Mangiferin: An effective therapeutic agent against several disorders (Review)

Abstract

Mangiferin (1,3,6,7‑tetrahydroxyxanthone‑C2‑β‑D‑glucoside) is a bioactive ingredient predominantly isolated from the mango tree, with potent antioxidant activity and multifactorial pharmacological effects, including antidiabetic, antitumor, lipometabolism regulating, cardioprotective, anti‑hyperuricemic, neuroprotective, antioxidant, anti‑inflammatory, antipyretic, analgesic, antibacterial, antiviral and immunomodulatory effects. Therefore, it possesses several health‑endorsing properties and is a promising candidate for further research and development. However, low solubility, mucosal permeability and bioavailability restrict the development of mangiferin as a clinical therapeutic, and chemical and physical modification is required to expand its application. This review comprehensively analyzed and collectively summarized the primary pharmacological actions of mangiferin that have been demonstrated in the literature, to support the potential future development of mangiferin as a novel therapeutic drug.

Full text

MOLECULAR MEDICINE REPORTS 18: 4775-4786, 2018
Abstract. Mangiferin (1,3,6,7-tetrahydroxyxanthone-C2-β-D-
glucoside) is a bioactive ingredient predominantly isolated from
the mango tree, with potent antioxidant activity and multifactorial
pharmacological effects, including antidiabetic, antitumor,
lipometabolism regulating, cardioprotective, anti-hyperuricemic,
neuroprotective, antioxidant, anti-inflammatory, antipyretic,
analgesic, antibacterial, antiviral and immunomodulatory effects.
Therefore, it possesses several health-endorsing properties and
is a promising candidate for further research and development.
However, low solubility, mucosal permeability and bioavailability
restrict the development of mangiferin as a clinical therapeutic,
and chemical and physical modication is required to expand
its application. This review comprehensively analyzed and
collectively summarized the primary pharmacological actions
of mangiferin that have been demonstrated in the literature, to
support the potential future development of mangiferin as a
novel therapeutic drug.
Contents
1. Introduction
2. Potential application of mangiferin in antidiabetic therapy
3. Anti-tumor effects of mangiferin
4. The neuroprotective properties of mangiferin
5. Cardiovascular effects of mangiferin
6. Other properties of mangiferin
7. Conclusions
1. Introduction
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 phar-
macological mechanisms have been revealed, which provides
further information for the design and development of mangif-
erin as a clinical therapeutic. However, Wang et al (6) reported
that the solubility of mangiferin was only 0.111 mg/ml. In addi-
tion, Han et al (7) demonstrated that the oral bioavailability of
mangiferin was only 1.2%. This may be due to its low lipophi-
licity 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, mangif-
erin may be identied to represent a more promising, novel
therapeutic drug in clinic.
Based on previous studies concerning the structural modi-
cation, pharmacological activities and therapeutic molecular
Mangiferin: An effective therapeutic agent
against several disorders (Review)
SUYA DU1*, HUIRONG LIU2*, TIANTIAN LEI3*, XIAOFANG XIE3*,
HAILIAN WANG2, XIA HE4, RONGSHENG TONG4 and YI WANG4
1Department of Pharmacy, Chengdu Military General Hospital, Chengdu, Sichuan 610083;
2Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital,
Chengdu, Sichuan 610072; 3School of Medicine, University of Electronic Science and Technology of China,
Chengdu, Sichuan 610054; 4Personalized Drug Therapy Laboratory of Sichuan Province, Department of Pharmacy,
Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
Received February 9, 2018; Accepted August 20, 2018
DOI: 10.3892/m m r.2 018.952 9
Correspondence to: Dr Yi Wang or Dr Rongsheng Tong,
Personalized Drug Therapy Laboratory of Sichuan Province,
Department of Pharmacy, Sichuan Academy of Medical Science
and Sichuan Provincial People's Hospital, 32 West First Ring Road,
Chengdu, Sichuan 610072, P.R. China
E-mail: w_yi@yahoo.com
E-mail: tongrs@126.com
*Contributed equally
Key word s: mangiferin, pharmacological activities, bioactive
compound, structural modification

DU et al: MANGIFERIN: AN EFF ECTIVE TH ERAPEUTIC AGENT AGAINST SEVERAL DISORDERS
4776
mechanisms of mangiferin in recent decades, the pharmaco-
logical effects of mangiferin were reviewed herein, in order to
provide references for further drug research and development.
2. Potential application of mangiferin in antidiabetic
therapy
Prevalence and main features of diabetes mellitus. Diabetes
mellitus is a common endocrine and metabolic disease that
affects public health and quality of life (10,11). Statistics
from the International Diabetes Federation Diabetes
Atlas (http://www.diabetesatlas.org/resources/2017-atlas.
html) revealed that there were an estimated 425 million adult
patients with type 2 diabetes (T2D) in 2017, of whom 212
million were not diagnosed (12). Notably, China has the largest
number of adult diabetic patients. The prevalence of diabetes
and prediabetes in China is 11.6 and 50.1%, respectively,
accounting for 113.9 million patients with diabetes and 493.4
million individuals with prediabetes, according to China's
non-communicable disease surveillance group in 2013 (13).
These data indicate that diabetes has become a major public
health problem worldwide.
The main feature of diabetes is hyperglycemia, which is
caused by disrupted glucose homeostasis (14,15). β‑cell de-
ciency in the pancreas results in insufcient insulin secretion
and type 1 diabetes, whereas insulin resistance may lead to
decreased insulin sensitivity in T2D. Glucose homeostasis
requires coordinated regulation of the pancreas and insulin
target organs, such as adipose tissue, muscle, the liver and the
brain (15). In the pancreas, α cells secrete glucagon and β cells
secrete insulin, which respond to blood glucose alterations.
High glucose stimulates insulin secretion, which increases
glucose uptake, use and storage in adipose and muscle tissue.
Low glucose stimulates glucagon release, which promotes
hepatic glucose production in the liver to increase the blood
glucose levels (16). Fat cells release adipokines, including
leptin, adiponectin and cytokines, as well as free fatty acids
(FFA) to regulate food intake, insulin secretion and insulin
sensitivity (17). The interaction between various organs or
tissues associated with blood glucose regulation is essential.
Disordered regulation of this system may lead to the occur-
rence of diabetes (18). Patients with type 1 and T2D may have
progressive complications, including heart disease, stroke,
blindness, diabetic nephropathy and kidney failure (19-22), if
the disease is not effectively controlled. Therefore, it is neces-
sary prevent and treat diabetes in the early stage.
Effect of mangiferin on diabetes and diabetic complications.
Although drugs with multiple pharmacological mechanisms
are the most effective regimens to alleviate the effects of type
2 diabetes, they cannot completely prevent disease progres-
sion (23,24). Therefore, novel and effective drugs are urgently
needed. It was recently reported that mangiferin treatment
was beneficial in streptozotocin (STZ)-induced diabetic
mice. Biochemical, toxicological and hematological param-
eters were evaluated following oral treatment with 40 mg/kg
mangiferin for 30 days. Compared with diabetic control mice,
the levels of blood glucose, glycosylated hemoglobin, aspar-
tate aminotransferase (AST), alanine aminotransferase (ALT)
and alkaline phosphatase (ALP) were signicantly reduced in
mangiferin-tre ated diabetic mice. Furthermore, the levels of red
and white blood cells were notably improved (25,26). Therefore,
mangiferin was demonstrated to possess anti‑diabetic ef-
cacy without toxicity in chemically induced diabetic mice
(Fig. 2A). Additionally, in a high-fat high fructose diet and
STZ-induced diabetic insulin-resistant rat model, mangiferin
was demonstrated to concurrently alleviate insulin resistance,
improve β-cell function, reduce serum levels of triglyceride
(TG), total cholesterol (TC) and low-density lipoprotein
cholesterol (LDL-C), as well decrease the atherogenic index,
liver TG and liver TC content. Liver glycogen content was also
enhanced (27). These results validated that mangiferin may
effectively improve insulin sensitivity in the treatment of type
2 diabetes accompanied with metabolic disorders (Fig. 2B).
Similarly, Muruganandan et al (28), Miura et al (29,30) and
Suman et al (31) veried that mangiferin exerted signicant
antidiabetic, antihyperlipidemic and antiatherogenic effects
in diabetic rat models. As for the promotion of islet function
induced by mangiferin, our previous study performed 70%
partial pancreatectomy (PPx) in mice to elucidate the anti-
diabetic mechanisms of mangiferin. The results indicated that
mangiferin facilitates β-cell proliferation and islet regenera-
tion through the regulation of crucial genes in cell cycle and
islet regeneration (Fig. 2C) (32). Furthermore, our upcoming
report successfully conrmed that mangiferin increases islet
regeneration in young and old diabetic mice (unpublished
data). Taken together, these data provide evidence that mangif-
erin has promising application prospects in the treatment of
diabetes.
As one of the most common and serious diabetic compli-
cations, diabetic nephropathy (DN) is a renal impairment
caused by diabetes-induced microangiopathy and glomeru-
losclerosis. Hypertension, proteinuria and hydropsy are the
clinical manifestations of DN (33). Surprisingly, Pal et al (34)
demonstrated that mangiferin could protect kidneys from DN.
They investigated the specific mechanisms underlying the
protective effects of mangiferin in a STZ-induced diabetic
nephropathy rat model and observed that mangiferin markedly
decreased plasma glucose, kidney to body weight ratio, blood
urea nitrogen (BUN), plasma creatinine, uric acid and urinary
albumin. Additionally, glomerular hypertrophy and hydropsy
was attenuated following mangiferin treatment at an oral
dose of 40 mg/kg body weight/day in water for 30 days (34).
Similarly, in animal experiments performed by Liu et al (35)
in an STZ-induced DN rat model, evidential decreases in
albuminuria, BUN, kidney weight index, periodic acid-Schiff
stain positive mesangial matrix area, glomerular extracellular
matrix expansion and accumulation and glomerular basement
membrane thickness were observed following oral mangiferin
treatment (15, 30 and 60 mg/kg) for 9 weeks, via targeting of
glyoxalase 1. These results validate the benecial actions of
mangiferin in DN, although body weight and blood glucose
levels were not improved (35). Furthermore, mangiferin (15,
30 and 60 mg/kg/day for 9 weeks) effectively attenuated renal
brosis through the inhibition of osteopontin overproduction
and inammation in a STZ‑induced rat diabetic model (36).
Cardiovascular events may also occur in patients with
T2DM, including stroke, myocardial infarction and endo-
thelial dysfunction, which are major physical and economic
burdens (37-39). Hyperglycemia-induced oxidative stress and

MOLECULAR MEDICINE REPORTS 18: 4775-4786, 2018 4777
inammation are thought to be involved in the development of
cardiovascular disease. The activation of advanced glycation
end products-receptor for advanced glycation end products
(AGE‑RAGE) results in increased oxidative stress, inam-
mation and apoptosis in ischemia-reperfusion (IR)-induced
myocardial injury in diabetic rats (40). Notably, mangiferin
inhibits activation of the AGE-RAGE/mitogen-activated
protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and
p38 pathways (41). The expression of extracellular regulated
kinase 1/2 (ERK1/2) in the myocardium is also increased (41).
In addition, chronic treatment with mangiferin (20 mg/kg for
16 weeks) decreased the level of myocardial enzymes creatine
kinase-MB and lactate dehydrogenase (LDH), as well as the
inammatory mediators tumor necrosis factor (TNF)‑α and
interleukin (IL)-1β in the serum and left ventricular myocar-
dium (41). In diabetic cardiomyopathy (DCM) rats, mangiferin
reduces AGE production, and decreases the mRNA and protein
expression of RAGE (42), suggesting that mangiferin treatment
may be benecial in DCM. A previous study determined the
effect of mangiferin on myocardial IR injury in diabetic rats
and further investigated the underlying mechanisms involved
in its cardioprotective effects. In a diabetic rat model induced
by STZ, mangiferin (60 mg/kg; oral gavage for 12 weeks)
reduces blood glucose and cardiomyocyte apoptosis, downreg-
ulates inositol‑requiring enzyme 1, apoptotic signal‑regulating
kinase and JNK (43). This suggests that mangiferin inhibits the
apoptosis of myocardial cells in diabetic rats via mechanisms
associated with blood glucose regulation and endoplasmic
reticulum (ER) stress prevention. Endothelial dysfunction,
under conditions of ER stress and increased reactive oxygen
species (ROS) production, is tightly associated with cardio-
vascular complications in diabetes (44). The expression of
thioredoxin-interacting protein (TXNIP), NLR family pyrin
domain containing 3 (NLRP3), IL-1β and IL-6, as well as the
phosphorylation of AMP-activated protein kinase (AMPK),
was attenuated in endothelial cells cultured with mangiferin at
concentrations of 0.1, 1 and 10 µM, demonstrating its inhibi-
tory effects on TXNIP/NLRP3 inammasome activation and
it ameliorative effects on endothelial dysfunction (45).
3. Anti‑tumor effects of mangiferin
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 onco-
therapy. Mangiferin efcaciously 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). Not ably,
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 inhibi-
tory 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 activa-
tion 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 tumorigen-
esis (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 nasopharyn-
geal carcinoma cells. Additionally, a study of the antitumor
efcacy 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). I n
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
xenograft 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
Figure 1. Chemical structu re of mangiferin.

DU et al: MANGIFERIN: AN EFF ECTIVE TH ERAPEUTIC AGENT AGAINST SEVERAL DISORDERS
4778
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).
4. The neuroprotective properties of mangiferin
Abundant research on the effects of mangiferin has revealed
the antioxidant and anti‑inammatory 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 reac-
tive molecules that are implicated in the pathology of traumatic
brain injury and cerebral ischemia through oxidative stress and
inammation (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 inam-
mation 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, proinamma-
tory 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 decits caused by neuro-
inammation (70). Oral mangiferin pre-treatment (50 mg/kg)
and treatment (50 mg/kg) following LPS injection in mice
demonstrated that mangiferin ameliorates cognitive decits
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 mangif-
erin 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
Figure 2. Overview of the functions of mangiferin in diabetes mellitus. (A) A signicant reduction of biochemical and toxicological parameters, as well as a
marked improvement in hematological parameters were simultaneously observed in diabetic rats. (B) Mangiferin notably increased insulin sensitivity and β
cell function, and improved parameters associated with metabolic disorders. (C) Mangiferin regulated the expression of genes involved in cell cycle regulation
and islet regeneration to improve islet function. AST, aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; TG, triglyceride; TC, total
cholesterol; LDL-C, low density lipoprotein cholesterol; Cdk4, cyclin-dependent kinase 4; PDX-1, pancreatic and duodenal homeobox 1; Ngn3, neurogenin 3;
GLUT-2, glucose transporter 2; Foxo-1, forkhead box protein O1; GCK, glucokinase.
Figure 3. Schematic of the molecular mechanisms underlying the antitumor
effects of mangiferin. NF-κB, nuclear factor-κB.

MOLECULAR MEDICINE REPORTS 18: 4775-4786, 2018 477 9
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 -P GF 2α) production (72). Ta ken
together, these data demonstrated mangiferin exhibits potent
antioxidant and anti‑inammatory properties, by decreasing
PGE-2 production, free radical formation and COX-2 synthesis.
The underlying mechanisms of neuroinammation 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 cere-
brum, 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 dysregula-
tion, neuroinammation and oxidative damage. Pretreatment
with mangiferin inhibits an increase in the levels of glucocorti-
coids (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 decits 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 inammasome
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 mangif-
erin (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).
5. Cardiovascular effects of mangiferin
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 pretreat-
ment with mangiferin (100 mg/kg) for 28 days regulates the
tissues defense system against cardiac damage. Specically,
the activities of heart tissue enzymic antioxidants, including
superoxide dismutase, catalase, glutathione peroxidase,
Figure 4. Overview of the neuroprotective activities of mangiferin against LPS-, stress-, SAH- and CIRI-induced models. Mangiferin has been demonstrated
to exert protective effects against cognitive decits, depression, anxiety, neuroinammation, oxidative damage, neurological decits and brain edema. LPS,
lipopolysaccharide; SAH, subarachnoid hemorrhage; CIRI, cerebral ischemia reperfusion injury; IL, interleuki n; HO-1, heme oxygenase-1; SOD, superoxide
dismutase; PGE-2, prostaglandin E2; 8-iso-PGF 2α, 8-iso-prostaglandin F2α; GCs, glucocorticoids; TNF-α, tumor necrosis factor-α; iNOS, inducible nitr ic
oxide synthase; NF-κB, nuclear factor-κB; COX-2, cyclooxygenase-2; HPA, hypothalamic-pituitary-adrenal axis; Nrf2, nuclea r factor erythroid 2-related
factor 2; NLRP3, NLR family pyrin doma in containing 3; GSH, glutathione.

DU et al: MANGIFERIN: AN EFF ECTIVE TH ERAPEUTIC AGENT AGAINST SEVERAL DISORDERS
4780
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 benecial 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 activi-
ties 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 metab-
olism (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 lyso-
somal 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 injec-
tion 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 accu-
mulation 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 expres-
sion 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 brosis
induced by MI. Therefore, mangiferin may be used in combi-
nation with clinical treatments in the future, including with
surgery or other therapeutics (Fig. 5A).
Mangiferin in atherosclerosis an d hyperlipemia. Hyperlipidemia
and elevated FFAs are risk factors for atherosclerosis, hyperli-
pemia 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 intra-
cellular reactive ROS production. Mangiferin is a polyphenol
compound extracted from mango leaves and is the main
active ingredient of food supplement of the ood supplement
VIMANG, which is widely popular in Cuba (83). VI MANG
is extracted from the bark of Mangiferaindica and is typi-
cally 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 concentra-
tion, 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 translo-
case (CD36) and carnitine palmitoyl transferase 1 (CPT-1) (86).
Wistar rats were fed a high-fat diet and administered mangif-
erin (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 accumula-
tion was decreased in HepG2 cells. Furthermore, the AMPK
pathway is associated with this therapeutic effect of mangif-
erin (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 phosphory-
lation, 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 proles in overweight patients with hyperlipid-
emia. Mangiferin supplementation substantially increases the
serum levels of mangiferin, high-density lipoprotein cholesterol,
L-ca rniti ne, β-hydroxybutyrate and acetoacetate, and increases
lipoprotein lipase activity. However, mangiferin did not effec-
tively 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 mangif-
erin in overweight patients with hyperlipidemia stimulated
carbohydrate oxidation and improved glucose and insulin
proles (88). The activity of mangiferin on lipogenesis regu-
lation was further studied by proteomic analysis, in which
C57BL6/J mice were fed mixed granules containing mangif-
erin and HFD for 18 weeks. It was demonstrated that out of
865 quantied proteins, 87 of them are differentially regulated
by mangiferin. Of these proteins, ~50% are involved in energy
metabolism and metabolite biosynthesis. Further classica-
tion 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, mangif-
erin 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 meta-
bolic disorders, by improving the protein expression proles in
mitochondrial synthesis and lipogenesis.

MOLECULAR MEDICINE REPORTS 18: 4775-4786, 2018 47 81
Mangiferin in vein endothelium. The abnormal structure and
function of vascular endothelial cells are the pathological basis
of many cardiovascular diseases, and vascular endothelial
cells are vulnerable to a series of harmful factors (90). Under
the stimulation of high blood pressure, oxidative stress and
high levels of blood glucose/lipids, vascular endothelial cells
synthesize and release vasodilator factors and vasoconstrictor
factors, which have important roles in vascular homeostasis,
thrombosis and inflammation (91). In recent decades, the
protective effects of mangiferin on human umbilical vein
Figure 5. Potential effects of mangiferin in ca rdiovascular disease. (A) Mangiferin exhibited ma rked cardioprotective effects in ISPH-induced myocardia l
infarction rat models. (B) Mangifer in alleviated lipometabolic abnormalities in the cardiovascular system. (C) Mangiferin protected vascula r endothelium
function. SOD, TNF-α, Bcl-2, PPAR-α, peroxisome proliferator-activated receptor-α; CPT-1, carnitine palmitoyltransferase 1; DGAT2, diacylglycerol
O-acyltransferase 2; ACC, acetyl-CoA carboxylase; TG, triglyceride; FFA, free fatt y acid; Dhtkd1, dehydrogenase E1 and transketolase domain containing
1; Cox6b1, cytochrome C oxidase subunit 6B1; Acac1, acetyl-CoA carboxylase 1; Scd1, stearoyl-CoA desaturase 1; FRAP, ferric reducing ability of plasma;
LPO, lipid peroxidation.

DU et al: MANGIFERIN: AN EFF ECTIVE TH ERAPEUTIC AGENT AGAINST SEVERAL DISORDERS
4782
endothelial cells (HUVECs) have been extensively demon-
strated (Fig. 5C). It has been demonstrated that mangiferin
(20 µΜ) decreases high cellular permeability and endothelial
injury induced by paraquat intoxication in HUVECs, through
modulation of p120-catenin protein (92). In addition, cell
survival increases in H2O2-treated HUVECs when mangiferin
(10 and 20 µΜ) is administered, through its free‑radical scav-
enging ability. A ferric reducing ability of plasma assay also
demonstrated it antioxidant capacity (93). Similarly, incubation
of HUVECs with glycated protein alone, or in combination
with iron chelate, resulted in increased lipid peroxidation
(LPO), accompanied by depletion of SOD, catalase, gluta-
thione peroxidase and glutathione reductase levels. These data
suggest that mangiferin (5 and 10 µM) has a protective effect
against glycated protein-iron chelate-induced toxicity (94),
which provides a promising perspective for the prevention of
oxidative stress and toxicant-associated disease.
6. Other properties of mangiferin
Mangiferin is used to prepare medicinal and food supplements
as a bioactive compound, where it may exert protective effects
against neurodegenerative disease, cancer, obesity, cardio-
vascular disease and diabetes. However, mangiferin is also
associated with other miscellaneous properties.
Mangiferin in respiratory system. Mangiferin exerts protec-
tive effects against bronchial asthma and other allergic
diseases. Research has demonstrated that mangiferin inhibits
tracheal contractions induced by distinct stimuli, including
allergens, histamine, 5-hydroxytryptamine and carbachol, in
a dose-dependent manner (95). The antispasmodic effect of
mangiferin on allergic and non-allergic tracheal contraction
of guinea pig tracheal rings are a result of increased intracel-
lular levels of nitric oxide synthase 3 and cyclic GMP (95). In
addition, in an allergic murine experimental model, mice were
orally treated with M. indica extract (50, 100 or 250 mg/kg) or
mangiferin (50 mg/kg) from day 0 to 24. The results revealed
that mangiferin produces a remarkable reduction in airway
inammation around vessels and bronchi, decreases immu-
noglobulin (Ig)E levels and lymphocyte proliferation. In
addition, it was demonstrated that mangiferin inhibits IL-4
and IL‑5 cytokine production in bronchoalveolar lavage uid
and lymphocyte culture supernatant (96). These experiments
may be an important part of pre-clinical research that is
necessary for the application of mangiferin in the treatment of
respiratory diseases (Fig. 6A).
Mangiferin in liver and gallbladder disorders. Live r
disease has become a major burden of human health (97).
Gentiopicroside and mangiferin are regarded as two impor-
tant medicinal monomers of Swertia mussotii, a herb used in
Tibetan folk medicine. These may exert hepatoprotective and
choleretic effects (Fig. 6B) (98,99).
Pal et al (100) investigated the molecular mechanisms under-
lying the protective action of mangiferin against lead-induced
liver injury and cellular apoptosis (100). It was revealed that
mangiferin (100 mg/kg, orally for 6 days) inhibits ROS produc-
tion and reduces the levels of serum marker enzymes, such as
ALT and ALP. Overall, it was demonstrated that mangiferin
exhibits both antioxidative and antiapoptotic properties via
MAPK /NF-κB/mitochondria-dependent pathways (100).
Figure 6. Overview of the various actions of mangiferin on (A) respiratory diseases, (B) liver and gallbladder disorders, (C) immunological abnormalities
and (D) pathogenic microorganisms. 5-HT, 5-hydroxytryptamine; IL, interleukin; NOS 3, nitric oxide synthase 3; cGMP, cyclic guanosine monophosphate;
MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; ROS, reactive oxygen species; ALT, alanine a minotransferase; ALP, alkaline phospha-
tas e; TNF-β, tumor necrosis factor-β; Nrf2, nuclear factor, erythroid like 2; HO-1, heme oxygenase-1; DGAT-2, diacylglycerol O-acyltransferase 2; HSV,
herpes simplex virus; CPK, creatine phosphokinase; HA, humora l antibody; DT H, delayed-type hypersensitivity; Ig, immunoglobulin.

MOLECULAR MEDICINE REPORTS 18: 4775-4786, 2018 478 3
Compared with silymarin, a standard hepatoprotective drug,
the intraperitoneal pretreatment of mangiferin (30 mg/kg)
possesses an extensive protective effect via reduction of serum
aspartate and alanine aminotransferases, alkaline phospha-
tase, bilirubin and inammatory mediator TNF‑β (101). These
results suggest that mangiferin exhibits potent hepatoprotec-
tive effects on CCl-4-induced liver damages in mice (101).
In addition, in LPS and D-galactosamine (D-GalN)-induced
acute liver injury, mangiferin upregulates the expression of
Nrf2 and HO-1 in a dose-dependent manner. Furthermore,
mangiferin markedly inhibits LPS/D-GalN-induced
inflammatory factors, including IL-1β, TNF-α, N L R P3,
apoptosis-associated speck-like protein containing a CARD
and caspase-1 (102). Mangiferin treatment ameliorates fatty
liver in fructose-fed spontaneously hypertensive rats (SHR)
by inhibiting hepatic DGAT2, which catalyzes the nal step
of triglyceride biosynthesis (103). Mangiferin may enhance
de novo fatty acid synthesis and oxidation in the treatment of
fatty liver. Furthermore, the experiment of bile duct drainage
in rats also demonstrated that mangiferin (20 mg/kg) mark-
edly increases bile secretion and bilirubin content. In addition,
gallbladder smooth muscle spasms are inhibited at a dose of
10 mg/kg (104).
Mangiferin and the immune system. The role of mangiferin in
the immune system has gained increasing attention (Fig. 6C).
Mangiferaindica (extract contai ning 2.6% mangiferin) has been
investigated for its immunoprotective effects, via increasing
the frequency of delayed type hypersensitivity (DTH) reactions
and the humoral antibody (HA) titer in mice (105). Similarly,
mangiferin stimulates the immune systems and increases the
resistance of Labeo rohita to Aeromonas hydrophila infection,
by promoting superoxide anion, serum protein obtained from
Labeo rohita and albumin production, as well as lysozyme
and serum bactericidal activity (106). In order to compare the
immunoprotective effects of mangiferin (the major polyphenol
of Vimang) and VIMANG (an aqueous extract of Mangifera
indica) on mouse antibody responses induced by inoculation
with spores of microsporidian parasites, it was suggested
that the components of Mangifera indica extracts may be
of potential value for modulating the humoral response in
different immunopathological disorders (107). Howeve r,
VIMANG contains other extracts in addition to mangiferin
polyphenol; therefore, the researchers may have neglected to
take into account the inhibitory effects of other compounds
isolated from VIMANG on the humoral response (107). In
addition, mangiferin markedly suppresses tissue injury and
immunotoxicity caused by cyclophosphamide treatment,
through decreasing serum CPK activity and antigen‑specic
IgM levels (108). Thus, it was evident that mangiferin exerts
an immunoprotective role via inhibition of reactive interme-
diate-induced oxidative stress in lymphocytes, neutrophils and
macrophages (108). These data suggest that mangiferin has the
potential to reduce the immunotoxicity of cyclophosphamide
in oncotherapy.
The antimicrobial and antiviral effects of mangiferin.
Anemarrhena asphodeloides, a plant widely used in tradi-
tional Chinese medicine, has been reported to possess antiviral
and antibacterial activities (109). Mangiferin is the main
effective component of Anemarrhena asphodeloides (109).
In addition to its antioxidative, antidiabetic and antitumor
properties, the antibacterial and antiviral effects of mangiferin
are also prominent (110). Mangiferin has been demonstrated
to exert antibacterial activity against two bacterial species:
Staphylococcus aureus (Gram positive) and Salmonella typhi
(Gram negative) (111). Through tissue culture techniques, the
antiviral effects of mangiferin and isomangiferin on herpes
simplex virus-1 (HSV-1) were demonstrated, with average
plaque reduction rates of 56.8 and 69.5%, respectively (112).
The EC50 of mangiferin against herpes simplex virus-2
(HSV‑2) plaque formation in HeLa cells was 111.7 mg,
and the therapeutic index (IC50/EC50) was 8.1 (113). Ora l
mangiferin (50 mg/kg) suppresses the growth of nematode
Trichinella spiralis throughout the parasitic life cycle, by
inhibiting mast cell degranulation, decreasing the serum levels
of specic anti‑Trichinella IgE and reducing the number of
parasitic larvae (114). These studies conrm the antibacterial
effects of isolated mangiferin, which may further processed as
an antibacterial agent (Fig. 6D).
The main barrier for xenobiotic absorption through the
skin is the stratum corneum. Research has revealed the ability
of mangiferin to reversibly inhibit elastase and collagenase
activity, as well as to permeate the stratum corneum and pass
into the epidermis and dermis (115). As the fat and water
distribution coefcient of mangiferin is relatively high, oral
absorption is low (9), which suggests that mangiferin may be
better absorbed through the skin.
7. Conclusions
Mangiferin has been demonstrated to possess several benecial
properties, including antioxidant, antimicrobial, antidiabetic,
antiallergic, neuroprotective, cardiovascular protective, anti-
cancer, hypocholesterolemic and immunomodulatory effects.
Although it has been regarded as a compound with extensive
pharmacological activity, the pharmacodynamics of mangif-
erin 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 demon-
strated 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 pharmaco-
dynamics 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

DU et al: MANGIFERIN: AN EFF ECTIVE TH ERAPEUTIC AGENT AGAINST SEVERAL DISORDERS
4784
pharmacodynamic parameters caused by its physicochemical
properties, including bioavailability, half-life, adverse reac-
tions and toxicity. In addition, further clinical trials should be
implemented to allow the broad application of this effective
bioactive compound.
Acknowledgements
Not applicable.
Funding
This review was supported by the National Science Foundation
of China (grant no. 81802504), the Sichuan National Science
Research Funding (grant no. 2018JY0645) and Sichuan
Health and Family Planning Commission Funding (grant
no. 16ZD0253), and Dr. Yi Wang received funding from the
Sichuan Provincial People's Hospital and a Sichuan Scientic
Research Grant for Returned Overseas Chinese Scholars
(grant no. 30305031014). The study was also supported by
the National Key Specialty Construction Project of Clinical
Pharmacy (grant no. 30305030698).
Availability of data and materials
Not applicable.
Authors' contributions
SD and HL wrote the manuscript. TL prepared the gures.
XX, HW and XH searched for the relevant literature. RT and
YW reviewed and edited the manuscript. All authors have read
and approved the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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