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Cited by 48Mangiferin and Mango ExtractsLiver Disease Diagnosis and TreatmentNatural Antidiabetic Agents Studies

Mangiferin Ameliorates HFD-Induced NAFLD through Regulation of the AMPK and NLRP3 Inflammasome Signal Pathways

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Yong, Zhang, Ruiqi, Wang, Hongji, Yao, Ning, Ma, Chenzuo, Jiang, Yu, Zhou, Zhixuan, Xia, Qiang, Liu +3 more·2021·Journal of Immunology Research
DOI 10.1155/2021/4084566PMC PMC8560285
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is closely related to glycolipid metabolism and liver inflammation. And there is no effective drug approved for its clinical therapy. In this study, we focused on mangiferin (Man) and explored its effects and mechanisms on NAFLD treatment based on the regulation of glycolipid metabolism and anti-inflammatory in vivo and in vitro. The results exhibited that Man can significantly attenuate liver injury, insulin resistance, and glucose tolerance in high-fat diet- (HFD-) induced NAFLD mice and significantly reduce fat accumulation and inflammation in hepatic tissue of NAFLD mice. The transcriptome level RNA-seq analysis showed that the significantly different expression genes between the Man treatment group and the HFD-induced NAFLD model group were mainly related to regulation of energy, metabolism, and inflammation in liver tissue. Furthermore, western blots, real-time PCR, and immunohistochemistry experiments confirmed that Man significantly activated the AMPK signal pathway and inhibited NLRP3 inflammasome activation and pyroptosis in NAFLD mice. In in vitro cell experiments, we further confirmed that Man can promote glucose consumption and reduce intracellular triglyceride (TG) accumulation induced by free fatty acids in HepG2 cells and further that it can be blocked by AMPK-specific inhibitors. Western blot results showed that Man upregulated p-AMPKα levels and exhibited a significant AMPK activation effect, which was blocked by compound C. At the same time, Man downregulated the expression of NLRP3 inflammasome-related proteins and inhibited the activation of NLRP3 inflammasome, alleviating cell pyroptosis and inflammation effects. These results indicate that Man anti-NAFLD activity is mediated through its regulation of glucolipid metabolism by AMPK activation and its anti-inflammatory effects by NLRP3 inflammasome inhibition. Our study indicates that Man is a promising prodrug for the therapy of NAFLD patients.

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  • Several frequently cited mechanisms (NF-κB or MMP-9 modulation, G2/M arrest, AMPK activation) are highly context dependent and inconsistently replicated.

    “Notably, the results vary across cell lines and animal strains, and several mechanisms that are frequently cited (for example, NF-κB or MMP-9 modulation, G2/M arrest and AMPK activation) appear to be highly context dependent, with inconsistent replication under different stimuli or dosing conditions (4,13,117,124,186,187).”

    From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [124]

    Results §3.6 and §3.8 (page not provided) report mangiferin-associated AMPK activation in HFD-fed mice and HepG2 cells, supporting AMPK activation as a mechanism studied by this paper. The paper does not report inconsistent replication across cell lines, animal strains, stimuli, or dosing conditions, nor does it establish the claimed context dependence of NF-κB modulation, MMP-9 modulation, or G2/M arrest. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In a rodent model of high-fat diet-induced nonalcoholic fatty liver disease, MGF (25-100 mg/kg, 12 weeks) activates AMPK and suppresses NLRP3 inflammasome signaling, reducing hepatic inflammation and steatosis.

    “In a rodent model of high-fat diet-induced nonalcoholic fatty liver disease (NAFLD), MGF (25-100 mg/kg, 12 weeks) activates AMPK and suppresses NLRP3 inflammasome signaling, reducing hepatic inflammation and steatosis (124).”

    From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [124]

  • Results vary across cell lines and animal strains.

    “Notably, the results vary across cell lines and animal strains, and several mechanisms that are frequently cited (for example, NF-κB or MMP-9 modulation, G2/M arrest and AMPK activation) appear to be highly context dependent, with inconsistent replication under different stimuli or dosing conditions (4,13,117,124,186,187).”

    From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [124]

    The Methods (§§2.1, 2.7) describe one mouse strain and one cell line, while Results (§§3.8–3.9) report mangiferin-related AMPK effects in those models. Our copy does not compare results across cell lines or animal strains, or report inconsistent replication under different stimuli or doses; searches for those comparisons and conflicting findings found no supporting passage. Page numbers were not available in the indexed copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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  1. [1]Malaguarnera M. di Rosa M. Nicoletti F. Malaguarnera L. Molecular mechanisms involved in NAFLD progression Journal of Molecular Medicine 2009 87 7 679 695 10.1007/s00109-009-0464-1 2-s2.0-67649448956 19352614 · DOI
  2. [2]Katzelnick L. C. Gresh L. Halloran M. E. Antibody-dependent enhancement of severe dengue disease in humans Science 2017 358 6365 929 932 10.1126/science.aan6836 2-s2.0-85033583899 29097492 PMC5858873 · DOI
  3. [4]Buzzetti E. Pinzani M. Tsochatzis E. A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) Metabolism 2016 65 8 1038 1048 10.1016/j.metabol.2015.12.012 2-s2.0-84957812743 26823198 · DOI · Paper page
  4. [5]Huang M. Kim H. G. Zhong X. Sestrin 3 protects against diet-induced nonalcoholic steatohepatitis in mice through suppression of transforming growth factor β signal transduction Hepatology 2020 71 1 76 92 10.1002/hep.30820 2-s2.0-85073981480 31215672 PMC6920605 · DOI
  5. [6]Zhong X. Huang M. Kim H. G. SIRT6 protects against liver fibrosis by deacetylation and suppression of SMAD3 in hepatic stellate cells Cellular and Molecular Gastroenterology and Hepatology 2020 10 2 341 364 10.1016/j.jcmgh.2020.04.005 32305562 PMC7327931 · DOI
  6. [7]Chen S. Zhao X. Wan J. Dihydromyricetin improves glucose and lipid metabolism and exerts anti- inflammatory effects in nonalcoholic fatty liver disease: a randomized controlled trial Pharmacological Research 2015 99 74 81 10.1016/j.phrs.2015.05.009 2-s2.0-84930681002 26032587 · DOI
  7. [8]Jazayeri-Tehrani S. A. Rezayat S. M. Mansouri S. Nano-curcumin improves glucose indices, lipids, inflammation, and Nesfatin in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD): a double-blind randomized placebo-controlled clinical trial Nutrition & Metabolism 2019 16 1 1 13 10.1186/s12986-019-0331-1 2-s2.0-85060673005 30705687 PMC6348610 · DOI
  8. [9]Wang C. Jiang J. D. Wu W. Kong W. J. The compound of mangiferin-berberine salt has potent activities in modulating lipid and glucose metabolisms in HepG2 cells BioMed Research International 2016 2016 5 1 14 PMC4829696 27123455
  9. [10]Byrd C. M. Grosenbach D. W. Berhanu A. Novel benzoxazole inhibitor of dengue virus replication that targets the NS3 helicase Antimicrobial Agents and Chemotherapy 2013 57 4 1902 1912 10.1128/AAC.02251-12 2-s2.0-84875173228 23403421 PMC3623359 · DOI
  10. [12]Zhang B. B. Zhou G. Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome Cell Metabolism 2009 9 5 407 416 19416711
  11. [13]Day E. A. Ford R. J. Steinberg G. R. AMPK as a therapeutic target for treating metabolic diseases Trends in Endocrinology & Metabolism 2017 28 8 545 560 28647324
  12. [14]Ogawa Y. Imajo K. Honda Y. Palmitate-induced lipotoxicity is crucial for the pathogenesis of nonalcoholic fatty liver disease in cooperation with gut-derived endotoxin Scientific Reports 2018 8 1 1 14 10.1038/s41598-018-29735-6 2-s2.0-85050775070 30054551 PMC6063851 · DOI
  13. [15]Farrell G. C. Haczeyni F. Chitturi S. Pathogenesis of NASH: how metabolic complications of overnutrition favour lipotoxicity and pro-inflammatory fatty liver disease Obesity, Fatty Liver and Liver Cancer 2018 1061 19 44 29956204
  14. [16]Wang Z. Zhang S. Xiao Y. NLRP3 inflammasome and inflammatory diseases Oxidative Medicine and Cellular Longevity 2020 2020 11 10.1155/2020/4063562 PMC7049400 32148650 · DOI
  15. [17]di A. Xiong S. Ye Z. The TWIK2 potassium efflux channel in macrophages mediates NLRP3 inflammasome-induced inflammation Immunity 2018 49 1 56 65.e4 10.1016/j.immuni.2018.04.032 2-s2.0-85047883137 29958799 PMC6051907 · DOI
  16. [18]Shi J. Zhao Y. Wang K. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death Nature 2015 526 7575 660 665 10.1038/nature15514 2-s2.0-84942892037 26375003 · DOI · Paper page
  17. [19]Yuan Y. Y. Wang S. L. Yuan L. W. Inflammatory caspase-related pyroptosis: mechanism, regulation and therapeutic potential for inflammatory bowel disease Gastroenterology Report 2018 6 3 167 176 10.1093/gastro/goy011 2-s2.0-85055493557 30151200 PMC6101557 · DOI
  18. [20]Xu B. Jiang M. Chu Y. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice Journal of Hepatology 2018 68 4 773 782 10.1016/j.jhep.2017.11.040 2-s2.0-85040443938 29273476 · DOI · Paper page
  19. [21]Wu J. Lin S. Wan B. Velani B. Zhu Y. Pyroptosis in liver disease: new insights into disease mechanisms Aging and Disease 2019 10 5 1094 1108 10.14336/AD.2019.0116 31595205 PMC6764727 · DOI
  20. [23]Saha S. Sadhukhan P. Sil P. C. Mangiferin: a xanthonoid with multipotent anti-inflammatory potential BioFactors 2016 42 5 459 474 27219011
  21. [25]Yon C. Teramoto T. Mueller N. Modulation of the nucleoside triphosphatase/RNA helicase and 5′-RNA triphosphatase activities of dengue virus type 2 nonstructural protein 3 (NS3) by interaction with NS5, the RNA-dependent RNA polymerase The Journal of Biological Chemistry 2005 280 29 27412 27419 10.1074/jbc.M501393200 2-s2.0-22844443626 15917225 · DOI
  22. [27]Beier J. I. Banales J. M. Pyroptosis: an inflammatory link between NAFLD and NASH with potential therapeutic implications Journal of Hepatology 2018 68 4 643 645 29408544 PMC6185810
  23. [28]Joshi-Barve S. Barve S. S. Amancherla K. Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes Hepatology 2007 46 3 823 830 10.1002/hep.21752 2-s2.0-34548746833 17680645 · DOI
  24. [29]Musso G. Cassader M. Gambino R. Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies Nature Reviews. Drug Discovery 2016 15 4 249 274 26794269
  25. [31]Chao H.-W. Chao S. W. Lin H. Ku H. C. Cheng C. F. Homeostasis of glucose and lipid in non-alcoholic fatty liver disease International Journal of Molecular Sciences 2019 20 2 p. 298 10.3390/ijms20020298 2-s2.0-85060016472 30642126 PMC6359196 · DOI
  26. [32]Apontes P. Liu Z. Su K. Mangiferin stimulates carbohydrate oxidation and protects against high fat diet induced metabolic disorders Diabetes 2014 PMC4207399 24848064
  27. [33]Shao Y. Yuan G. Zhang J. Guo X. Liraglutide reduces lipogenetic signals in visceral adipose of db/db mice with AMPK activation and Akt suppression Drug Design Development & Therapy 2015 2015 9 1177 1184 10.2147/dddt.s79175 2-s2.0-84923210591 PMC4342181 25733821 · DOI
  28. [34]Fritzen A. M. Lundsgaard A. M. Jordy A. B. New Nordic diet-induced weight loss is accompanied by changes in metabolism and AMPK signaling in adipose tissue Journal of Clinical Endocrinology & Metabolism 2015 100 9 3509 3519 10.1210/jc.2015-2079 2-s2.0-84941730257 26126206 · DOI
  29. [36]Lebeaupin C. Proics E. de Bieville C. H. D. ER stress induces NLRP3 inflammasome activation and hepatocyte death Cell Death & Disease 2015 6 9, article ??? 10.1038/cddis.2015.248 2-s2.0-84989336849 PMC4650444 26355342 · DOI
  30. [39]Ikarashi N. Toda T. Okaniwa T. Ito K. Ochiai W. Sugiyama K. Anti-obesity and anti-diabetic effects of acacia polyphenol in obese diabetic KKAy mice fed high-fat diet Evidence-Based Complementary and Alternative Medicine 2011 2011 5 10 10.1093/ecam/nep241 2-s2.0-79957855436 PMC3137845 21799697 · DOI

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Authors
Yong, Z., Ruiqi, W., Hongji, Y., Ning, M., Chenzuo, J., Yu, Z., Zhixuan, X., Qiang, L., Qibing, L., Weiying, L., & Xiaopo, Z.
Affiliations
  • Department of Pharmacology, Hainan Medical University, Haikou, Hainan 571199, China
  • Hainan Medical University (CN)
  • Reproductive Medical Center, Hainan Women and Children’s Medical Center, Haikou 570206, China
  • Key Laboratory of Tropical Translational Medicine of the Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China
ORCID
Venue
Journal of Immunology Research
Publisher
Wiley
Published
2021-10-25
Volume
2021
Pages
1-17
ISSN
  • 2314-7156 (ISSN-L)
  • 2314-8861
DOI
10.1155/2021/4084566
PMC
PMC8560285
OpenAlex
W3209757547
Cited by
48
References
5
Citations by year
2026: 9 · 2025: 11 · 2024: 13 · 2023: 11 · 2022: 4
FWCI
7.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Immunology Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81760628, 82060778, ZDYF2019157, Hnky2019ZD-32, 819QN226)
  • Key Research and Development Program of Hainan Province (81760628, 82060778, ZDYF2019157, Hnky2019ZD-32, 819QN226)
  • Key Scientific Research Projects of Higher Education in Hainan Province (81760628, 82060778, ZDYF2019157, Hnky2019ZD-32, 819QN226)
  • Hainan Provincial Natural Science Foundation of China (81760628, 82060778, ZDYF2019157, Hnky2019ZD-32, 819QN226)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
mangiferin, non-alcoholic fatty liver disease, AMPK signaling, NLRP3 inflammasome, pyroptosis, liver inflammation, insulin resistance, glucose tolerance, lipid metabolism, hepatic steatosis, HepG2 cells, liver transcriptome
MeSH terms
Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Disease Models, Animal, Humans, Liver, Male, Signal Transduction, Xanthones, Lipid Metabolism, Mice, AMP-Activated Protein Kinases, Hep G2 Cells, Inflammasomes, Diet, High-Fat, Non-alcoholic Fatty Liver Disease

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