Mangiferin, a C-glucosyl xanthone with the formula 1,3,6,7-tetrahydroxyxanthone-C2-β-D-glucoside (Fig. 1), has been extensively studied both in vivo and in vitro. It has been demonstrated to possess numerous pharmacological activities, including antioxidative, antiaging, antitumor, antibacterial, antiviral, immunomodulatory, antidiabetic, hepatoprotective and analgesic effects (1–3). Mangiferin has been detected in many plant species and may be abundantly isolated from various parts of Mangiferaindica (mango), including the leaves, stem bark, fruit peels and root (4,5).

With advances in pharmacology and molecular biology, research regarding mangiferin has increased and more pharmacological mechanisms have been revealed, which provides further information for the design and development of mangiferin as a clinical therapeutic. However, Wang et al (6) reported that the solubility of mangiferin was only 0.111 mg/ml. In addition, Han et al (7) demonstrated that the oral bioavailability of mangiferin was only 1.2%. This may be due to its low lipophilicity properties, poor intestinal membrane permeability and low oral absorption (8). These experimental data collectively indicate that despite a wide range of pharmacological activities, mangiferin has low solubility, transmembrane permeability and bioavailability, which restricts the clinical development and application of mangiferin. In order to identify more effective therapeutic compounds, mangiferin derivatives with improved solubility, bioavailability and potency were obtained by chemical or biotransformation methods (9). Therefore, with the progress of biotechnology and research practice, mangiferin may be identified to represent a more promising, novel therapeutic drug in clinic.

Based on previous studies concerning the structural modification, pharmacological activities and therapeutic molecular mechanisms of mangiferin in recent decades, the pharmacological effects of mangiferin were reviewed herein, in order to provide references for further drug research and development.

The research and development of antitumor agents with fewer adverse effects has become a popular topic of research. As a monomer of traditional Chinese medicine, mangiferin has been demonstrated to have direct and auxiliary roles in oncotherapy. Mangiferin efficaciously inhibits tumor cell cycle progression. It has been widely accepted that cell growth prior to cell division is strictly controlled by the cyclin-dependent kinase 1 (CDK1)/cyclin B1 complex (46–48). Notably, mangiferin has been validated to trigger G2/M phase cell cycle arrest via regulation of the CDK1-cyclin B1 signaling pathway (49–51). DNA synthesis is accomplished during the S phase of the cell cycle, and treatment with mangiferin causes S phase delay in colorectal cancer HT29 cells and cervical cancer HeLa cells (52). In addition to its inhibitory actions on cell cycle, mangiferin induces apoptosis in tumor cells. Nuclear factor-κB (NF-κB) is a transcription factor that induces the proliferation of cancer cells (53). RelA and RelB, important members of NF-κB family, are transformed into activated NF-κB following dimerization. It was demonstrated that mangiferin inhibits the expression of RelA and RelB, activates inhibitor of NF-κB (IκB) and suppresses the phosphorylation of NF-κB kinase, thereby inhibiting the transcriptional activity of NF-κB and inducing apoptosis tumor cells (54–56). IκB kinase α and IκB kinase β-dependent IκB degradation and subsequent NF-κB activation have been widely acknowledged as the canonical NF-κB activation pathway (57). However, a collective patent review on mangiferin unveiled that multiple signaling pathways, including nuclear NF-κB signaling and cyclooxygenase-2 (COX-2) protein expression are involved in the antitumor effects of mangiferin (56). This patent review concluded that mangiferin is a candidate molecule in the development of novel antitumor drugs. Furthermore, caspase activation may participate in the apoptosis-inducing effects of mangiferin in oncotherapy. A disturbance in the balance between cell proliferation and apoptosis is known to initiate tumorigenesis (58). Caspase activation serves a critical role in apoptosis, particularly via the mitochondria-initiated pathway (59). Pan et al (60) demonstrated that through regulation of Bcl-2, apoptosis regulator (Bcl-2) and Bcl-2 associated X, apoptosis regulator (Bax) expression, mangiferin potently inhibits tumor cell proliferation and induces apoptosis in nasopharyngeal carcinoma cells. Additionally, a study of the antitumor efficacy and underlying mechanisms of mangiferin in human cervical carcinoma HeLa cells demonstrated that the protein expression of BH3 interacting domain death agonist, Bcl-2 and pro-caspase-3 and −8 is downregulated in response to mangiferin treatment, which results in the activation of caspase-3, −7, −8 and −9, ultimately leading to apoptosis (61).

Our previous studies contributed to the understanding of the underling molecular mechanism of mangiferin in oncotherapy (55,62,63). In human breast carcinoma MCF-7 cells, mangiferin down regulates the cyclin-dependent kinase 1-cyclin Bl signaling pathway and induces G2/M phase cell-cycle arrest to inhibit tumor cell growth (62). In addition, it was demonstrated to inhibit the protein kinase C (PKC)-NF-κB pathway to induce apoptotic cell death (62). Furthermore, in vivo experiments performed in a MCF-7 ×enograft rat model confirmed the in vitro results (62). Similarly, in human lung carcinoma A549 cells, mangiferin exhibits antineoplastic properties, by inducing G2/M phase cell cycle arrest via downregulation of the cyclin-dependent kinase 1-cyclin B1 signaling pathway and inducing apoptotic cell death by inhibiting the PKC-NF-κB pathway (55). In addition, in-depth research into the underlying mechanisms of mangiferin successfully elucidated that caspase-dependent apoptosis and obviously downregulated Notch3 expression occurs in mangiferin-treated human ovarian adenocarcinoma OVCAR3 cells (63). Based on these previous studies, it may be concluded that mangiferin exhibits prominent anti-tumor action in certain malignant neoplasms through multifactorial molecular mechanisms (Fig. 3).

Abundant research on the effects of mangiferin has revealed the antioxidant and anti-inflammatory properties, due to its C-glycosylxanthone structure (64). The C-glucosy l linkage and polyhydroxy component in mangiferin contributes to its free radical-scavenging activity (65). Free radicals are highly reactive molecules that are implicated in the pathology of traumatic brain injury and cerebral ischemia through oxidative stress and inflammation (66–68). In recent decades, the role of free radicals in the pathology of traumatic brain injury and cerebral ischemia has been elucidated by investigating oxidative stress and inflammation with other pathogenic processes, such as excitotoxicity, calcium overload, mitochondrial cytochrome c release, caspase activation and apoptosis in trauma and ischemia of central nervous system (CNS) (69). Furthermore, mangiferin is capable of modulating the expression of proinflammatory signaling molecules, including the expression of TNF-α and COX-2, as well as regulating various transcription factors, such as NF-κB, and NF-E2-related factor 2 (Nrf-2) (64). Research regarding the protective effects of mangiferin in CNS injury, proinflammatory cytokine expression, oxidative stress and neurobehavioral abnormalities induced by lipopolysaccharide (LPS) in cerebrum are detailed herein.

Accumulating evidence has revealed that mangiferin is able to attenuate LPS-induced cognitive deficits caused by neuroinflammation (70). Oral mangiferin pre-treatment (50 mg/kg) and treatment (50 mg/kg) following LPS injection in mice demonstrated that mangiferin ameliorates cognitive deficits by decreasing LPS-induced IL-6 expression and increasing heme oxygenase-1 (HO-1) expression in mice hippocampi. Similarly, in behavioral experiments, mice were treated with LPS (0.83 mg/kg) intraperitoneal injection following oral pretreatment with mangiferin (20 and 40 mg/kg, 14 days), which subsequently attenuated depressive and anxiety-like behaviors (71). Further research has ascertained that mangiferin increases glutathione concentration, superoxide dismutase (SOD) and catalase activity in mice; as well as decreasing lipid peroxidation and nitrite level in the hippocampus and prefrontal cortex (71). Furthermore, mangiferin reduces LPS-induced IL-1β expression and oxidative stress when used in depressive and anxiety disorders (71). Therefore, these studies indicated that mangiferin greatly contributes to cerebral protection. By decreasing COX-2 transcript stability, mangiferin potently reduces LPS-induced prostaglandin E2 (PGE-2) synthesis and 8-iso-prostaglandin F2α (8-iso-PGF2α) production (72). Taken together, these data demonstrated mangiferin exhibits potent antioxidant and anti-inflammatory properties, by decreasing PGE-2 production, free radical formation and COX-2 synthesis.

The underlying mechanisms of neuroinflammation and oxidative damage in the brain are complicated. Young adult male Wistar rats were exposed to a high-stress environment and neurological and neuropsychiatric diseases associated with cell damage and apoptosis were observed in their cerebrum, such as neurodegenerative diseases, depression, and schizophrenia (73). It was demonstrated that mangiferin administration (15, 30 and 60 mg/kg; oral gavage) prevents hypothalamic/pituitary/adrenal (HPA) stress axis dysregulation, neuroinflammation and oxidative damage. Pretreatment with mangiferin inhibits an increase in the levels of glucocorticoids (GCs), IL-1β, TNF-α, TNF receptor 1, NF-κB, inducible nitric oxide synthase (iNOS) and COX-2 (73). Furthermore, mangiferin effectively protects against early brain injury (EBI) that is involved in the process of cerebral tissue damage induced by subarachnoid hemorrhage (SAH) (74). It was demonstrated that mangiferin decreases the mortality of animals with SAH, ameliorates neurological deficits and brain edema, attenuates SAH-induced oxidative stress and decreases cortical cell apoptosis in a dose-dependent manner. Mechanism analysis of mangiferin demonstrated that it exerts its neuroprotective effects against EBI by promoting the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 cascade in the mitochondrial apoptosis pathway, as well as through NLRP3 inflammasome activation and NF-κB inhibition (74). In addition, in Wistar male rats with cerebral IR injury, the activation of Nrf2/HO-1 cascade is promoted in a dose-dependent manner by mangiferin (75). Furthermore, mangiferin ameliorates the activities of SOD, glutathione and IL-10, which has a protective role in oxidative stress induced by cerebral IR injury (Fig. 4).

Cardioprotective effects of mangiferin. Increasing amounts of evidence regarding the cardioprotective effects of mangiferin in isoproterenol (ISPH)-induced myocardial infarction (MI) rats has emerged. Prabhu et al (76) demonstrated that pretreatment with mangiferin (100 mg/kg) for 28 days regulates the tissues defense system against cardiac damage. Specifically, the activities of heart tissue enzymic antioxidants, including superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase and glutathione reductase, as well as non-enzymic antioxidants such as cerruloplasmin, Vitamin C, Vitamin E and glutathione, were all notably upregulated (76). It was concluded that mangiferin exerts its beneficial effects due to its antioxidant potential, which reduces myocardial oxygen consumption and relieves angina pectoris (76). In addition, mangiferin protects the myocardium against ISPH-induced MI by reducing lipid peroxide formation and retaining the activities of myocardial marker enzymes, including LDH, creatine phosphokinase (CPK), AST and ALT (77). Those results suggested that mangiferin effectively alleviates free radical release in the ischemic myocardium and delays membrane lipid oxidation. In addition, studies in myocardial cells under the condition of ISPH-induced MI demonstrated mangiferin protects the structural integrity of by reducing the effects of oxidative damage and increasing mitochondrial energy metabolism (78). Mangiferin markedly increases the activities of the tricarboxylic acid cycle and antioxidant defense enzymes in MI (78). In addition, mangiferin has been reported to prevent free radical-mediated lipid peroxidation and increase lysosomal instability, thus alleviating MI injury (79).

It has also been demonstrated that mangiferin improved heart blood flow parameters and fiber disturbance in a dose-dependent manner, following a single intravenous injection of mangiferin (5, 10 or 20 mg/kg) in a MI experimental model (80). Mangiferin administration (20 mg/kg for 4 weeks) restores the function of cardiac ejection, reduces the accumulation of TNF-α and cleaved caspase-3, and upregulates Bcl-2 (80). In addition, mangiferin has a therapeutic effect on post-MI left ventricular remodeling and improves cardiac function. Mangiferin administration (50 or 100 mg/kg for 5 weeks) also protects against doxorubicin-induced mortality and electrocardiogram abnormality, decreases the expression of biochemical cardiac toxicity markers, such as dehydrogenase and creatine phosphokinase isoenzyme (81). Histopathologically, mangiferin treatment results in obvious reductions in inflammatory cell number, fibrotic area and necrotic foci (81), which indicates that mangiferin may have a preventive effect against ventricular hypertrophy and fibrosis induced by MI. Therefore, mangiferin may be used in combination with clinical treatments in the future, including with surgery or other therapeutics (Fig. 5A).

Mangiferin in atherosclerosis and hyperlipemia. Hyperlipidemia and elevated FFAs are risk factors for atherosclerosis, hyperlipemia and cardiovascular disease (82). Therefore, research into the effects of mangiferin on abnormal lipid metabolism in the cardiovascular system is increasing (Fig. 5B). Atherosclerosis is closely associated with abundant oxidative events, including low-density lipoprotein (LDL) oxidation and increased intracellular reactive ROS production. Mangiferin is a polyphenol compound extracted from mango leaves and is the main active ingredient of food supplement of the flood supplement VIMANG, which is widely popular in Cuba (83). VIMANG is extracted from the bark of Mangiferaindica and is typically administered as a tablet, containing 300 mg of mango bark extract (83). Oral supplementation with VIMANG, or its main polyphenol mangiferin, markedly reduces ROS generation in isolated LDL receptor (−/−) liver mitochondria and spleen lymphocytes (84). In addition, treatment prevents mitochondrial nicotinamide-adenine dinucleotide phosphate hydrate (NADPH)-linked substrate depletion and NADPH spontaneous oxidation, making them suitable antioxidants with potential use in atherosclerosis susceptible conditions (84).

Guo et al (85) discovered that mangiferin (50 and 150 mg/kg) ameliorates hypertriglyceridemia by modulating the expression of genes involved in lipid oxidation and lipogenesis. Body weight, liver weight, visceral fat-pad weight, serum TG, FFA concentration, hepatic TG levels, hepatic FFA and muscle FFA contents are immensely decreased following mangiferin treatment (85). It was observed that mangiferin upregulates the mRNA levels of peroxisome proliferator-activated receptor-α, fatty acid translocase (CD36) and carnitine palmitoyl transferase 1 (CPT-1) (86). Wistar rats were fed a high-fat diet and administered mangiferin (50, 100, 150 mg/kg) simultaneously for 6 weeks, which confirmed that mangiferin improves FFA metabolism in a dose-dependent manner through promoting FFA uptake and oxidation (86). Similarly, it was also observed in Wistar rats and HepG2 cells that levels of intracellular FFA and TG accumulation was decreased in HepG2 cells. Furthermore, the AMPK pathway is associated with this therapeutic effect of mangiferin (86). Mangiferin increases the AMP/ATP ratio upstream of AMPK, decreases acyl-CoA:diacyl gycerol acyltransferase 2 (DGAT2) expression, decreases acetyl-CoA carboxylase (ACC) activity. Furthermore, mangiferin promotes AMPK phosphorylation, and upregulates the expression of CD36 and CPT-1 (86). Based on the preliminary results of cell and animal experiments, Na et al (87) conducted a 12-week double-blind randomized clinical trial to evaluate the effects of mangiferin (150 mg/day) on blood lipid profiles in overweight patients with hyperlipidemia. Mangiferin supplementation substantially increases the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate and acetoacetate, and increases lipoprotein lipase activity. However, mangiferin did not effectively decrease serum levels of total cholesterol, low-density lipoprotein cholesterol, serum glucose or insulin (87).

Apontes et al (88) administered mangiferin (400 mg/kg) and a high fat diet (HFD) to C57BL6/J mice for 16 weeks, demonstrating that mangiferin protects against HFD-induced weight gain, promotes aerobic mitochondrial capacity and increases thermogenesis. In addition, treatment with mangiferin in overweight patients with hyperlipidemia stimulated carbohydrate oxidation and improved glucose and insulin profiles (88). The activity of mangiferin on lipogenesis regulation was further studied by proteomic analysis, in which C57BL6/J mice were fed mixed granules containing mangiferin and HFD for 18 weeks. It was demonstrated that out of 865 quantified proteins, 87 of them are differentially regulated by mangiferin. Of these proteins, ~50% are involved in energy metabolism and metabolite biosynthesis. Further classification indicated that mangiferin increases the expression of proteins that are crucial for mitochondrial biogenesis and oxidative activity, including oxoglutarate dehydrogenase E1 and cytochrome c oxidase subunit 6B1. In addition, mangiferin decreases the expression of proteins that are critical for lipogenesis, including fatty acid stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase 1 (89). Taken together, these data suggest that mangiferin may be used in the treatment of metabolic disorders, by improving the protein expression profiles in mitochondrial synthesis and lipogenesis.

Mangiferin is used to prepare medicinal and food supplements as a bioactive compound, where it may exert protective effects against neurodegenerative disease, cancer, obesity, cardiovascular disease and diabetes. However, mangiferin is also associated with other miscellaneous properties.

Mangiferin has been demonstrated to possess several beneficial properties, including antioxidant, antimicrobial, antidiabetic, antiallergic, neuroprotective, cardiovascular protective, anticancer, hypocholesterolemic and immunomodulatory effects. Although it has been regarded as a compound with extensive pharmacological activity, the pharmacodynamics of mangiferin remain unclear. Mangiferin appears to have diverse pharmacological effects. However, further clinical research into the pharmacology and pharmacokinetics of mangiferin is required, as most of these effects have only been demonstrated in in vivo and in vitro experiments. The administration of mangiferin to animals or humans will inevitably result in alterations in the body, at the molecular, cellular, tissue and/or organs level, along with its curative effects. Therefore, genomic, proteomic and metabolomic analysis should be the main strategies utilized in order to determine the pharmacodynamics of mangiferin.

The research and development of mangiferin is expected to provide novel drugs for disease treatment. However, among the numerous studies on the pharmacology of mangiferin, researchers did not use a standardized therapeutic approach. Specifically, the pharmacodynamic indexes of mangiferin in existing researches, including dose, concentration and IC50, were not compared and analyzed at the same base line; therefore, the experimental results are not universal. Thus, the unified and standardized evaluation of the efficacy of mangiferin is a central component in the further exploration of pharmacodynamics and quality assurance. Furthermore, in the clinical research of mangiferin, researchers should focus on pharmacodynamic parameters caused by its physicochemical properties, including bioavailability, half-life, adverse reactions and toxicity. In addition, further clinical trials should be implemented to allow the broad application of this effective bioactive compound.