Mangiferin: a Metabolic Nootropic ?

Mangiferin is one of the rising stars of the Nutraceutical industry.

Extracted from mango leaves, it has demonstrated Nootropic benefits and has recently shown promising potential for Metabolic regulation.

Could mangiferin become a staple ingredient in metabolism-related applications – both on its own or combined with other potent phytoactives ?

1. INTRODUCTION

Mangiferin is a xanthonoid, more specifically a glycosylated form of norathyriol. As its name suggests, it is found in the mango tree (Mangifera indica) but also in the red kapok tree (Bombax ceiba) or even in the less exotic yellow gentian root (Gentiana lutea).

Xanthones and xanthonoids are a relatively unknown class of phytonutrients in the West. They are nonetheless well renowned in Asian medicine and can be extracted from the mango (mangiferin) and the mangosteen tree (mangostines), both of which are found in the traditional pharmacopoeias.

Given the available scientific data and the increasing incidence of metabolic imbalances in the Western world, it seems that this category of molecules with promising health effects is not to be neglected for this application. Therefore, this article aims at reviewing the available scientific data on mangiferin, while highlighting the interest of combining it with other phytonutrients for an effective nutraceutical approach or even in the context of a 2.0 clinical nutrition protocol.

2. OVERVIEW OF MANGIFERIN PROPERTIES

2.1. Metabolic regulation

 

Although it has recently been put forward for its properties on the neurological sphere – and more specifically for its nootropic effects – mangiferin is mainly studied for its impact on metabolic regulation. Indeed, many studies have highlighted its ability to influence various aspects of metabolic balance, showing mangiferin acted on both glycaemic [1-6] and lipidemic metabolism [7-12].

The mechanisms involved in the regulatory action of mangiferin have not yet been entirely identified at this stage, however, the following effects have already been demonstrated:

  • Stimulation of the SIRT1/AMPK cascade [12-15].
  • Stimulation of Adiponectin [7; 16; 17] (which could be linked to the previous point).
  • Activation of alpha and gamma PPAR related pathways [3; 18-20].
  • inhibition of alpha-Glucosidase [21].

The underlying mechanisms behind these effects have also been related to autophagy [10; 22-25], as well as anti-inflammatory properties. The extended physiological impact of mangiferin therefore suggests its significant action on the intestine-microbiota-liver axis, through modulation of bile acids in particular (FXR, TGR5, SERBP, etc.).

 

2.2. Neurological effects

 

As far as scientific literature is concerned, mangiferin is essentially a metabolic regulator. However, several studies clearly highlight its neurological benefits [26], thus justifying its use in a nootropic context. Indeed, mangiferin shows neuroprotective effects [27-30], as well as a positive impact on various models of neurological pathologies, stemming – at least partially – from its neuroprotective effects [31-35]. In addition, a recent clinical study on ZYNAMITE, a mango leaf extract highly concentrated in mangiferin has shown significant nootropic effects [36].

It should be noted that the regulatory effects on the metabolic sphere are not necessarily to be dissociated from the neuroprotective and nootropic benefits. Indeed, many phytonutrients with demonstrated impact on the cognitive sphere do so through metabolic regulation – at least partially. For example, bile acids can act at the cerebral level and can thus influence the neurological sphere. Modulation of adipokines can also have a neurological impact.

Moreover, from a more practical point of view, the idea of ​​supporting cognitive functions while promoting metabolic performance is clearly fits well in the “active lifestyle” trends observed on the market, which can target several segments of the population – from “active senior” to the “young sports executive” and the “professional gamer”.

 

2.3. Other Health Perspectives

 

The health potential of mangiferin does not stop at the first and second brains. Its potential has been highlighted in various processes related to inflammation [37-50], cardiovascular health [51-57] or even oncology [58-70].

 

3. MANGIFERIN: AN ADAPTOGEN BOOSTER?

The concepts of “metabolic regulation”, “nootropic activity” and “vitality” in general are often associated with adaptogens. Indeed, these plants can deploy a true pleiotropic activity thanks to the diversity of their active compounds, which can intervene in a myriad of physiological mechanisms in aims to strengthen the overall resilience of the organism. Certain aspects of this pleiotropic activity can thus be optimized by combining adaptogens with more “targeted” active ingredients. Indeed, the diversity of the health benefits of an adaptogenic plant is reflected in the diversity of its molecular profile; the use of targeted active ingredients with a complementary mechanism of action could therefore be a promising strategy to reinforce and enhance their health properties.

In this context, the association between Korean ginseng (Panax ginseng) and mangiferin shows many advantages. Beyond the fact that ginseng is the most studied adaptogen in the world, its benefits are widely associated with mental performance, as well as resilience against fatigue. Moreover, ginseng’s effects on metabolic balance have been widely demonstrated and documented. Strengthening this metabolic dimension by adding mangiferin to ginseng could allow the nutraceutical industry to offer an effective active tandem in the short and long term and maximize the results.

4. MANGIFERIN & BERBERINE: A PROMISING DUO?

When thinking of natural compounds used in metabolic regulation, berberine is probably the one that most often comes to mind for Western practitioners. It is an isoquinoline alkaloid found in the genus Berberis (Berberis aristata probably being the most common commercial source) but also in other medicinal plants such as Goldenseal (Hydrastis canadensis). Although health professionals may recommend it as an alternative to metformin, it should be remembered that berberine is marketed as a food supplement and not as a drug, and this despite it having significant pharmacological properties in high doses recognized by the ANSM.

However, berberine has a major drawback: its significant daily active dose must be divided into multiple doses to minimize the risk of intestinal disorders, a well-known side effect. But the idea of ​​having 5 daily intakes of a food supplement is not particularly pleasant and patient compliance may be affected. Furthermore, the health authorities consider that high doses of berberine also present a risk of drug interactions, which limits the possibilities of use in a clinical setting. This is an invitation to consider reducing the dose, however at the risk of diminishing the efficacy and potential interest of the substance.

The idea of ​​combining complementary phytonutrients with lower doses of berberine is therefore of great interest, whether in the context of dietary supplementation or in clinical nutrition. However, it should be noted that the “complementarity” of action is not integral since there are potential similarities in certain physiological mechanisms of action between Berberine and Mangiferin – in particular the mechanisms related to autophagy or PPARα, SIRT1 pathways.

CONCLUSION

Although still little known in Europe, mangiferin shows significant activity on the metabolic sphere and its resulting benefits (nootropic, ergogenic, etc.) make it a phytonutrient of choice for the future of clinical nutrition. Its association with adaptogenic plants such as Korean ginseng (Panax ginseng) and specific medicinal mushrooms such as Reishi (Ganoderma lucidum), or with other “metabolic phytoactives” such as berberine, could well make it a flagship in clinical nutrition. 2.0. Mangiferin’s future on the nutraceutical market on the other hand, appears to be all mapped out.

REFERENCES

[1] Wu Y, Liu W, Yang T, Li M, Qin L, Wu L, Liu T (2021) – “Oral administration of mangiferin ameliorates diabetes in animal models: a meta-analysis and systematic review.” Nutr Res. 2021 Mar;87:57-69.

[2] Aswal S, Kumar A, Chauhan A, Semwal RB, Kumar A, Semwal DK (2020) – “A Molecular Approach on the Protective Effects of Mangiferin Against Diabetes and Diabetes-related Complications.” Curr Diabetes Rev. 2020;16(7):690-698.

[3] Zhang Q, Kong X, Yuan H, Guan H, Li Y, Niu Y (2019) – “Mangiferin Improved Palmitate-Induced-Insulin Resistance by Promoting Free Fatty Acid Metabolism in HepG2 and C2C12 Cells via PPARalpha: Mangiferin Improved Insulin Resistance.” J Diabetes Res. 2019 Jan 27;2019:2052675.

[4] Liu Z, Apontes P, Fomenko EV, Chi N, Schuster VL, Kurland IJ, Pessin JE, Chi Y (2018) – « Mangiferin Accelerates Glycolysis and Enhances Mitochondrial Bioenergetics. » Int J Mol Sci. 2018 Jan 9;19(1):201.

[5] Xu X, Chen Y, Song J, Hou F, Ma X, Liu B, Huang F.(2018) – “Mangiferin suppresses endoplasmic reticulum stress in perivascular adipose tissue and prevents insulin resistance in the endothelium.” Eur J Nutr. 2018 Jun;57(4):1563-1575.

[6] Zhou L, Pan Y, Chonan R, Batey R, Rong X, Yamahara J, Wang J, Li Y. (2016) – “Mitigation of Insulin Resistance by Mangiferin in a Rat Model of Fructose-Induced Metabolic Syndrome Is Associated with Modulation of CD36 Redistribution in the Skeletal Muscle.” J Pharmacol Exp Ther. 2016 Jan;356(1):74-84.

[7] Sferrazzo G, Palmeri R, Vanella L, Parafati L, Ronsisvalle S, Biondi A, Basile F, Li Volti G, Barbagallo I (2019) – “Mangifera indica L. Leaf Extract Induces Adiponectin and Regulates Adipogenesis.” Int J Mol Sci. 2019 Jun 29;20(13):3211.

[8] Li M , Wu C , Guo H , Chu C , Hu M , Zhou C (2019) – “Mangiferin improves hepatic damage-associated molecular patterns, lipid metabolic disorder and mitochondrial dysfunction in alcohol hepatitis rats.” Food Funct. 2019 Jun 19;10(6):3514-3534.

[9] Guo F, Zi T, Liu L, Feng R, Sun C (2017) – « A (1)H-NMR based metabolomics study of the intervention effect of mangiferin on hyperlipidemia hamsters induced by a high-fat diet.” Food Funct. 2017 Jul 19;8(7):2455-2464.

[10] Wang H, Zhu YY, Wang L, Teng T, Zhou M, Wang SG, Tian YZ, Du L, Yin XX, Sun Y (2017) – “Mangiferin ameliorates fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice.” Biomed Pharmacother. 2017 Dec;96:328-335.

[11] Na L, Zhang Q, Jiang S, Du S, Zhang W, Li Y, Sun C, Niu Y (2015) – “Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: a double-blind randomized controlled trial.” Sci Rep. 2015 May 19;5:10344. doi: 10.1038/srep10344.

[12] Niu Y, Li S, Na L, Feng R, Liu L, Li Y, Sun C. (2012) – “Mangiferin decreases plasma free fatty acids through promoting its catabolism in liver by activation of AMPK.” PLoS One. 2012;7(1):e30782.

[13] Chen M, Wang Z, Zhou W, Lu C, Ji T, Yang W, Jin Z, Tian Y, Lei W, Wu S, Fu Q, Wu Z, Wu X, Han M, Fang M, Yang Y (2021) – “SIRT1/PGC-1alpha signaling activation by mangiferin attenuates cerebral hypoxia/reoxygenation injury in neuroblastoma cells.” Eur J Pharmacol. 2021 Sep 15;907:174236.

[14] Rahman MS, Kim YS. (2020) – “Mangiferin induces the expression of a thermogenic signature via AMPK signaling during brown-adipocyte differentiation.” Food Chem Toxicol. 2020 Jul;141:111415.

[15] Li J, Liu M, Yu H, Wang W, Han L, Chen Q, Ruan J, Wen S, Zhang Y, Wang T (2018) – “Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling.” Front Pharmacol. 2018 Mar 7;9:201.

[16] Yang CQ, Xu JH, Yan DD, Liu BL, Liu K, Huang F (2017) – “Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition.” Chin J Nat Med. 2017 Sep;15(9):664-673.

[17] Saleh S, El-Maraghy N, Reda E, Barakat W (2014) – “Modulation of diabetes and dyslipidemia in diabetic insulin-resistant rats by mangiferin: role of adiponectin and TNF-alpha.” An Acad Bras Cienc. 2014 Dec;86(4):1935-48.

[18] El-Sayyad SM, Soubh AA, Awad AS, El-Abhar HS (2017) – “Mangiferin protects against intestinal ischemia/reperfusion-induced liver injury: Involvement of PPAR-γ, GSK-3β and Wnt/β-catenin pathway.” Eur J Pharmacol. 2017 Aug 15;809:80-86.

[19] Qu Y, Zhou L, Wang C (2017) – “Mangiferin Inhibits IL-1β-Induced Inflammatory Response by Activating PPAR-γ in Human Osteoarthritis Chondrocytes.” Inflammation. 2017 Feb;40(1):52-57.

[20] Mahmoud-Awny M, Attia AS, Abd-Ellah MF, El-Abhar HS (2005) – “Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways.” PLoS One. 2015 Jul 21;10(7):e0132497.

[21] Shi ZL, Liu YD, Yuan YY, Song D, Qi MF, Yang XJ, Wang P, Li XY, Shang JH, Yang ZX. (2017) – “In Vitro and In Vivo Effects of Norathyriol and Mangiferin on alpha-Glucosidase.” Biochem Res Int. 2017;2017:1206015.

[22] Yu L, Chen M, Zhang R, Jin Z (2019) – “Inhibition of cancer cell growth in gemcitabine-resistant pancreatic carcinoma by mangiferin phytochemical involves induction of autophagy, endogenous ROS production, cell cycle disruption, mitochondrial mediated apoptosis and suppression of cancer cell migration and invasion.” J BUON. 2019 Jul-Aug;24(4):1581-1586.

[23] Li Y, Wu Y, Jiang K, Han W, Zhang J, Xie L, Liu Y, Xiao J, Wang X (2019) – “Mangiferin Prevents TBHP-Induced Apoptosis and ECM Degradation in Mouse Osteoarthritic Chondrocytes via Restoring Autophagy and Ameliorates Murine Osteoarthritis.” Oxid Med Cell Longev. 2019 Oct 15;2019:8783197.

[24] Hou J, Zheng D, Xiao W, Li D, Ma J, Hu Y (2018) – “Mangiferin Enhanced Autophagy via Inhibiting mTORC1 Pathway to Prevent High Glucose-Induced Cardiomyocyte Injury.” Front Pharmacol. 2018 Apr 17;9:383.

[25] Bai Y, Liu C, Fu L, Gong X, Dou C, Cao Z, Quan H, Li J, Kang F, Dai J, Zhao C, Dong S (2018) – « Mangiferin enhances endochondral ossification-based bone repair in massive bone defect by inducing autophagy through activating AMP-activated protein kinase signaling pathway.” FASEB J. 2018 Aug;32(8):4573-4584.

[26] López-Ríos L, Wiebe JC, Vega-Morales T, Gericke N (2020) – “Central nervous system activities of extract Mangifera indica L.” J Ethnopharmacol. 2020 May 27;260:112996.

[27] Peng S, Hou Y, Yao J, Fang J (2019) – “Neuroprotection of mangiferin against oxidative damage via arousing Nrf2 signaling pathway in PC12 cells.” Biofactors. 2019 May;45(3):381-392.

[28] Xi JS, Wang YF, Long XX, Ma Y (2018) – “Mangiferin Potentiates Neuroprotection by Isoflurane in Neonatal Hypoxic Brain Injury by Reducing Oxidative Stress and Activation of Phosphatidylinositol-3-Kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) Signaling.” Med Sci Monit. 2018 Oct 19;24:7459-7468.

[29] Yang Z, Weian C, Susu H, Hanmin W (2016) – “Protective effects of mangiferin on cerebral ischemia-reperfusion injury and its mechanisms.” Eur J Pharmacol. 2016 Jan 15;771:145-51.

[30] Wang Z, Guo S, Wang J, Shen Y, Zhang J, Wu Q (2017) – “Nrf2/HO-1 mediates the neuroprotective effect of mangiferin on early brain injury after subarachnoid hemorrhage by attenuating mitochondria-related apoptosis and neuroinflammation.” Sci Rep. 2017 Sep 19;7(1):11883.

[31] Lum PT, Sekar M, Gan SH, Pandy V, Bonam SR (2021) – “Protective effect of mangiferin on memory impairment: A systematic review.” Saudi J Biol Sci. 2021 Jan;28(1):917-927.

[32] Feng ST, Wang ZZ, Yuan YH, Sun HM, Chen NH, Zhang Y (2019) – “Mangiferin: A multipotent natural product preventing neurodegeneration in Alzheimer’s and Parkinson’s disease models.” Pharmacol Res. 2019 Aug;146:104336.

[33] Du Z, Fanshi F, Lai YH, Chen JR, Hao E, Deng J, Hsiao CD (2019) – “Mechanism of anti-dementia effects of mangiferin in a senescence accelerated mouse (SAMP8) model.” Biosci Rep. 2019 Sep 20;39(9):BSR20190488.

[34] Infante-Garcia C, Ramos-Rodriguez JJ, Delgado-Olmos I, Gamero-Carrasco C, Fernandez-Ponce MT, Casas L, Mantell C, Garcia-Alloza M (2017) – “Long-Term Mangiferin Extract Treatment Improves Central Pathology and Cognitive Deficits in APP/PS1 Mice.” Mol Neurobiol. 2017 Aug;54(6):4696-4704.

[35] Fu Y, Liu H, Song C, Zhang F, Liu Y, Wu J, Wen X, Liang C, Ma K, Li L, Zhang X, Shao X, Sun Y, Du Y, Song Y (2015) – “Mangiferin regulates cognitive deficits and heme oxygenase-1 induced by lipopolysaccharide in mice.” Int Immunopharmacol. 2015 Dec;29(2):950-956.

[36] Wightman EL, Jackson PA, Forster J, Khan J, Wiebe JC, Gericke N, Kennedy DO (2020) – “Acute Effects of a Polyphenol-Rich Leaf Extract of Mangifera indica L. (Zynamite) on Cognitive Function in Healthy Adults: A Double-Blind, Placebo-Controlled Crossover Study.” Nutrients. 2020 Jul 23;12(8):E2194.

[37] Zhang D, Han S, Zhou Y, Qi B, Wang X (2020) – “Therapeutic effects of mangiferin on sepsis-associated acute lung and kidney injuries via the downregulation of vascular permeability and protection of inflammatory and oxidative damages.” Eur J Pharm Sci. 2020 Sep 1;152:105400.

[38] Piao CH, Fan YJ, Nguyen TV, Song CH, Chai OH (2020) – “Mangiferin Alleviates Ovalbumin-Induced Allergic Rhinitis via Nrf2/HO-1/NF-κB Signaling Pathways.” Int J Mol Sci. 2020 May 12;21(10):3415.

[39] Li Y, Wu Y, Jiang K, Han W, Zhang J, Xie L, Liu Y, Xiao J, Wang X (2019) – “Mangiferin Prevents TBHP-Induced Apoptosis and ECM Degradation in Mouse Osteoarthritic Chondrocytes via Restoring Autophagy and Ameliorates Murine Osteoarthritis.” Oxid Med Cell Longev. 2019 Oct 15;2019:8783197.

[40] Garrido-Suárez BB, Garrido G, Piñeros O, Delgado-Hernández R (2020) – “Mangiferin: Possible uses in the prevention and treatment of mixed osteoarthritic pain.” Phytother Res. 2020 Mar;34(3):505-525.

[41] Yun C, Chang M, Hou G, Lan T, Yuan H, Su Z, Zhu D, Liang W, Li Q, Zhu H, Zhang J, Lu Y, Deng J, Guo H (2019) – “Mangiferin suppresses allergic asthma symptoms by decreased Th9 and Th17 responses and increased Treg response.” Mol Immunol. 2019 Oct;114:233-242.

[42] Li H, Chen Z, Zhong X, Li J, Li W (2019) – “Mangiferin alleviates experimental peri-implantitis via suppressing interleukin-6 production and Toll-like receptor 2 signaling pathway.” J Orthop Surg Res. 2019 Oct 17;14(1):325.

[43] Jia L, Sun P, Gao H, Shen J, Gao Y, Meng C, Fu S, Yao H, Zhang G (2019) – “Mangiferin attenuates bleomycin-induced pulmonary fibrosis in mice through inhibiting TLR4/p65 and TGF-β1/Smad2/3 pathway.” J Pharm Pharmacol. 2019 Jun;71(6):1017-1028.

[44] Mahalanobish S, Saha S, Dutta S, Sil PC (2019) – “Mangiferin alleviates arsenic induced oxidative lung injury via upregulation of the Nrf2-HO1 axis.” Food Chem Toxicol. 2019 Apr;126:41-55.

[45] Liang CL, Lu W, Zhou JY, Chen Y, Zhang Q, Liu H, Qiu F, Dai Z (2018) – “Mangiferin Attenuates Murine Lupus Nephritis by Inducing CD4+Foxp3+ Regulatory T Cells via Suppression of mTOR Signaling.” Cell Physiol Biochem. 2018;50(4):1560-1573.

[46] Garrido-Suárez BB, Garrido G, Castro-Labrada M, Pardo-Ruíz Z, Bellma Menéndez A, Spencer E, Godoy-Figueiredo J, Ferreira SH, Delgado-Hernández R (2018) – “Anti-allodynic Effect of Mangiferin in Rats With Chronic Post-ischemia Pain: A Model of Complex Regional Pain Syndrome Type I.” Front Pharmacol. 2018 Oct 2;9:1119.

[47] Pal R, Chaudhary MJ, Tiwari PC, Nath R, Pant KK (2018) – “Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats.” Inflammopharmacology. 2018 Jun 22.

[48] Qu S, Wang W, Li D, Li S, Zhang L, Fu Y, Zhang N (2017) – “Mangiferin inhibits mastitis induced by LPS via suppressing NF-ĸB and NLRP3 signaling pathways.” Int Immunopharmacol. 2017 Feb;43:85-90.

[49] Li H, Wang Q, Chen X, Ding Y, Li W (2016) – “Mangiferin inhibits lipopolysaccharide-induced production of interleukin-6 in human oral epithelial cells by suppressing toll-like receptor signaling.” Arch Oral Biol. 2016 Nov;71:155-161.

[50] Wei Z, Yan L, Chen Y, Bao C, Deng J, Deng J. (2016) – “Mangiferin inhibits macrophage classical activation via downregulating interferon regulatory factor 5 expression.” Mol Med Rep. 2016 Aug;14(2):1091-8.

[51] Song J, Meng Y, Wang M, Li L, Liu Z, Zheng K, Wu L, Liu B, Hou F, Li A (2020) – “Mangiferin activates Nrf2 to attenuate cardiac fibrosis via redistributing glutaminolysis-derived glutamate.” Pharmacol Res. 2020 Jul;157:104845.

[52] Jiang T, Han F, Gao G, Liu M (2020) – “Mangiferin exert cardioprotective and anti-apoptotic effects in heart failure induced rats.” Life Sci. 2020 May 15;249:117476.

[53] Ren K, Li H, Zhou HF, Liang Y, Tong M, Chen L, Zheng XL, Zhao GJ (2019) – “Mangiferin promotes macrophage cholesterol efflux and protects against atherosclerosis by augmenting the expression of ABCA1 and ABCG1.” Aging (Albany NY). 2019 Dec 2;11(23):10992-11009.

[54] Alañón ME, Palomo I, Rodríguez L, Fuentes E, Arráez-Román D, Segura-Carretero A (2019) – “Antiplatelet Activity of Natural Bioactive Extracts from Mango (Mangifera Indica L.) and its By-Products.” Antioxidants (Basel). 2019 Oct 29;8(11):517.

[55] Liu K, Wang F, Wang S, Li WN, Ye Q (2019) – “Mangiferin Attenuates Myocardial Ischemia-Reperfusion Injury via MAPK/Nrf-2/HO-1/NF-κB In Vitro and In Vivo.” Oxid Med Cell Longev. 2019 May 13;2019:7285434.

[56] Jiang F, Zhang DL, Jia M, Hao WH, Li YJ (2018) – “Mangiferin inhibits high-fat diet induced vascular injury via regulation of PTEN/AKT/eNOS pathway.” J Pharmacol Sci. 2018 Jul;137(3):265-273.

[57] Yang H, Bai W, Gao L, Jiang J, Tang Y, Niu Y, Lin H, Li L (2018) – “Mangiferin alleviates hypertension induced by hyperuricemia via increasing nitric oxide releases.” J Pharmacol Sci. 2018 Jun;137(2):154-161.

[58] Zeng Z, Lin C, Wang S, Wang P, Xu W, Ma W, Wang J, Xiang Q, Liu Y, Yang J, Ye F, Xie K, Xu J, Luo Y, Liu SL, Liu H (2020) – “Suppressive activities of mangiferin on human epithelial ovarian cancer.” Phytomedicine. 2020 Jun 15;76:153267.

[59] Lin YS, Tsai KL, Chen JN, Wu CS (2020) – “Mangiferin inhibits lipopolysaccharide-induced epithelial-mesenchymal transition (EMT) and enhances the expression of tumor suppressor gene PER1 in non-small cell lung cancer cells.” Environ Toxicol. 2020 May 18.

[60] Wen J, Qin Y, Li C, Dai X, Wu T, Yin W (2020) – “Mangiferin suppresses human metastatic osteosarcoma cell growth by down-regulating the expression of metalloproteinases-1/2 and parathyroid hormone receptor 1.” AMB Express. 2020 Jan 18;10(1):13.

[61] Delgado-Hernández R, Hernández-Balmaseda I, Rodeiro-Guerra I, Cesar Rodriguez Gonzalez J, De Wever O, Logie E, Declerck K, Pérez-Novo C, Vanden Berghe W (2020) – “Anti-angiogenic effects of mangiferin and mechanism of action in metastatic melanoma.” Melanoma Res. 2020 Feb;30(1):39-51.

[62] Yu L, Chen M, Zhang R, Jin Z (2019) – “Inhibition of cancer cell growth in gemcitabine-resistant pancreatic carcinoma by mangiferin phytochemical involves induction of autophagy, endogenous ROS production, cell cycle disruption, mitochondrial mediated apoptosis and suppression of cancer cell migration and invasion.” J BUON. 2019 Jul-Aug;24(4):1581-1586.

[63] Yang G, Shang X, Cui G, Zhao L, Zhao H, Wang N (2019) – “Mangiferin Attenuated Diethynitrosamine-Induced Hepatocellular Carcinoma in Sprague-Dawley Rats via Alteration of Oxidative Stress and Apoptotic Pathway.” J Environ Pathol Toxicol Oncol. 2019;38(1):1-12.

[64] He W, You Y, Du S, Lei T, Wang H, Li X, He X, Tong R, Wang Y (2019) – “Anti-neoplastic effect of mangiferin on human ovarian adenocarcinoma OVCAR8 cells via the regulation of YAP.” Oncol Lett. 2019 Jan;17(1):1008-1018.

[65] Sadhukhan P, Saha S, Dutta S, Sil PC (2018) – “Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf-2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin.” Front Pharmacol. 2018 Jun 18;9:638.

[66] Tan HY, Wang N, Li S, Hong M, Guo W, Man K, Cheng CS, Chen Z, Feng Y (2018) – “Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma.” Cell Physiol Biochem. 2018;47(5):1819-1834.

[67] Deng Q, Tian YX, Liang J (2018) – “Mangiferin inhibits cell migration and invasion through Rac1/WAVE2 signalling in breast cancer.” Cytotechnology. 2018 Apr;70(2):593-601.

[68] Du M, Wen G, Jin J, Chen Y, Cao J, Xu A (2017) – “Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway.” Anticancer Drugs. 2017 Dec 5.

[69] Zou B, Wang H, Liu Y, Qi P, Lei T, Sun M, Wang Y (2017) – “Mangiferin induces apoptosis in human ovarian adenocarcinoma OVCAR3 cells via the regulation of Notch3.” Oncol Rep. 2017 Sep;38(3):1431-1441.

[70] Cuccioloni M, Bonfili L, Mozzicafreddo M, Cecarini V, Scuri S, Cocchioni M, Nabissi M, Santoni G, Eleuteri AM, Angeletti M (2016) – “Mangiferin blocks proliferation and induces apoptosis of breast cancer cells via suppression of the mevalonate pathway and by proteasome inhibition.” Food Funct. 2016 Oct 12;7(10):4299-4309.