular diseases (hypertension, retinal injury, and atherosclerosis), fatty liver, dyslipidemia, and renal diseases [68].
Eight weeks of mangiferin treatment significantly lowered plasma glucose and triglyceride (TG) levels in db/ db mice. It enhanced pancreatic β cell mass and amount of glucose and insulin uptake along with increased the phosphorylation of AMP-activated protein kinase (AMPK) in n 3 T3-L1 cells. It also activated the AMPactivated protein kinase (AMPK) phosphorylation of AMPK and activated along its downstream target, acetyl -CoA carboxylase (ACC) in the liver, hypothalamus, muscle and adipose tissue of C57BL/6 mice [69]. Likewise, the oral administration of mangiferin (20 mg/kg, intraperitoneal administration (i.p.)) for 4 weeks in streptozotocin-induced hyperglycemic rats improved insulin sensitivity, modulated lipid profile, and reverted adipokine levels [70]. Similarly, different concentrations of mangiferin (15,30, and 60 mg/kg/day oral administration) were given to diabetic rats for 9 weeks, resulting in a reduction of osteopontin production, kidney inflammation, and renal fibrosis. Chronic treatment with mangiferin prevented renal glomeruli fibrosis, as well as decreased α-smooth muscle actin and collagen IV expression in the diabetic rat. In contrast, this also reduced the expression of osteopontin in the renal-cortex of diabetic rats, COX-2 and NF-κB P65 subunits. Finally, mangiferin reduced interleukin-1β in the serum and kidneys of diabetic rats [71].
Mangiferin (15,30 and 60 mg/kg) treatment for nine weeks significantly improved chronic renal insufficiency of diabetic rats, and was demonstrated to reduce kidney weight index, albuminuria, glomerular extracellular matrix expansion, blood urea nitrogen, and glomerular and accumulation basement membrane thickness. Meanwhile, it also enhanced the enzymatic activity, as well as the protein and mRNA expression of Glo-1, as well as decreased the mRNA and protein expression of advanced glycation endproducts (AGEs) and receptor for advanced glycation end products (RAGE) receptor in diabetic rat renal cortex. Moreover, it also reduced the concentrations of malondialdehyde (MDA) and enhanced the concentrations of glutathione in the diabetic rat kidney [74].
Mangiferin (10 and 20 mg/kg) administered once daily for 28 days in STZ-induced diabetic rats exhibited antidiabetic activity. It significantly reduced plasma lowdensity lipoprotein cholesterol LDL-C) and TG levels, lowered total cholesterol level and increased highdensity lipoprotein cholesterol (HDL-C) levels. Furthermore, the atherogenic index of diabetic rats decreased and mangiferin improved oral-glucose tolerance in normal rats loaded with glucose [75].
In diabetic nephropathy rats, mangiferin considerably lowered the serum levels of advanced glycation end products, red blood cell sorbitol concentrations, malonaldehyde level, 24 h albuminuria excretion, and enhanced serum antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In addition, it inhibits the expansion of glomerular extracellularmatrix and diabetic nephropathy rat glomeruli TGF-β1 accumulation and transformation, high glucoseinduced mesangial cell proliferation and mesangial cells collagen IV in a glomerular diabetic nephropathy rat model [76]. The health perspectives of mangiferin is shown in Table 1.

Cardiovascular protective role
Cardiovascular diseases such as congenital heart disease, cerebrovascular disease, thyroid abnormalities (hypoand hyperthyroidism), hypertension, peripheral artery disease, diabetes mellitus (both types 1 and 2), heart failure, and rheumatic heart disease are the most prevalent diseases around the globe, and are responsible for high rates of morbidity and mortality [77].
In response to endoplasmic reticulum stress, thioredoxin interacting protein (TXNIP) expression increases, followed by activation of small NACHT, LRR and PYD domains-containing protein 3 (NLRP3) and increased secretion of IL-1β. Mangiferin reduced the production of free radicals and also inhibited ER stress-related oxidative stress by attenuating endoribonuclease inositol-requiring enzyme 1 (IRE1α) phosphorylation. It also attenuated NLRP3 and TXNIP expression, reduced IL-1β and IL-6 production, and aided inhibition of TXNIP/NLRP3 inflammatory activation. Mangiferin also prevented oxidative stress through multiple mechanisms, including (1) restoring mitochondrial Δψ, (2) suppressing caspase-3 activity, (3) protecting from apoptosis induced by high glucose, (4) ameliorating the inhibition of ET-1 secretion and reduction of NO production, and (5) increasing AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects. Mangiferin improved endothelial dysfunction by inhibiting endothelial cell endoplasmic reticulum stress-related TXNIP/NLRP3 activation-induced inflammation [78].
Mangiferin, delivered orally or via injection to rats at doses of 50 and 100 mg/kg for 5 weeks provided protection against doxorubicin (DOX) (15 mg/kg). Mangiferin reduced serum levels of lactate dehydrogenase (LDH) and creatine kinase, reduced MDA levels in plasma and cardiac tissue, and increased cardiac tissue levels of the antioxidant enzyme superoxide dismutase (SOD). Rats treated with doxorubicin (DOX) have significantly reduced necrotic foci, fibrotic area, and inflammatory cell number [79]. Mangiferin mitigates diabetic cardiomyopathy (DCM) and prevents the accumulation of myocardial collagen [80].
Isoproterenol-induced myocardial infarction is associated with imbalance of heart tissue and serum marker enzymes such as creatine phosphokinase (CPK), aspartate transaminase, alanine transaminase (ALT) and LDH, as well as enhanced levels of lipid peroxidation and histopathological changes. Mangiferin (10 mg/100 g BW) treatment for 4 weeks ameliorated effect of pHinduced pathological changes, reduced the formation of lipid peroxides, and retained the activity of cardiac markers [81].
Mangiferin has a significant role in the reduction of cholesterol, triglycerides, and free fatty acid (FFA) levels in both serum and heart, and can also enhance heart tissue phospholipid levels in isoproterenol-induced cardiotoxic rats [82]. Mangiferin preserved lysosomal integrity by decreasing the inflammatory process. Isoproterenol (two subcutaneous administrations of 200 mg/kg BW) treatment for 2 days significantly increased plasma TNFα production as well as heart and serum lysosomal hydrolase activity, and also lowered the membrane stability. Mangiferin treatment (100 mg/kg BW) for 4 weeks prevented these alterations and restored the enzyme activity in rats [81].

Oxidative stress
During the metabolic process, free radicals are produced in the human body, causing oxidation in biological macromolecules such as proteins, fatty acids, and nucleic acids. Free radicals at high concentration levels in the human body can cause oxidative stress, thus destroying internal redox balance and causing a variety of chronic diseases [83,84].
Mangiferin has demonstrated a cytoprotective role against schizophrenia in a ketamine-induced rat model (50 miligram/kilogram, i.p., for seven days, twice a day). Mangiferin (10 to 100 μM for 7 days) treatment significantly prevented 6-hydroxydopamine (6-OHDA)-induced cell death in a concentration-dependent manner. It also significantly decreased the levels of IL-6 and MDA in brain tissues [89]. Wang et al. [90] found that concentrations of mangiferin (100,200, and 400 mg/kg) enhanced the levels of SOD and NO in the BALF and serum of rats with chronic bronchitis, as well as decreased MDA levels, and content of TNF-α and IL-8 in lung tissues whereas the RAW264.7 macrophages COX-2 mRNA expression induced by LPS were also lowered.
In hyperuricemic mice induced by potassium oxonate, different concentrations of mangiferin (50, 100, and 200 mg/kg) lowered serum uric acid, urea nitrogen levels and creatinine concentration. Additionally, it also down regulated murine glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) mRNA and protein levels, and upegulated the murine organic anion transporter 1 (mOAT1). It lowered uric acid reabsorption and significantly increased renal organic cation levels, as well as carnitine transporter (mOCTN1, mOCTN2, mOCT1 and mOCT2) expression levels. Finally, it increased urinary and decreased kidney and serum mUMOD levels [91].
Mangiferin has protective role against the genotoxicity induced by cadmium chloride in Swiss albino mice. Treatment with a single intraperitoneal dose of mangiferin dose (2.5 mg/kg) significantly reduced the ratio of MnPCE and MnNCE, and increased the PCE/NCE ratio. Moreover, it also reduced lipid peroxidation and increased SOD, GSH, CAT, and GST activities in the liver [92]. Mangiferin has an effective role in N2A cells against 1-Methyl-4-phenyl-pyridine ion (MPP + -induced cyto-toxicity by restoring GSH content, and decreased the mRNA expression of both SOD and CAT [93]. Mangiferin (50 μM) exerted cytoprotection against magnesium chloride-induced toxicity by significantly increasing levels of SOD, GSH, CAT, GST, and by quenching free radicals, decreasing the percentage of HgCl(2) induced apoptotic cells, and normalized mitochondrial membrane potential and cellular antioxidant levels [94]. The application of Ca 2+ increased mitochondriagenerated ROS levels in the liver, but mangiferin treatment (40 miligram/kilogram BW) were treated in-vitro to Ca ++ that prevented Ca 2+ -induced depletion of antioxidant enzymes and inhibited the production of free radicals in the liver [95].

Neuroprotective role
Mangiferin has a cytotoprotective role against the neurotoxicity and cognitive impairment induced by aluminium chloride in male Swiss albino mice. Mangiferin (20 and 40 mg/kg) significantly reduced oxidative stress marker levels, as well as inflammatory cytokine levels and hippocampal brain-derived neurotrophic-factor (BDNF) content [96].
The mangiferin oral administration (10 and 20 miligram/kilogram daily) enhanced cellular responses, antigen-specific IgM levels, and lymphoid organ weights in cyclophosphamide-treated male Wistar rats after 2 weeks. It also reduced lipid peroxidation, lymphocytes amount, macrophages, and polymorphonuclear cells, as well as SOD and CAT activity [2].
Mangiferin provided protection against neuroinflammation and oxidative damage in the brains of young male Wistar rats. Different concentrations of mangiferin (15,30, and 60 mg/kg) prevented from (1) enhanced IL-1β and glucocorticoid (GC) plasma levels, (2) loss of redox balance and reduction in catalase brain levels, (3) increase in proinflammatory mediators such as TNF-α, NF-κB, TNF receptor 1, as well as synthesis enzymes such as iNOS and COX-2, and (4) increased in lipid peroxidation. These aspects of the protective effect proved mangiferin use may be a novel strategy for treatment of neuropsychiatric/neurological pathologies [99]. In another study conducted by [100], oral administration of mangiferin (10, 50, or 100 mg/ kg) increased novel object recognition when immediate post-training was given. Cell proliferation stimulated by mangiferin and it is induced a significant-increase in the level of supernatant of nerve growth factor and TNF-alpha, as well as greater levels of cytokines and neurotrophic factors, in human U138-MG glioblastoma cells.

Hyperlipidemia
Mangiferin is protective against hyperlipidemia through the regulation of metabolic pathways such as the glyoxylate, tricarboxylic acid (TCA)and taurine cycles, as well as metabolism of dicarboxylate, glycerophospholipid, hypotaurine, and threonine, and serine, glycine, and primary bile acid biosynthesis [101]. Likewise, mangiferin enhances proteins which lead to mitochondrial biogenesis and oxidative activity such as cytochrome c oxidase subunit 6B1 (Cox6b1) and oxoglutarate dehydrogenase E1 (DHTKD1). It also lowers the levels of proteins which are critical for lipogenesis, such as acetyl-CoA carboxylase 1 (Acac1) gene and fatty acid stearoyl-CoA desaturase 1 (Scd1), and upregulates proteins important to bioenergetics, downregulates mitochondrial proteins which control de novo lipogenesis, and prevents adiposity [102]. In human neuroblastoma SK-N-SH cells, mangiferin considerably increased cell viability, improved mitochondrial membrane potential, and reduce apoptosis induced by rotenone [103].
Mangiferin also enhanced muscle glucose oxidation in high fat diet (HFD)-fed mice without altering fatty acid oxidation. In cultured C2C12 myocytes, mangiferin increased glucose and pyruvate oxidation and ATP production, without affecting the oxidation of fatty acids. Furthermore, it suppressed the conversion of pyruvate to lactate via anaerobic metabolism, but increased the oxidation of pyruvate [104].
It also decreased the production of reactive oxygen species through both mitochondria isolated from the LDLr (-/-) liver and lymphocytes from the spleen. It also protects the depletion of mitochondrial substrates NAD(P)H-bound and spontaneous-oxidation NAD(P)H [105]. In another study, mangiferin (50, 100, 150 mg/kg) treatment for 6 weeks lowered FFA and TG levels in the plasma and liver of hyperlipidemic rats and increased levels of β-hydroxybutyrate. It markedly increased FFA uptake and markedly reduced intracellular accumulation of FFA and TG in HepG2 cells. Mangiferin knowingly increased phosphorylation of AMP -AMPK (activated protein kinase) and its proteins downstream comprises carnitine palmitoyltransferase 1 (CPT1) and fatty acid translocase (CD36), but significantly reduced the expression of acyl -CoA: diacylglycerol acyl transferase Enzyme 2 (DGAT2) and activity of acetyl-CoA carboxylase (ACC), by increasing the phosphorylation levels in their in vivo and in vitro studies [106].

Miscellaneous properties
Mangiferin exerted protective effects against atopic dermatitis, bronchial asthma, and other allergic diseases. It also inhibited IgE production, anaphylaxis reaction, histamine-induced vascular permeability, histamine release, and the lymphocyte proliferative response in rats. Furthermore, it lowered the amount of B and T lymphocytes, which are responsible for allergic responses [109]. Mangiferin administration significantly reduced alveolar bone loss (ABL) through inhibition of COX-2 expression and leukocyte rolling and adhesion, while maintaining normal levels of lipoxin A4 [110].
Mangiferin provided a shielding effect against the damaging effect of hydrogen peroxide in human keratinocytes (HaCaT). It also neutralized free radicals, including oxyl, peroxyl, and superoxide radicals. These radicals regulate the expression and activation of the plasminogen protease gene, and mangiferin inhibited MMP-1 gene and protein expression levels. It also inhibited DNA binding activity of activator protein-1 (AP-1), a transcription factor for MMP-1, down stream of ERK and JNK [111]. Treatment with mangiferin (50 mg/kg) resulted in significant reduction of airway inflammation in peripheral blood vessels and bronchial inhibition of IL-4 and IL-5 in bronchoalveolar lavage fluid for 24 days and lymphocyte culture supernatant [109]. Mangiferin also protected normal human intestinal epithelial cells (HIECs) from radiation-induced injuries by modulating their genotoxic effects and eliminating 46.8% of the total double strand breaks (DSBs) of the cells which were exposed to 2 Gy ionizing irradiation (IR) [112]. Significant reduction had been seen in TNF-α (tumor necrosis factor) levels tempted by inhibited nuclear factor-kappa-B stimulation in scopolamine in mice brain or TNF stimulated cells by using mangiferin (20 mg/kg). Additionally, mangiferin enhances the deficits of long-term cholinergic-memory by inhibiting stimulation of cholinergic receptor and NF-κB activation suppression [113].
Mangiferin inhibits bone resorption and osteoclast formation by weakening RANKL-induced signaling. It also decreased expression of osteoclast gene markers such as calcitonin receptor, cathepsin K, V-ATPase d2 and DC-STAMP. Mechanistically, mangiferin suppressed RANKL-induced activation of NF-κB, as well as p65 nuclear translocation and IκB-α degradation. Moreover, inhibitory effect of mangiferin on induction of ERK phosphorylated RANKL [114]. The administration of galactosamine (GAL) (400 mg/kg) in rats showed the elevation in ALP, ALT, triglycerides level, lipid-peroxidation, total cholesterol and reduction of total proteins, serum albumin and cellular GSH. Meanwhile, in GAL treated rats, mangiferin, owing to its antioxidant defense mechanisms, significantly altered GAL-induced adverse effects, and suppressed the Nrf2 pathway, reduced inflammation, and inhibited NFκB activity [115].
Mangiferin possesses antibacterial activity against grampositive (i.e. Bacillus pumilus) and gram-negative bacteria (i.e. Salmonella agona). It also protects from the harmful effects of. Enterococci and Mycobacterium tuberculosis, and showed antifungal effects against trichoderma reesei,, aspergillus flavus, and Thermoascus aurantiacus [116,117]. It also acts as a curative and preventive agent against periodontal disease, as well as free radical-mediated oxidative damage in neurons, cardiac muscle, liver, and kidney tissue [110,118]. It also exhibited good anti-HIV-1 activity through inhibition of the HIV-1 protease, and lowered intestinal neoplasms in rats and was active against herpes simplex virus (HSV-1) [8,119]. Mangiferin oral supplementation (50 mg/kg) suppressed the growth of nematode Trichinella spiralis. It inhibited themast cell degranulation, lowered the serum levels of specific anti-Trichinella IgE and declined the number of parasitic larvae through out the life cycle of parasite [3,120].
Mice were challenged with LPS (0.83 mg/kg, i.p.), which induced oxidative stress. Different concentrations of mangiferin (20 and 40 mg/kg) significantly ameliorated anxiety-like behaviour and also improved anhedonic behaviour. It also enhanced glutathione concentrations, CAT and SOD activity, and reduced lipid peroxidation and nitrite levels in the hippocampus and the prefrontal cortex. It also attenuated neuroinflammation in the prefrontal cortex and hippocampus by reducing IL-1β levels [121].

Conclusions
Mangiferin is a bioactive compound that demonstrates many health perspectives and has been used to prepare medicinal and food supplements. Owing to the presence of mangiferin in leaves, bark, seed, peel, flowers, and pulp, a potential source of dietary polyphenols with elevated antioxidative properties could be available for industrial purposes. The phenolic compounds present in the mango peel are greatly affected by the geographic locations of the plants. Mangiferin has also been demonstrated to exert protective effects against degenerative diseases such as atherosclerosis, cancers (i.e. breast, colon, neural, skin and cervical), obesity and diabetes. It also protects the body against damage associated with oxidative stress. There should be more clinical trials by using this miracle bioactive compound in future.