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Cited by 35Mangiferin and Mango ExtractsChemotherapy-induced cardiotoxicity and mitigationGenomics, phytochemicals, and oxidative stress

Mangiferin Inhibits Apoptosis in Doxorubicin-Induced Vascular Endothelial Cells via the Nrf2 Signaling Pathway

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Ismail, Mohammad Bani, Rajendran, Peramaiyan, AbuZahra, Hamad Mohammed, Veeraraghavan, Vishnu Priya·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22084259PMC PMC8073066
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Abstract

Doxorubicin increases endothelial permeability, hence increasing cardiomyocytes’ exposure to doxorubicin (DOX) and exposing myocytes to more immediate damage. Reactive oxygen species are major effector molecules of doxorubicin’s activity. Mangiferin (MGN) is a xanthone derivative that consists of C-glucosylxanthone with additional antioxidant properties. This particular study assessed the effects of MGN on DOX-induced cytotoxicity in human umbilical vein endothelial cells’ (HUVECs’) signaling networks. Mechanistically, MGN dramatically elevated Nrf2 expression at both the messenger RNA and protein levels through the upregulation of the PI3K/AKT pathway, leading to an increase in Nrf2-downstream genes. Cell apoptosis was assessed with a caspase-3 activity assay, transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) staining was performed to assess DNA fragmentation, and protein expression was determined by Western blot analysis. DOX markedly increased the generation of reactive oxygen species, PARP, caspase-3, and TUNEL-positive cell numbers, but reduced the expression of Bcl-2 and antioxidants’ intracellular concentrations. These were effectively antagonized with MGN (20 μM), which led to HUVECs being protected against DOX-induced apoptosis, partly through the PI3K/AKT-mediated NRF2/HO-1 signaling pathway, which could theoretically protect the vessels from severe DOX toxicity.

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  • Available data suggest that MGF-driven restoration of redox homeostasis represents a central mechanistic axis of its antitumor activity, rather than merely a downstream branch of apoptosis.

    “However, available data suggest that MGF-driven restoration of redox homeostasis represents a central mechanistic axis of its antitumor activity, rather than merely a downstream branch of apoptosis (84,85).”

    From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [85]

    The Discussion and Conclusions (sections 3 and 5; pages unavailable) describe mangiferin activating antioxidant signaling through PI3K/AKT–Nrf2 and reducing apoptosis in doxorubicin-exposed endothelial cells. They support a redox mechanism that is not merely downstream of apoptosis, but they do not establish it as a central mechanism of mangiferin’s antitumor activity; the studied effect is protection from treatment-related vascular damage. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Ismail, M. B., Rajendran, P., AbuZahra, H. M., & Veeraraghavan, V. P.
Affiliations
  • King Faisal University (SA)
  • Saveetha University (IN)
Corresponding author
  • Ismail, Mohammad Bani
  • Rajendran, Peramaiyan
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-04-20
Volume
22
Issue
8
Pages
4259
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22084259
PMC
PMC8073066
OpenAlex
W3154122321
Cited by
35
References
0
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 9 · 2022: 9 · 2021: 2
FWCI
7.04
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Deanship of Scientific Research, King Faisal University (216026)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Keywords
mangiferin, doxorubicin, cardiotoxicity, vascular endothelial cells, apoptosis, Nrf2 signaling, PI3K/Akt signaling, heme oxygenase-1, reactive oxygen species, caspase-3, Bcl-2, xanthones, cardioprotection
MeSH terms
Antioxidants, Cell Survival, Doxorubicin, Fluorescent Antibody Technique, Humans, Blotting, Western, Signal Transduction, Apoptosis, Reactive Oxygen Species, Oxidative Stress, In Situ Nick-End Labeling, Xanthones, NF-E2-Related Factor 2, DNA Fragmentation, Human Umbilical Vein Endothelial Cells

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