Mangiferin

Mangiferin is a Nrf2 activator. Mangiferin suppresses nuclear translocation of the NF-κB subunits p65 and p50.

In Vitro:Mangiferin is glucosylxanthone extracted from plants of the Anacardiaceae and Gentianaceae families. Mangiferin (50 μM) significantly increases Nrf2 protein accumulation in HL-60 cells, particularly in the nucleus. Mangiferin also enhances the binding of Nrf2 to an antioxidant response element (ARE), significantly up-regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and reduces intracellular ROS in HL60 cells. Mangiferin alone dose-dependently inhibits the proliferation of HL-60 cells. In mononuclear cells (MNCs), Mangiferin significantly relieves oxidative stress, but attenuates etoposide-induced cytotoxicity[1]. Mangiferin is a natural phytopolyphenol that exhibits various pharmacological properties. Mangiferin is present in several plant species such as Mangifera indica, Iris unguicularis, and Anemarrhena asphodeloides. Mangiferin downregulates TNF-α-induced MMP-9 mRNA and protein expression by suppressing NF-κB activity, consequently suppressing the invasion of LNCaP cells.To assess whether Mangiferin influences the viability of LNCaP cells, MTT assay is performed 24 h after treatment with different concentrations of Mangiferin in the presence or absence of TNF-α in serum and serum-free conditions. There are no cytotoxic evident in LNCaP cells treated with up to 400 μM of Mangiferin alone under both serum and serum-free conditions. Additionally, in the presence of TNF-α (20 ng/mL), Mangiferin does not affect cell viability. Mangiferin (400 μM) treatment significantly decreases the NF-κB luciferase activity in TNF-α-stimulated LNCaP cells. Pretreatment with Mangiferin (400 μM) for 1 h significantly decreases TNF-α-induced NF-κB activity. The RT-PCR shows that Mangiferin (400 μM) significantly suppresses the TNF-α-induced MMP-9 expression in LNCaP cells[2].

References:
[1]. Zhang BP, et al. Mangiferin activates Nrf2-antioxidant response element signaling without reducing the sensitivity to etoposide of human myeloid leukemia cells in vitro. Acta Pharmacol Sin. 2014 Feb;35(2):257-66. [2]. Dilshara MG, et al. Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity. BMB Rep. 2015 Oct;48(10):559-64.

Protective effects of Mangifera indica L extract (Vimang), and its major component mangiferin, on iron-induced oxidative damage to rat serum and liver.[Pubmed:18243014]

Pharmacol Res. 2008 Jan;57(1):79-86.

In vivo preventive effects of a Mangifera indica L extract (Vimang) or its major component Mangiferin on iron overload injury have been studied in rats given respectively, 50, 100, 250 mg kg(-1) body weight of Vimang, or 40 mg kg(-1) body weight of Mangiferin, for 7 days prior to, and for 7 days following the administration of toxic amounts of iron-dextran. Both Vimang or Mangiferin treatment prevented iron overload in serum as well as liver oxidative stress, decreased serum and liver lipid peroxidation, serum GPx activity, and increased serum and liver GSH, serum SOD and the animals overall antioxidant condition. Serum iron concentration was decreased although at higher doses, Vimang tended to increase it; percent tranferrin saturation, liver weight/body mass ratios, liver iron content was decreased. Treatment increased serum iron-binding capacity and decreased serum levels of aspartate-amine transferase (ASAT) and alanine-amine transferase (ALAT), as well as the number of abnormal Kupffer cells in iron-loaded livers. It is suggested that besides acting as antioxidants, Vimang extract or its Mangiferin component decrease liver iron by increasing its excretion. Complementing earlier in vitro results from our group, it appears possible to support the hypothesis that Vimang and Mangiferin present therapeutically useful effects in iron overload related diseases.

Mangiferin attenuates renal fibrosis through down-regulation of osteopontin in diabetic rats.[Pubmed:25380391]

Phytother Res. 2015 Feb;29(2):295-302.

This study was designed to investigate the effects of Mangiferin on renal fibrosis, osteopontin production, and inflammation in the kidney of diabetic rats. Diabetes was induced through the single administration of streptozotocin (55 mg/kg, i.p.). Diabetic rats were treated with Mangiferin (15, 30, and 60 mg/kg/day, i.g.) for 9 weeks. The kidney was fixed in 10% formalin for glomerulus fibrosis examination using Masson trichrome staining. Kidney and blood were obtained for assays of the associated biochemical parameters. Chronic Mangiferin treatment prevented renal glomerulus fibrosis evidenced by decreases in Mason-stained positive area of glomeruli, protein expression of type IV collagen, and alpha-smooth muscle actin in the kidney of diabetic rats, in comparison with decreases in mRNA and protein expression of osteopontin as well as protein expression of cyclooxygenase 2 and NF-small ka, CyrillicB p65 subunit in the renal cortex of diabetic rats. Moreover, Mangiferin reduced the levels of interleukin 1beta in both the serum and the kidney of diabetic rats. Our findings demonstrate that Mangiferin prevents the renal glomerulus fibrosis of diabetic rats, which is realized through the suppression of osteopontin overproduction and inflammation likely via inactivation of NF-small ka, CyrillicB.

New antidiabetic compounds, mangiferin and its glucoside.[Pubmed:9881663]

Biol Pharm Bull. 1998 Dec;21(12):1389-90.

Mangiferin (MF) and its glucosides (Mangiferin-7-O-beta-glucoside) (MG) isolated from Anemarrhena asphodeloides Bunge rhizome, were tested for their antidiabetic activity in KK-Ay mice, an animal model of non-insulin-dependent diabetes mellitus (NIDDM). MF and MG lowered the blood glucose level of KK-Ay mice after oral administration. However, no affect on the blood glucose level in normal mice was seen, indicating that MF and MG are useful in treating NIDDM. In addition, MF or MG improved hyperinsulinemia in KK-Ay mice. From these findings, it seems likely that MF and MG exert their its antidiabetic activity by increasing insulin sensitivity.

Mangiferin induces cell cycle arrest at G2/M phase through ATR-Chk1 pathway in HL-60 leukemia cells.[Pubmed:25966274]

Genet Mol Res. 2015 May 12;14(2):4989-5002.

This study aimed to determine the effect of Mangiferin on the cell cycle in HL-60 leukemia cells and expression of the cell cycle-regulatory genes Wee1, Chk1 and CDC25C and to further investigate the molecular mechanisms of the antileukemic action of Mangiferin. The inhibitory effect of Mangiferin on HL-60 leukemia cell proliferation was determined by the MTT assay. The impact of Mangiferin on the HL-60 cell cycle was evaluated by flow cytometry. After the cells were treated with different concentrations of Mangiferin, the expression levels of Wee1, Chk1 and CDC25C mRNA were determined by RT-PCR, and Western blot was used to evaluate the expression levels of cdc25c, cyclin B1, and Akt proteins. The inhibition of HL-60 cell growth by Mangiferin was dose- and time-dependent. After treatment for 24 h, cells in G2/M phase increased, and G2/M phase arrest appeared with increased mRNA expression of Wee1, Chk1 and CDC25C. Mangiferin inhibited Chk1 and cdc25c mRNA expression at high concentrations and induced Wee1 mRNA expression in a dose-dependent manner. It significantly inhibited ATR, Chk1, Wee1, Akt, and ERK1/2 phosphorylation but increased cdc2 and cyclin B1 phosphorylation. Furthermore, Mangiferin reduced cdc25c, cyclin B1, and Akt protein levels while inducing Wee1 protein expression. It also antagonized the phosphorylation effect of vanadate on ATR, and the phosphorylation effect of EGF on Wee1. These findings indicated that Mangiferin inhibits cell cycle progression through the ATR-Chk1 stress response DNA damage pathway, leading to cell cycle arrest at G2/M phase in leukemia cells.

Mangiferin attenuates osteoclastogenesis, bone resorption, and RANKL-induced activation of NF-kappaB and ERK.[Pubmed:20683903]

J Cell Biochem. 2011 Jan;112(1):89-97.

Osteolytic bone diseases such as osteoporosis have a common pathological feature in which osteoclastic bone resorption outstrips bone synthesis. Osteoclast formation and activation are regulated by receptor activator of nuclear factor kappaB ligand (RANKL). The induction of RANKL-signaling pathways occurs following the interaction of RANKL to its cognate receptor, RANK. This specific binding drives the activation of downstream signaling pathways; which ultimately induce the formation and activation of osteoclasts. In this study, we showed that a natural immunomodulator, Mangiferin, inhibits osteoclast formation and bone resorption by attenuating RANKL-induced signaling. Mangiferin diminished the expression of osteoclast marker genes, including cathepsin K, calcitonin receptor, DC-STAMP, and V-ATPase d2. Mechanistic studies revealed that Mangiferin inhibits RANKL-induced activation of NF-kappaB, concomitant with the inhibition of IkappaB-alpha degradation, and p65 nuclear translocation. In addition, Mangiferin also exhibited an inhibitory effect on RANKL-induced ERK phosphorylation. Collectively, our data demonstrates that Mangiferin exhibits anti-resorptive properties, suggesting the potential application of Mangiferin for the treatment and prevention of bone diseases involving excessive osteoclastic bone resorption.

Anthelminthic and antiallergic activities of Mangifera indica L. stem bark components Vimang and mangiferin.[Pubmed:14669257]

Phytother Res. 2003 Dec;17(10):1203-8.

This study investigated the antiallergic and anthelmintic properties of Vimang (an aqueous extract of Mangifera indica family stem bark) and Mangiferin (the major polyphenol present in Vimang) administered orally to mice experimentally infected with the nematode, Trichinella spiralis. Treatment with Vimang or Mangiferin (500 or 50 mg per kg body weight per day, respectively) throughout the parasite life cycle led to a significant decline in the number of parasite larvae encysted in the musculature; however, neither treatment was effective against adults in the gut. Treatment with Vimang or Mangiferin likewise led to a significant decline in serum levels of specific anti-Trichinella IgE, throughout the parasite life cycle. Finally, oral treatment of rats with Vimang or Mangiferin, daily for 50 days, inhibited mast cell degranulation as evaluated by the passive cutaneous anaphylaxis test (sensitization with infected mouse serum with a high IgE titre, then stimulation with the cytosolic fraction of T. spiralis muscle larvae). Since IgE plays a key role in the pathogenesis of allergic diseases, these results suggest that Vimang and Mangiferin may be useful in the treatment of diseases of this type.

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver.[Pubmed:25123789]

Toxicol Appl Pharmacol. 2014 Oct 15;280(2):207-15.

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of Mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of Mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by Mangiferin treatment. Mechanistically, Mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, Mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that Mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of Mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation.

Mangiferin regulates proliferation and apoptosis in glioma cells by induction of microRNA-15b and inhibition of MMP-9 expression.[Pubmed:25901555]

Oncol Rep. 2015 Jun;33(6):2815-20.

Mangiferin, a flavonoid extracted from the leaves of the Anacardiaceae plant, the mango tree, has physiological activity and pharmacological effects in many aspects. The present study aimed to clarify the effect of Mangiferin on proliferation and apoptosis of glioma cells and the mechanism of these curative effects of Mangiferin. In this experiment, we detected the proliferation using 3-(4,5-dimethylthylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Then, cell apoptosis of U87 glioma cells was measured with the Annexin V-FITC/propidium iodide (PI) apoptosis detection kit, DAPI staining assay and the caspase-3 and caspase-9 activity assay kit. Next, quantitative real-time PCR and gelatin zymography were used to analyze the expression of microRNA-15b (miR-15b) and matrix metalloproteinase-9 (MMP-9), respectively. MMP-9 agonist, miR-15b mimics and anti-miR-15b mimics were added to the U87 glioma cells for elucidating the mechanisms involved in the curative effects of Mangiferin. In the present study, Mangiferin notably restrained the proliferation and increased the apoptosis of the U87 glioma cells. Meanwhile, Mangiferin specifically promoted the expression of miR-15b and suppressed the level of MMP-9 in the U87 glioma cells. miR-15b regulated the expression of MMP-9 in the U87 glioma cells. MMP-9 agonist and anti-miR15b reduced the curative effects of Mangiferin in the U87 glioma cells. In summary, Mangiferin regulates proliferation and apoptosis in glioma cells by induction of miR-15b and inhibition of MMP-9 expression.

Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells.[Pubmed:25499441]

Metabolism. 2015 Mar;64(3):428-37.

BACKGROUND: Endothelial dysfunction is tightly associated with cardiovascular complications in diabetic patients. This study aims to investigate the effects of Mangiferin on the regulation of endothelial homeostasis under endoplasmic reticulum stress (ER stress) conditions. RESULTS: High glucose (25 mmol/L) exposure induced ER stress and promoted ROS production in endothelial cells. Mangiferin effectively inhibited ER stress-associated oxidative stress by attenuating IRE1alpha phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1beta secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1beta and IL-6 production, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation. NLRP3 inflammasome activation is responsible for mitochondrial cell death. Mangiferin restored the loss of the mitochondrial membrane potential (Deltapsim) and inhibited caspase-3 activity, and thereby protected cells from high glucose-induced apoptosis. Moreover, Mangiferin inhibited ET-1 secretion and restored the loss of NO production when cells were exposed to high glucose. Mangiferin enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects, indicating the potential role of AMPK in its action. CONCLUSION: Our work showed the beneficial effects of Mangiferin on the improvement of endothelial homeostasis and elucidated the molecular pathway through which Mangiferin ameliorated endothelial dysfunction by inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells. SIGNIFICANCE: These findings demonstrated the beneficial effects of Mangiferin on the regulation of endothelial homeostasis and indicated its potential application in the management of diabetic cardiovascular complications.