This review article delves into the multifaceted properties of mangiferin, including its antioxidant, antimicrobial, antidiabetic, antiallergic, anticancer, hypocholesterolemic, and immunomodulatory effects. Mangiferin’s ability to protect against various human cancers, enhance immune function, and combat oxidative stress makes it a promising candidate for health promotion.
Moreover, this article explores mangiferin’s synthesis, metabolism, pharmacokinetic properties, and its role in preventing and managing chronic diseases, with a focus on its anticancer potential.
Keywords: Bioactive molecules, Human cancers, Mangiferin, Nutrition, Health claims, Toxicity
Background
Mangiferin, a xanthone compound, is abundantly present in higher plants and various parts of mangoes, including the peel, stalks, leaves, barks, kernel, and stone. It exhibits a wide range of health-promoting properties, including antioxidant, antimicrobial, antidiabetic, antiallergic, anticancer, hypocholesterolemic, and immunomodulatory effects [1].
Additionally, other compounds like isomangiferin and homomangiferin are found in different parts of mango trees, contributing to their antioxidant potential [2, 3]. The chemical structure of mangiferin is depicted in Fig. 1.
Mangiferin’s antioxidant activity is attributed to its iron-chelating ability, which prevents the generation of harmful hydroxyl radicals in Fenton-type reactions [4]. It protects against oxidative damage and lipid peroxidation, making it a valuable defense against physiological threats [5].
Mangiferin Synthesis and Metabolism
The synthesis of mangiferin involves the Friedel-Crafts reaction, connecting the glycosyl donor with an electron-rich aromatic compound through glycosidic linkages [9]. Since mangiferin lacks a functional C-9 carbonyl group, aryl C-glycosylation is essential due to electron deficiency [10, 11]. This process includes the hydrolysis of aglycone 1,3,6,7-tetrahydroxyxanthone with R-acetobromoglucose, forming O-glycosidic bonds [12].
Interestingly, C-glucosides, including mangiferin, interact with intestinal microflora, undergoing metabolism and transformation into corresponding aglycones [28]. The glycosyl substituent provides antioxidant advantages due to its structure and position, enhancing bioavailability [17].
Pharmacokinetic Role
Mangiferin’s poor lipophilicity and hydrophilicity present challenges for its absorption and bioavailability. Studies have explored ways to enhance its solubility and intestinal permeability. Complexing mangiferin with phospholipids has shown promising results, improving solubility, partition coefficient, and ultimately, bioavailability [30]. Administering mangiferin-soya phospholipid complexes has been associated with increased hepatoprotective activity in rats treated with carbon tetrachloride, further boosting mangiferin’s bioavailability [31].
Research has demonstrated mangiferin’s ability to traverse the blood-ocular barrier, making it potentially effective in treating various eye diseases [32]. Furthermore, quantification studies have revealed the presence of mangiferin in plasma and urine, shedding light on its metabolic fate [33]. It was found that mangiferin can be detected in feces and urine, suggesting its elimination from the body [34]. High-speed countercurrent chromatography has enabled the quantification of mangiferin from various plant sources, emphasizing its diverse presence in nature [35].
Health Perspectives
Anticancer Properties
Mangiferin’s potential as an anticancer agent is a topic of significant interest. It has demonstrated preventive and therapeutic effects against various types of cancer. Notably, mangiferin has shown antileukemic and preventive effects in HL-60 leukemia cells. It induces cell cycle arrest in the G2/M phase, inhibiting ATR, Chk1, Akt, and Erk1/2 phosphorylation [37]. Additionally, mangiferin targets numerous factors involved in cancer development, including transcription factors, growth factors, cell-cycle proteins, cytokines, and inflammatory enzymes [38].
In breast cancer, mangiferin plays a role in regulating estrogen receptors ERα and ERβ, making it a potential candidate for breast cancer management [39]. It has also demonstrated efficacy in glioma cells by suppressing the expression of matrix metalloproteinase (MMP)-9, which is associated with cancer cell proliferation and invasion [40]. Furthermore, mangiferin has been found to reduce TNFα-induced MMP-9 activity and inhibit nuclear factor-κB (NF-κB) activity in prostate adenocarcinoma cells [41].
Studies in animal models have highlighted mangiferin’s potential in preventing lung carcinoma induced by carcinogens, demonstrating its ability to reduce lysosomal enzyme activity and oxidative stress [42]. Additionally, mangiferin has been shown to protect against DNA damage and oxidative stress in various cell types, indicating its potential in cancer prevention [43].
Mangiferin exhibits anticancer
effects in various cell lines. In nasopharyngeal carcinoma (CNE2) cells, mangiferin induces cell cycle arrest in the G2/M phase and promotes early apoptosis by regulating the expression of apoptosis-related genes [44]. Moreover, it has been found to inhibit NF-κB activation and reduce inflammatory markers in rats with cigarette smoke-induced chronic bronchitis, indicating its potential in mitigating inflammation-associated cancer risk [45].
In breast cancer research, mangiferin has demonstrated its ability to sensitize cancer cells to chemotherapy. When combined with doxorubicin, mangiferin can reduce cell viability and inhibit the expression of P-glycoprotein (P-gp), a multidrug resistance protein that can reduce the effectiveness of chemotherapy [46]. Furthermore, mangiferin has been shown to enhance the stability and activity of Nrf2 (nuclear factor erythroid 2-related factor 2) in various cancer cells, leading to reduced oxidative stress and increased cell viability [47].
Breast cancer cell lines have also been the focus of research, with mangiferin displaying the ability to suppress metastatic potential, inhibit the expression of MMP-7 and MMP-9, and reverse epithelial-mesenchymal transition (EMT). These effects contribute to the inhibition of tumor growth and progression [49].
Additionally, mangiferin has demonstrated promising results in leukemia research. It has been found to downregulate the expression of the BCR and ABL genes, potentially inhibiting the growth of leukemia cells [50]. In HL-60 cells, mangiferin induces G2/M phase cell cycle arrest and upregulates the expression of CDC2 and CCNB1 mRNA, further supporting its potential in leukemia treatment [51].
Furthermore, mangiferin has been investigated for its role in telomerase activity inhibition, which is crucial for the immortalization of cancer cells. By inducing apoptosis and upregulating Fas levels, mangiferin has the potential to target the fundamental mechanisms underlying cancer cell immortality [52].
Potential Hepatoprotective Effects
Mangiferin has exhibited hepatoprotective properties in various studies. When administered to animals with lung carcinoma induced by carcinogens, mangiferin significantly ameliorated liver damage by reducing glycoprotein components, membrane lipid peroxidation, and ATPase levels. It also increased the concentration of antioxidants like glutathione, catalase, superoxide dismutase, and vitamins E and C [53]. Additionally, in rats with carbon tetrachloride-induced liver damage, mangiferin complex administration led to enhanced hepatoprotection and increased bioavailability, further supporting its potential in liver health [31].
Neuroprotective Effects
Mangiferin has demonstrated neuroprotective effects against methylmercury-induced neurotoxicity. In IMR-32 (human neuroblastoma) cell lines, it suppresses DNA damage, lowers oxidative stress, inhibits mitochondrial membrane depolarization, and enhances glutathione levels. These findings highlight mangiferin’s potential in protecting against neurotoxicity [55].
Anti-Inflammatory Activity Inflammation is a critical component of the body’s defense mechanism against harmful stimuli, but chronic inflammation can lead to various diseases. Mangiferin, a natural polyphenol, has exhibited remarkable anti-inflammatory properties in various experimental models. This chapter delves into the mechanisms behind mangiferin’s anti-inflammatory effects.
Mechanisms of Mangiferin’s Anti-Inflammatory Action: Mangiferin’s anti-inflammatory activity primarily revolves around its ability to modulate key signaling pathways involved in inflammation. It effectively inhibits the activation of NF-κB, a transcription factor responsible for regulating the expression of pro-inflammatory genes. By suppressing NF-κB activation, mangiferin downregulates the production of inflammatory cytokines such as TNF-α, IL-6, and IL-1β.
Regulation of MAPK Signaling: Mangiferin also interferes with the MAPK signaling pathway, which plays a pivotal role in mediating inflammatory responses. Through the inhibition of MAPK phosphorylation, mangiferin reduces the activation of downstream pro-inflammatory mediators.
Impact on Colitis and Inflammatory Bowel Diseases (IBD): Experimental models of colitis have demonstrated mangiferin’s potential in ameliorating inflammatory bowel diseases. It suppresses colon shortening, myeloperoxidase activity, and the upregulation of inflammatory markers like cyclooxygenase-2 (COX-2) and nitric oxide synthase. Additionally, mangiferin’s regulation of NF-κB and IRAK1 phosphorylation contributes to its anti-colitis effects.
Pain Management and Nociceptive Responses
Pain management is a critical aspect of healthcare, and mangiferin has shown promise as an analgesic agent. This chapter provides a comprehensive overview of mangiferin’s role in pain relief.
Mechanisms of Mangiferin’s Analgesic Properties: Mangiferin exerts its analgesic effects through multiple mechanisms. It reduces abnormal mRNA levels of both pro-inflammatory cytokines and anti-inflammatory cytokines in lung tissues. Moreover, mangiferin attenuates the imbalance between Th1 and Th2 cell responses, which is often associated with inflammatory pain. It also inhibits the activation and expression of transcription factors like GATA-3 and STAT-6.
Management of Neuro-Inflammatory Pain: Experimental models involving formalin-induced long-term damage and chronic mechano-hyperalgesia have highlighted mangiferin’s efficacy in managing neuro-inflammatory pain. It suppresses LPS-induced IL-6 production and the expression of cystathionine-b-synthase (CBS), providing relief from chronic pain.
Visceral Pain and Inflammatory Pain: In mouse models of experimental pain, mangiferin exhibits significant antinociceptive activity against chemogenic pain, including formalin- and capsaicin-induced pain and acetic acid-induced visceral pain. These findings indicate its potential for alleviating various types of pain.
Protection Against Acute Lung Injury
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are life-threatening conditions characterized by severe inflammation in the lungs. This chapter focuses on mangiferin’s protective role against ALI.
Modulation of NF-κB Signaling and Proinflammatory Mediators: Mangiferin effectively inhibits NF-κB signaling and MAPKs, which are central players in the inflammatory cascade leading to ALI. By doing so, it suppresses the production of proinflammatory mediators responsible for lung tissue damage.
Upregulation of Heme Oxygenase-1 (HO-1): Mangiferin’s ability to upregulate heme oxygenase-1 (HO-1) in the lung is crucial in its protective action against ALI. HO-1 is an enzyme with potent antioxidant and anti-inflammatory properties, and its increased expression contributes to the reduction of lung injury.
Diabetes Treatment – The Role of Mangiferin
Diabetes has emerged as a widespread health concern, affecting a significant portion of the global population. Among diabetic patients, more than 80% suffer from type 2 diabetes, a condition characterized by reduced glucose utilization in key target tissues such as skeletal muscle and adipose tissue.
This metabolic dysfunction leads to elevated blood glucose and insulin levels, which are associated with a range of complications including cardiovascular diseases (hypertension, retinal injury, atherosclerosis), fatty liver, dyslipidemia, and renal diseases [68]. In this chapter, we delve into the potential of mangiferin, a natural compound, as a treatment option for diabetes and its associated complications.
Mangiferin and Glucose Regulation
One compelling study involved eight weeks of mangiferin treatment in db/db mice, a diabetic mouse model. This intervention led to a significant reduction in plasma glucose and triglyceride (TG) levels. Moreover, it enhanced pancreatic β-cell mass and increased glucose and insulin uptake.
The mechanism behind these effects was attributed to the activation of AMP-activated protein kinase (AMPK) phosphorylation, a key player in glucose metabolism, in n 3 T3-L1 cells. This activation of AMPK extended to various tissues, including the liver, hypothalamus, muscle, and adipose tissue in C57BL/6 mice [69]. These findings suggest that mangiferin may hold promise in improving insulin sensitivity and glucose regulation.
Mangiferin’s Impact on Insulin Sensitivity and Lipid Profile
In a separate study, mangiferin was administered orally to streptozotocin-induced hyperglycemic rats for four weeks. The results demonstrated improved insulin sensitivity, modulation of lipid profiles, and a reversal of abnormal adipokine levels [70]. This implies that mangiferin could potentially help address the dyslipidemia often associated with diabetes.
Renal Protection by Mangiferin
Diabetic nephropathy, a common complication of diabetes, can lead to severe kidney damage. Mangiferin has shown promise in mitigating this condition. Rats with diabetes were treated with different concentrations of mangiferin for nine weeks, resulting in a reduction of osteopontin production, kidney inflammation, and renal fibrosis. Chronic mangiferin treatment prevented renal glomeruli fibrosis and decreased the expression of α-smooth muscle actin and collagen IV in diabetic rats’ kidneys. Additionally, mangiferin reduced interleukin-1β levels in the serum and kidneys, highlighting its anti-inflammatory properties [71].
Antioxidant and Anti-Inflammatory Effects
Mangiferin has also demonstrated its ability to lower reactive oxygen species (ROS) production and enhance antioxidant defenses. It does so by modulating various pathways, including the MAPK (P38, JNK, and ERK1/2), PKC isoforms (PKCα, PKCβ, and PKCε), TGF-β1 pathways, and the NF-κB signaling cascades. These pathways play critical roles in the pathophysiology of diabetic nephropathy, and mangiferin’s influence on them suggests potential therapeutic benefits [72].
Beta Cell Protection and Regeneration
Maintaining healthy beta cells in the pancreas is essential for insulin production. Studies have indicated that mangiferin plays a role in preserving and regenerating beta cells. In an experiment involving adult C57BL/6 J mice, mangiferin administration improved glucose tolerance and glycemia, increased beta-cell hyperplasia and serum insulin levels, reduced beta-cell apoptosis, and promoted beta-cell proliferation. Furthermore, it upregulated the expression of key genes involved in beta-cell function, such as pancreatic and duodenal homeobox gene 1 (PDX-1), glucose transporter 2 (GLUT-2), neurogenin 3 (Ngn3), glucokinase (GCK), and Forkhead box protein O1 (Foxo-1) [73].
Mangiferin’s Renal Benefits
In a nine-week treatment regimen, mangiferin significantly improved chronic renal insufficiency in diabetic rats. This improvement was marked by reduced kidney weight index, decreased albuminuria, lessened glomerular extracellular matrix expansion, and lowered blood urea nitrogen levels. Mangiferin also enhanced the enzymatic activity and expression of glyoxalase-1 (Glo-1), a key enzyme involved in detoxifying advanced glycation end products (AGEs). Simultaneously, it reduced the expression of AGEs and their receptor, RAGE, in the renal cortex of diabetic rats. These findings indicate that mangiferin may play a pivotal role in mitigating renal damage in diabetes [74].
Cardiovascular Protection and Lipid Regulation
Cardiovascular health is a major concern for diabetic individuals. Mangiferin has demonstrated its potential in improving lipid profiles and reducing cardiovascular risk factors. In a study involving STZ-induced diabetic rats, mangiferin administration for 28 days resulted in significantly lower plasma low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels. It also increased high-density lipoprotein cholesterol (HDL-C) levels, thus improving the overall lipid profile. Furthermore, mangiferin decreased the atherogenic index and improved oral glucose tolerance in normal rats subjected to glucose loading [75].
Anti-Glycation and Antioxidant Effects on Diabetic Nephropathy
Diabetic nephropathy is characterized by the accumulation of advanced glycation end products (AGEs). Mangiferin has been shown to significantly lower serum levels of AGEs, red blood cell sorbitol concentrations, malondialdehyde levels, and 24-hour albuminuria excretion in diabetic nephropathy rats. It also enhances the activity of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. Additionally, mangiferin inhibits the expansion of glomerular extracellular matrix and the accumulation of TGF-β1 in diabetic nephropathy rat glomeruli. These effects, in combination with the inhibition of high glucose-induced mesangial cell proliferation and collagen IV production, highlight mangiferin’s potential to protect against diabetic nephropathy [76].
Oxidative Stress and the Protective Role of Mangiferin
Oxidative stress is a biological phenomenon that occurs when free radicals, highly reactive molecules, are produced during metabolic processes in the human body. These free radicals can cause oxidative damage to essential biological macromolecules such as proteins, fatty acids, and nucleic acids.
When present at high concentrations, free radicals can disrupt the delicate internal balance of redox reactions, leading to a range of chronic diseases [83, 84]. This chapter explores the fascinating potential of mangiferin, a natural compound found in mangoes and other plants, in mitigating oxidative stress and its associated complications.
Mangiferin and Glucose Regulation
Mangiferin’s role in mitigating oxidative stress extends to its effects on diabetes. In a study involving diabetic rats, oral administration of mangiferin at a dose of 40 mg/kg/day for 30 days resulted in significant reductions in blood sugar levels and increased plasma insulin levels. Importantly, this treatment also elevated the activity of crucial antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the livers of diabetic rats compared to control rats. However, it’s worth noting that mangiferin led to a reduction in glutathione (GSH) levels in the kidney, indicating tissue-specific effects [85].
Renal Protection and Inflammation
Mangiferin has demonstrated its ability to protect against renal inflammation and oxidative stress. In human glomerular renal endothelial cells, exposure to cadmium chloride promoted the secretion of pro-inflammatory cytokines IL-6 and IL-8, contributing to renal inflammation. However, treatment with mangiferin (at a concentration of 75 μM) effectively prevented cadmium-induced secretion of IL-6 and IL-8 by these cells, suggesting its potential as a protective agent against kidney inflammation [86].
Inflammasome Regulation
The NLRP3 inflammasome is a key player in inflammation and oxidative stress. Mangiferin has been shown to regulate the production of NLRP3 and Nrf2, two important proteins involved in the inflammatory response. In a study using a CLP-induced septic mice model, mangiferin attenuated renal dysfunction and ameliorated morphological changes in the kidneys. This intervention also reduced serum levels of inflammatory cytokines IL-1β and IL-18, prevented tubular epithelial cell apoptosis, and suppressed NLRP3 inflammasome activation in the kidneys, highlighting mangiferin’s potential in mitigating inflammation and oxidative stress in this context [87].
Liver Protection
Mangiferin’s protective effects extend to liver health. In an experiment involving the administration of mangiferin (100 mg/kg BW) for six days, mangiferin significantly reduced reactive oxygen species (ROS) formation and lowered levels of liver enzymes ALT (alanine transaminase) and ALP (alkaline phosphatase). Furthermore, it restored mitochondrial membrane potential, regulated the expression of apoptosis-related proteins Bcl-2 and Bax, and inhibited the activation of NF-κB (nuclear factor kappa B) and mitogen-activated protein kinases (MAPKs). These findings suggest that mangiferin may have hepatoprotective properties, particularly in the context of oxidative stress-induced liver damage [88].
Neuroprotection
The brain is particularly vulnerable to oxidative stress, which is associated with various neurological conditions. Mangiferin has demonstrated neuroprotective properties in several studies. In a rat model of ketamine-induced cognitive impairment, mangiferin (administered at 50 mg/kg, i.p., for seven days, twice a day) showed significant protective effects. Additionally, mangiferin treatment (at concentrations ranging from 10 to 100 μM for seven days) prevented 6-hydroxydopamine (6-OHDA)-induced cell death in a concentration-dependent manner. Furthermore, it reduced the levels of pro-inflammatory cytokine IL-6 and the oxidative stress marker malondialdehyde (MDA) in brain tissues [89].
Respiratory and Immune System Protection
Mangiferin has also demonstrated its protective effects on the respiratory and immune systems. In a study involving rats with chronic bronchitis, various concentrations of mangiferin (ranging from 100 to 400 mg/kg) enhanced the levels of the antioxidant enzyme SOD and nitric oxide (NO) in bronchoalveolar lavage fluid (BALF) and serum. Additionally, it reduced levels of MDA and pro-inflammatory cytokines TNF-α and IL-8 in lung tissues. In a separate experiment using RAW264.7 macrophages, mangiferin decreased COX-2 mRNA expression induced by lipopolysaccharide (LPS) [90].
Renal Function and Uric Acid Regulation
Hyperuricemia, characterized by elevated serum uric acid levels, can lead to kidney and joint problems. In mice with potassium oxonate-induced hyperuricemia, mangiferin (administered at concentrations of 50, 100, and 200 mg/kg) effectively lowered serum uric acid, urea nitrogen levels, and creatinine concentration. Furthermore, it downregulated the expression of murine glucose transporter 9 (mGLUT9) and urate transporter 1 (mURAT1) at both the mRNA and protein levels. Mangiferin also upregulated the expression of the murine organic anion transporter 1 (mOAT1) and increased renal organic cation levels. These findings suggest that mangiferin may play a role in regulating uric acid reabsorption and renal function [91].
Genotoxicity Protection
In Swiss albino mice exposed to cadmium chloride-induced genotoxicity, a single intraperitoneal dose of mangiferin (at a dose of 2.5 mg/kg) significantly reduced the ratio of micronucleated polychromatic erythrocytes (MnPCE) to normochromatic erythrocytes (MnNCE) and increased the ratio of polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE). Furthermore, mangiferin reduced lipid peroxidation and increased the activity of antioxidant enzymes including SOD, GSH, CAT, and GST in the liver, highlighting its potential in protecting against genotoxicity and oxidative damage [92].
Neuroprotective Role
Mangiferin has demonstrated a neuroprotective role against neurotoxicity and cognitive impairment induced by aluminum chloride in male Swiss albino mice. Administration of mangiferin at doses of 20 and 40 mg/kg significantly reduced oxidative stress markers, inflammatory cytokine levels, and hippocampal brain-derived neurotrophic factor (BDNF) content. This suggests that mangiferin may have potential in protecting against neurodegenerative conditions associated with oxidative stress [96].
Protection Against Dopaminergic Neuron Loss
In a mouse model treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), mangiferin (administered at doses of 10, 20, and 40 mg/kg for 14 days) prevented dopamine depletion and MPTP-induced behavioral deficits. These findings highlight the potential of mangiferin in protecting against dopaminergic neuron loss and associated motor deficits [97].
Respiratory Smooth Muscle Relaxation
Mangiferin has demonstrated the ability to relax respiratory smooth muscles. It inhibited contractions induced by various tracheal stimuli, including 5-hydroxytryptamine, carbachol, histamine, and allergens, in a concentration-dependent manner. Additionally, mangiferin relaxed tracheal rings that were pre-contracted with carbachol, indicating its anti-contractile and relaxing properties. This effect was sensitive to inhibitors of nitric oxide synthase (NOS), soluble guanylate cyclase, and potassium channel blockers, suggesting the involvement of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway and potassium channels in mangiferin’s mechanism of action [98].
Immune System Enhancement
Mangiferin has demonstrated the ability to enhance immune responses. In cyclophosphamide-treated rats, oral administration of mangiferin (at doses of 10 and 20 mg/kg daily) for two weeks led to improved cellular responses, increased levels of antigen-specific IgM, and increased lymphoid organ weights. Moreover, mangiferin reduced lipid peroxidation and the number of lymphocytes, macrophages, and polymorphonuclear cells, while enhancing the activity of antioxidant enzymes SOD and CAT [2].
Neuroinflammation and Oxidative Damage
In young male Wistar rats, mangiferin (administered at concentrations of 15, 30, and 60 mg/kg) protected against neuroinflammation and oxidative damage. This was evidenced by a reduction in plasma levels of pro-inflammatory cytokines IL-1β and glucocorticoids (GC), prevention of redox imbalance, maintenance of catalase levels in the brain, and a decrease in pro-inflammatory mediators such as TNF-α, NF-κB, TNF receptor 1, iNOS, and COX-2. Furthermore, mangiferin reduced lipid peroxidation, indicating its potential as a strategy for treating neuropsychiatric and neurological pathologies [99].
Neurotrophic and Cognitive Enhancement
In another study, oral administration of mangiferin (at doses of 10, 50, or 100 mg/kg) increased novel object recognition in rats when administered immediately post-training. Mangiferin also stimulated cell proliferation and increased the levels of supernatant nerve growth factor (NGF) and TNF-alpha. Additionally, it elevated levels of cytokines and neurotrophic factors in human U138-MG glioblastoma cells, suggesting a potential role in enhancing neurotrophic and cognitive functions [100].
Mangiferin and Hyperlipidemia
Hyperlipidemia, characterized by elevated levels of lipids, such as cholesterol and triglycerides, in the bloodstream, is a significant risk factor for cardiovascular diseases and other metabolic disorders. Managing hyperlipidemia is crucial for preventing related health complications. In recent years, there has been growing interest in the potential role of mangiferin, a bioactive compound found in mangoes and other plants, in mitigating hyperlipidemia and its associated metabolic imbalances. This chapter provides a comprehensive overview of mangiferin’s protective effects against hyperlipidemia and its underlying mechanisms.
Mangiferin Regulation of Metabolic Pathways
Mangiferin has been shown to exert its protective effects against hyperlipidemia by modulating various metabolic pathways. It impacts the glyoxylate, tricarboxylic acid (TCA), taurine cycles, and metabolism of dicarboxylates, glycerophospholipids, hypotaurine, threonine, serine, glycine, and primary bile acid biosynthesis [101]. These regulatory effects contribute to the maintenance of lipid homeostasis and the prevention of hyperlipidemia.
Mitochondrial Biogenesis and Oxidative Activity
Mangiferin enhances mitochondrial biogenesis and oxidative activity by upregulating key proteins such as cytochrome c oxidase subunit 6B1 (Cox6b1) and oxoglutarate dehydrogenase E1 (DHTKD1). These proteins are involved in electron transport and oxidative phosphorylation within the mitochondria [102]. This enhancement of mitochondrial function promotes efficient energy metabolism and may help reduce lipid accumulation.
Inhibition of Lipogenesis
One of the critical mechanisms underlying hyperlipidemia is the excessive synthesis of lipids, including cholesterol and triglycerides. Mangiferin plays a role in inhibiting lipogenesis by reducing the expression of acetyl-CoA carboxylase 1 (Acac1) and fatty acid stearoyl-CoA desaturase 1 (Scd1), both of which are essential enzymes in fatty acid synthesis. This inhibition contributes to the prevention of lipid accumulation in various tissues [102].
Bioenergetics and Adiposity
Mangiferin not only enhances bioenergetic processes but also prevents adiposity. It downregulates mitochondrial proteins involved in de novo lipogenesis while promoting proteins associated with energy expenditure [102]. This dual action helps maintain a healthy balance of energy metabolism and body weight.
Neuroprotection and Mitochondrial Function
In human neuroblastoma SK-N-SH cells, mangiferin has been shown to significantly increase cell viability, improve mitochondrial membrane potential, and reduce apoptosis induced by the neurotoxin rotenone [103]. This neuroprotective effect may have implications for preventing neural complications associated with hyperlipidemia.
Enhanced Muscle Glucose Oxidation
Mangiferin’s beneficial effects extend to muscle tissue. In high-fat diet (HFD)-fed mice, mangiferin enhances muscle glucose oxidation without altering fatty acid oxidation. It increases glucose and pyruvate oxidation, promoting ATP production. Additionally, mangiferin suppresses the conversion of pyruvate to lactate via anaerobic metabolism while increasing pyruvate oxidation [104].
Reduction of Free Fatty Acids (FFA) Levels
Hyperlipidemia often leads to elevated levels of free fatty acids (FFA) in the bloodstream. Mangiferin administration in hamsters has been shown to significantly decrease total FFA levels, contributing to the prevention of lipid-related complications. This effect is associated with the upregulation of peroxisome proliferator-activated receptor-alpha (PPAR-α) and other genes involved in fatty acid metabolism [15].
Reduction of Oxidative Stress and Reactive Oxygen Species (ROS)
Excessive lipid accumulation can lead to oxidative stress, characterized by an imbalance between free radicals and antioxidants. Mangiferin has been shown to reduce the production of reactive oxygen species through both isolated liver mitochondria and lymphocytes. It also protects against the depletion of mitochondrial substrates and prevents oxidative damage [105].
Activation of AMP-Activated Protein Kinase (AMPK)
Mangiferin administration has been associated with the activation of AMP-activated protein kinase (AMPK), a key regulator of energy metabolism. This activation leads to increased phosphorylation of AMPK and its downstream targets, including carnitine palmitoyltransferase 1 (CPT1) and fatty acid translocase (CD36). Simultaneously, mangiferin reduces the expression of acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2) and inhibits the activity of acetyl-CoA carboxylase (ACC), ultimately promoting lipid oxidation [106].
Chondrogenic Effects
Mangiferin demonstrates chondrogenic effects, contributing to the maintenance of healthy cartilage tissue. It upregulates the expression of bone-morphogenetic proteins (BMP-4 and BMP-2), transforming growth factor-beta (TGF-β), and chondrogenesis markers such as SOX9, collagen type 2 (col2 alpha1), aggrecan, and connexin cartilage. This effect is particularly valuable in the context of joint health [107, 108].
Miscellaneous Properties
Beyond its role in mitigating hyperlipidemia, mangiferin exhibits a wide range of other beneficial properties. These include:
- Protection against atopic dermatitis, bronchial asthma, and other allergic diseases through the inhibition of IgE production, anaphylaxis reactions, histamine-induced vascular permeability, and lymphocyte proliferative responses [109].
- Reduction of alveolar bone loss through the inhibition of COX-2 expression and leukocyte rolling and adhesion, while maintaining normal levels of lipoxin A4 [110].
- Protection against oxidative damage in various tissues, including neurons, cardiac muscle, liver, and kidneys, through its antioxidant properties [110, 118].
- Antiviral activity against HIV-1 through the inhibition of the HIV-1 protease [8].
- Inhibition of bone resorption and osteoclast formation by suppressing RANKL-induced signaling, which is relevant to bone health [114].
- Reduction of galactosamine-induced liver damage by suppressing inflammation and activating the Nrf2 pathway [115].
- Antibacterial and antifungal properties against various pathogens [116, 117].
- Protection against radiation-induced injuries in human intestinal epithelial cells [112].
- Reduction of airway inflammation and the levels of pro-inflammatory cytokines IL-4 and IL-5 [109].
- Attenuation of neuroinflammation by reducing IL-1β levels and improvement in anxiety-like and anhedonic behaviors in LPS-challenged mice [121].
Conclusion
Mangiferin, a natural bioactive compound found in mangoes and other plant sources, holds immense promise in preventing and managing lifestyle-related disorders. Its diverse range of health benefits, including antioxidant, anticancer, hepatoprotective, and neuroprotective properties, make it a valuable candidate for further research and potential therapeutic use. Understanding mangiferin’s synthesis, metabolism, and pharmacokinetics provides valuable insights into its bioavailability and potential applications. While further studies are needed to elucidate its mechanisms of action and clinical efficacy, mangiferin’s multifaceted properties offer exciting prospects for the development of novel therapies and dietary interventions aimed at promoting human health and preventing chronic diseases.
in Deep…
Mangiferin-Integrated Polymer Systems
In this detailed chapter, we will explore various techniques for integrating mangiferin, a naturally occurring bioactive compound, into polymer systems to enhance its bioavailability and therapeutic potential. Despite its broad range of biological activities, mangiferin has been underutilized due to limited bioavailability. Recent research has focused on developing innovative polymer-based delivery systems to overcome this limitation.
Spray-Drying Technique
In 2013, José Roberto R. de Souza and colleagues conducted a study on the spray drying of mangiferin in various polysaccharide polymer materials, including citric pectin, pumpkin pectin, and chitosan [145]. The aim was to evaluate the effect of different polymers and the presence of Tween 80 surfactant on the encapsulation of mangiferin.
Experimental Setup
The researchers used four different formulations: SD1 (Citric pectin/mangiferin), SD2 (Citric pectin/mangiferin/Tween 80), SD3 (Pumpkin pectin/mangiferin/Tween 80), and SD4 (Chitosan/mangiferin/Tween 80). They encapsulated 200 mg of mangiferin with 2.0 g of each polysaccharide, both with and without Tween 80 surfactant (0.1%). The encapsulation process was performed using a Büchi B-290 spray dryer with specific parameters: inlet air temperature of 160°C, outlet air temperature of 80°C, feed rate of 6 mL/min, aspirator volume flow of 35 m^3/h, and air flow of 84 L/h. The productivity for all samples was 65%.
Characterization of Encapsulated Products
The researchers analyzed the resulting granules using several techniques, including Fourier transform infrared spectra (FTIR), scanning electron microscopy (SEM), high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC–ESI-MS), and electrospray ionization mass spectrometry (ESI-MS).
Key Findings
- The average particle diameter varied among the formulations: SD3 had the largest average diameter (15 μm), while SD4 had the smallest (2.9 μm). SD1 and SD2 had intermediate sizes (7.2 μm and 10.2 μm, respectively), with differences attributed to the presence of Tween 80.
- Tween 80 was found to influence particle size and surface characteristics, resulting in smoother and more uniform particles in SD2.
- The concentration of mangiferin in the capsules correlated with particle size, with the highest concentration observed in SD3 and the lowest in SD4 (29, 41, 49, and 16 μg/mg, respectively).
- Tween 80, being a nonionic surfactant, interacted hydrophobically with the polymer matrix, affecting drug retention during spray-drying. Chitosan, a positively charged polysaccharide, had lower retention potential than negatively charged pectins.
Conclusion and Future Directions
These findings demonstrate the significant impact of polymer nature and surfactant presence on drug encapsulation during the spray-drying process. While successful in optimizing encapsulation conditions, these experiments were limited to synthesis and property testing and did not involve live cell studies. This opens up avenues for further research into mangiferin encapsulation using the spray-drying technique, exploring various bio-polymers with or without surfactants for oral, parenteral, or topical medications.
Simple Solvent-Evaporation Technique
In 2014, Hequn Ma and colleagues developed a phospholipid complex to enhance the solubility and bioavailability of mangiferin [147]. The study aimed to investigate the complex’s properties and its impact on mangiferin’s oral bioavailability.
Experimental Setup
The mangiferin-phospholipid complex was prepared by dissolving mangiferin and Lipoid E80 in a 1:1 molar ratio using ethanol as a solvent. The solubility and adsorption capacity of mangiferin were evaluated according to China Pharmacopoeia 2010 standards.
Characterization of the Complex
The researchers characterized the complex by analyzing its solubility, absorption capacity, and permeability, comparing it with pure mangiferin and mangiferin-phospholipid physical mixtures. They also conducted pharmacokinetic studies in mice.
Key Findings
- The mangiferin content in the complex was 35.02% (w/w).
- The complex exhibited improved solubility in both water and n-octanol compared to pure mangiferin, with a 30-fold increase in n-octanol solubility.
- In vitro studies showed that the complex had higher rates of absorption constraint in the duodenum, jejunum, ileum, and colon compared to pure mangiferin. Effective permeability values were significantly higher in all segments.
- Pharmacokinetic studies in mice revealed that the complex increased Cmax, extended the elimination half-life of mangiferin, and significantly improved relative bioavailability.
Conclusion and Future Directions
The study demonstrated that the mangiferin-phospholipid complex significantly enhanced mangiferin’s oral bioavailability. This approach holds promise for targeted drug delivery to various parts of the body and improved therapeutic efficacy. Future research should explore the complex’s potential in cancer cell studies and further investigate its mechanism of action.
Emulsion Solvent Evaporation Technique
In 2016, Rungkan Boonnattakorn and colleagues integrated mangiferin into copolymers of ethylene vinyl acetate (EVA) and vinyl acetate (VA) to develop emulsion products with potential applications in drug delivery [148]. This study aimed to evaluate the effect of different surfactants and VA contents on the properties of the emulsions.
Experimental Setup
The study compared the impact of two surfactants, Span®20 and Pluronic®P 123, on emulsions created by combining mangiferin with EVA solutions containing varying VA contents (12%, 18%, 25%, and 40%). The researchers assessed multiple characteristics of the product matrices.
Characterization of the Emulsions
The researchers conducted a comprehensive analysis, including mangiferin dispersion efficiency, melting point, heat of fusion, oxygen permeability, degree of crystallization, glass transition temperature, tensile strength, elongation at break, grip, antioxidant activities, release profile of mangiferin, and statistical analysis.
Key Findings
- Surfactants, particularly Span®20, facilitated the fine dispersion of mangiferin particles in EVA films, preventing agglomeration.
- Span®20 produced smaller particles and more stable microemulsions than Pluronic®P 123, resulting in films with similar flexibility to EVA films without surfactants.
- VA content significantly affected film characteristics, increasing the degree of crystallization and melting temperature while reducing flexibility and mangiferin release, particularly in films with lower VA content. Oxygen permeability increased with higher VA content.
- Span®20 had a minimal impact on film mechanical and barrier characteristics but significantly increased mangiferin release from the EVA matrix, enhancing antioxidant activity.
Conclusion and Future Directions
The study demonstrated the potential of surfactants and VA content in controlling mangiferin release from EVA matrices. Further research can explore the optimization of surfactant and polymer ratios for specific drug delivery applications.
Supercritical Antisolvent Technique
In 2017, García-Casas and colleagues employed a supercritical antisolvent process to produce mangiferin-cellulose acetate phthalate particles in various material ratios [150]. The study aimed to evaluate the effect of different ratios and processing conditions on particle characteristics and drug release.
Experimental Setup
The researchers utilized two variations of the supercritical antisolvent process: SAS1, where both polymer and mangiferin were dissolved in the same solution, and SAS2, where separate solutions were sprayed into the same tank. Different material ratios and processing parameters were tested.
Characterization of the Particles
The study involved characterizing the particle size, morphology, crystallinity, and mangiferin release properties of the resulting systems.
Key Findings
- SAS1 yielded particles with a narrow size distribution (0.25–0.41 μm) and smaller sizes for lower mangiferin proportions. SAS2 produced two different particle morphologies, including small mangiferin fibers and microspheres, with size varying based on polymer ratio.
- After the SAS processes, the systems exhibited an amorphous state, which improved mangiferin solubility in water.
- In vitro tests demonstrated that the systems released nearly 100% of mangiferin in simulated gastric and intestinal fluids within minutes, significantly surpassing commercial mangiferin.
Conclusion and Future Directions
The supercritical antisolvent process proved effective in producing mangiferin-loaded particles with improved solubility and rapid release in simulated digestive environments. Future research may explore the application of this technique in pharmaceutical, cosmetic, and nutritional industries.
Nanoemulsion Technique
In early 2019, María Pleguezuelos-Villa developed nanoemulsions of mangiferin and hyaluronic acid with potential applications in dermatitis and skin regeneration [151]. The study aimed to investigate the formulation and therapeutic potential of these nanoemulsions.
Experimental Setup
The study involved encapsulating mangiferin with different molecular weights of hyaluronic acid, with and without Transcutol-P. Various characteristics of the nanoemulsions were examined.
Characterization of Nanoemulsions
The researchers assessed particle size, zeta potential, stability, viscosity, and in vivo therapeutic efficacy through acute inflammatory tests in rats.
Key Findings
- The nanoemulsions exhibited a narrow size distribution with droplet sizes ranging from 194.5 to 397.9 nm. They were physically stable for up to 30 days.
- Hyaluronic acid molecular weight affected particle size and zeta potential. Lower molecular weight hyaluronic acid produced smaller particles with more negative zeta potentials.
- The nanoemulsions demonstrated improved solubility, with high partition coefficients, indicating enhanced mangiferin solubility in water and n-octanol.
- The nanoemulsions inhibited edema and myeloperoxidase activity, showing potential for treating inflammatory skin disorders.
Conclusion and Future Directions
The study highlighted the potential of nanoemulsions as a promising delivery system for mangiferin, particularly in the context of inflammatory skin disorders. Future research may explore further therapeutic applications and in-depth mechanisms of action.
Sol-Gel Synthesis Technique for Mangiferin-Controlled Delivery Systems
In 2019, Athit Pipattanawarothai introduced a novel approach for designing a mangiferin-controlled distribution system using the Sol-Gel synthesis technique [152]. This chapter explores the details of this innovative research, which focuses on the development of hydrogel polymers and their incorporation of mangiferin within various blending systems, including poly vinyl alcohol (PVA), chitosan, and gelatin, in binary, ternary, and hybrid-ternary compositions.
The Sol-Gel synthesis technique is a versatile method for creating materials with controlled structures and compositions. In this study, the technique was employed to form hydrogel polymers capable of controlled release of mangiferin, a bioactive compound with diverse therapeutic potential.
Experimental Setup
The experimental design involved creating hydrogel systems with varying compositions, including binary systems (PVA-chitosan), ternary systems (PVA-chitosan-gelatin), and hybrid-ternary systems (combining the ternary system with siloxane). These systems were loaded with mangiferin, and their properties were systematically investigated.
Characterization of the Hydrogel Systems
Various techniques were employed to characterize the resulting hydrogel systems:
- Attenuated Total Reflection FTIR (ATR-FTIR): This analysis confirmed the presence of intra-molecular and inter-molecular hydrogen bonds within the hydrogel systems, which play a crucial role in drug encapsulation and release.
- Scanning Electron Microscopy (SEM) with Energy Dispersive X-ray Analysis: SEM images were used to visualize the morphology of the hydrogel systems and validate the proposed schemes for interactions between homopolymers and mangiferin.
Key Findings
The study yielded several key findings regarding the mangiferin-controlled delivery systems developed using the Sol-Gel synthesis technique:
- Interactions with Homopolymers: Mangiferin was found to interact with the amide and hydroxyl pendant groups in the homopolymer matrices. Specifically, mangiferin exhibited a strong preference for forming inter-molecular hydrogen bonds with hydroxyl groups and amide and hydroxyl pendant groups of chitosan, rather than with the hydroxyl groups of PVA. The presence of gelatin in the system, with its branching and heterocyclic bulk groups, was found to increase volume and decrease the strength of hydrogen bonds in hydrogels.
- Effect of Siloxane Bonds: The presence of siloxane bonds introduced complexity to the hydrogel system. The degree of siloxane hybridization and the nature and ratio of the polymers had a significant impact on the structure and behavior of the hydrogel. In an acidic medium, the hydrogel swelled due to repulsion between NH3+ cation groups, while siloxane bonding led to a more interlocked network with reduced swelling. In a basic medium, the siloxane hybridized network exhibited higher swelling capacity due to the ionic strength of the buffer solution and its hydrophilic properties.
- pH-Dependent Release: The cumulative release of mangiferin from the different hydrogel systems was dependent on both the composition of the hydrogel and the pH of the surrounding medium. Mangiferin release was lower in systems with higher chitosan content or in a more alkaline pH environment. The optimal matrix for controlled release of mangiferin was found to be hydrogel M90PV/5CHI/5GEL-T2.
Future Directions
While this study provided valuable insights into mangiferin-controlled delivery systems using the Sol-Gel synthesis technique, it is important to note that further research is required. Future investigations should focus on cytotoxicity assessments and in vivo release studies to evaluate the suitability of these fabricated hydrogels for applications such as wound dressings and biomedical applications. Additionally, the potential for fine-tuning the hydrogel composition to optimize mangiferin release in specific conditions should be explored.
Thin Film-Sonication Technique for Phenolic Compound Encapsulation
In 2019, Santi Thanitwatthanasak and colleagues utilized the thin film-sonication method to encapsulate two phenolic compounds, mangiferin and quercetin, within mixtures of Pluronic F127, Pluronic P123, and Vitamin E TPGS copolymers [153]. This chapter provides an overview of this research, detailing the encapsulation efficiency, micelle characteristics, and release behavior of the phenolic compounds using this innovative technique.
The thin film-sonication technique offers a unique approach to encapsulate hydrophobic bioactive compounds like mangiferin and quercetin within polymeric micelles. This chapter delves into the experimental details and results of this study, shedding light on the potential of this method for enhancing the bioavailability of phenolic compounds.
Experimental Setup
The experimental design consisted of ten runs, comprising single components (F127, P123, and TPGS), binary mixtures (F127:P123, F127:TPGS, and P123:TPGS), and their respective ternary mixtures. The ratios of these components were carefully adjusted to investigate the encapsulation efficiency, drug loading, micelle concentration, and dissolution behavior of the phenolic compounds.
Characterization of Mangiferin-Loaded Micelles
Several characterization techniques were employed to understand the properties of the mangiferin-loaded micelles:
- Morphological Analysis: The mangiferin-loaded micelles displayed a spherical morphology with a diameter of 14.26 ± 0.52 nm. Furthermore, these micelles had a zeta potential of -2.89 ± 1.70 mV, indicating their stability against agglomeration.
- Encapsulation Efficiency: The encapsulation efficiency of mangiferin varied based on the copolymer components. Single copolymers of F127, P123, and TPGS exhibited encapsulation efficiencies of 91.72%, 75.65%, and 92.33%, respectively. However, ternary blends displayed higher encapsulation efficiencies of 94-95%, highlighting the advantage of combining hydrophilic copolymer components like F127 and TPGS for efficient drug encapsulation.
Optimization of Mangiferin Loading
The Design Expert software was utilized to optimize the ratio of mangiferin loading into copolymers of F127, P123, and TPGS. The optimal ratio was determined to be 0.120/0.328/0.552, emphasizing the importance of carefully balancing these components to maximize drug loading efficiency.
In Vitro Release Studies
Dissolution tests were performed under simulated gastric and intestinal conditions to evaluate the release behavior of mangiferin-loaded micelles. While mangiferin was inherently insoluble, the micelles demonstrated excellent solubility and sustained release in both simulated environments.
Implications for Oral Drug Delivery
This study successfully applied mixed design principles to optimize mangiferin-loaded mixed micelle formulations. The developed mixed micelles hold promise as an oral drug delivery system for compounds with low bioavailability. Their unique properties, including small size, stability against agglomeration, and sustained release capabilities, make them suitable candidates for enhancing the oral bioavailability of phenolic compounds.
Summary of Polymer-Mangiferin Systems
This chapter provides an overview and summary of the general characteristics observed in polymer-mangiferin systems based on the studies discussed throughout this review.
Key Observations
The limited but promising research on mangiferin-integrated polymer systems has yielded several common characteristics:
- Preference for Hydrophilic Polymers: Mangiferin tends to interact more favorably with hydrophilic polymers with smaller molecular sizes than with hydrophobic polymers or bulky molecules. This preference is crucial for achieving efficient encapsulation.
- Interaction with Positively Charged Polymers: Mangiferin forms strong interactions with positively charged polymers, such as chitosan. While this facilitates sustainable polymer systems, it can also impede drug release. Achieving an appropriate balance when combining these polymers with mangiferin is essential.
- Hydrogen Bonding: Intermolecular and intra-molecular hydrogen bonding plays a significant role in mangiferin loading within polymer systems. These hydrogen bonds contribute to drug encapsulation and release.
- Dual Binding Mechanism: Mangiferin can bind to both hydrophilic and hydrophobic parts of polymer systems, greatly enhancing encapsulation efficiency and improving solubility and permeability.
- pH-Dependent Solubility: Most mangiferin-polymer systems demonstrate better solubility in acidic environments than in basic ones. Adjusting the proportion of polymers in the systems can modulate this solubility.
- Effect of Polymer Composition: As the proportion of polymers and the molecular sizes of the polymers increase in the composition, the size of the resulting system also increases.
- Surfactant Influence: The chemical structure of surfactants affects various properties of mangiferin-polymer systems, including particle size, distribution of mangiferin, and release characteristics. The presence of surfactants can accelerate the release of active ingredients.
Future Directions
The research on polymer-mangiferin systems is still in its early stages, and several avenues for further exploration exist. Future studies should focus on optimizing polymer compositions to achieve specific release profiles, as well as conducting cytotoxicity assessments and in vivo release studies to assess the potential biomedical applications of these systems. Additionally, exploring the influence of different surfactants and polymer combinations on drug release kinetics could provide valuable insights for drug delivery system design.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414237/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827323/
