Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin-interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells
Abstract
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 IRE1α phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1β secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1β 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 (Δψm) 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 hom…
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In endothelial cells cultured with mangiferin at 0.1, 1 and 10 microM, expression of TXNIP, NLRP3, IL-1beta and IL-6, and phosphorylation of AMPK, was attenuated, demonstrating inhibitory effects on TXNIP/NLRP3 inflammasome activation and ameliorative effects on endothelial dysfunction.
“The expression of thioredoxin-interacting protein (TXNIP), NLR family pyrin domain containing 3 (NLRP3), IL-1β and IL-6, as well as the phosphorylation of AMP-activated protein kinase (AMPK), was attenuated in endothelial cells cultured with mangiferin at concentrations of 0.1, 1 and 10 µM, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation and it ameliorative effects on”
From Mangiferin: An effective therapeutic agent against several disorders (Review) (2018) · cites this paper as [45]
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“…compounds such as mangiferin and quercetin possess distinct chemical characteristics that influence their specific interactions within various cellular compartments [42,43], and both polyphenols (mangiferin and quercetin) exhibit significant capabilities in neutralizing free radicals [10,14].”
BackgroundThe effects of mango consumption on vascular health and immune function
Castro, R. J., Pedroza, K., & Hong, M.-Y. (2023) · Metabolism Open · doi:10.1016/j.metop.2023.100260 · Cited by 9 · see citing works
“It is possible that the antioxidant properties of mangiferin in mangos may be reducing endothelial dysfunction and maintaining homeostasis by reducing endoplasmic reticulum stress induced TXNIP/NLRP3 inflammasome activation, or by the positive regulation of AMPK activity [23].”
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“The increased expressions of TXNIP and NLRP3 and the attenuating effect of EMPA were concomitant, supporting a direct activation of NLRP3 by TXNIP in oxidized conditions (Yin et al. 2017; Mohamed et al. 2014; Liu et al. 2014; Zhao et al. 2015; Song et al. 2015; Li et al. 2015).”
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“The AMPK-mTOR pathway is the classical pathway in autophagy regulation and MG is discovered to motivate AMPK in many cell types (Song et al. 2015, Rahman and Kim 2020, Fan et al. 2023).”
Bioactive lead compounds and molecular targets for the treatment of heart diseases
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“In diabetic nephropathy models, mangiferin ( 47 ) provided renoprotective effects by inhibiting the MAPK/NF-κ B axis, activating the phosphorylated IRS-1/PI3K/Akt pathway, and mitigat-Foods ing renal ferroptosis through enhanced antioxidant activity and reduced pro-ferroptotic lipid production…”
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“Moreover, oxidative stress can activate the endoplasmic reticulum stress pathway, exacerbating endothelial dysfunction by promoting inflammation and apoptosis [9].”
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“Moreover, prolonged ER stress leads to cell death, inflammation, and oxidative stress [118–123].”
JIP3 knockout protects mice against high fat diet-induced liver injury.
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WITHDRAWN: JIP3 deficiency protects mice from high fat diet-induced liver injury.
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RetractedMangiferin: A multifunctional natural xanthone with therapeutic applications and in silico insights
Bhardwaj, S., Kapil, A., Gora, R., Garud, N., & Kumar, D. (2026) · In Silico Research in Biomedicine · doi:10.1016/j.insi.2026.100701
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- Authors
- Song, J., Li, J., Hou, F., Wang, X., & Liu, B.
- Affiliations
- Hebei University of Chinese Medicine (CN)
- Nanjing University of Chinese Medicine (CN)
- Corresponding author
- Liu, Baolin
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 64
- Issue
- 3
- Pages
- 428-437
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W2009497505
- Cited by
- 109
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 11 · 2020: 13 · 2019: 7 · 2018: 13 · 2017: 13 · 2016: 12 · 2015: 6
- FWCI
- 22.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Hebei University of Chinese Medicine College (QNZ 4014016)
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- mangiferin, endoplasmic reticulum stress, TXNIP, NLRP3 inflammasome, AMPK, endothelial dysfunction, endothelial cells, high glucose, oxidative stress, IRE1α, IL-1β, interleukin-6, mitochondrial membrane potential, caspase-3, apoptosis, endothelin-1, nitric oxide, cardiovascular complications of diabetes
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Carrier Proteins, Endoribonucleases, Humans, Hypoglycemic Agents, Inflammation, Nitric Oxide, Cytokines, Apoptosis, Protein Serine-Threonine Kinases, Reactive Oxygen Species, MAP Kinase Signaling System, Endothelial Cells, Xanthones, Membrane Potential, Mitochondrial, Endoplasmic Reticulum Stress, Human Umbilical Vein Endothelial Cells
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