Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: Role of AGE-RAGE/MAPK pathways
Open accessAbstract
Hyperglycemia induced advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) activation is thought to involve in the development of cardiovascular disease in diabetics. Activation of AGE-RAGE axis results in the oxidative stress and inflammation. Mangiferin is found in the bark of mango tree and is known to treat diseases owing to its various biological activities. Thus, this study was designed to evaluate the effect of mangiferin in ischemia-reperfusion (IR) induced myocardial injury in diabetic rats. A single injection of STZ (70 mg/kg; i.p.) was injected to male albino Wistar rats to induce diabetes. After confirmation of diabetes, rats were administered vehicle (2 ml/kg; i.p.) and mangiferin (40 mg/kg; i.p.) for 28 days. On 28 th day, left anterior descending coronary artery was ligated for 45 min and then reperfused for 60 min. Mangiferin treatment significantly improved cardiac function, restored antioxidant status, reduced inflammation, apoptosis and maintained myocardial architecture. Furthermore, mangiferin significantly inhibited the activation of AGE-RAGE axis, c-Jun N-terminal kinase (JNK) and p38 and increased the expression of extracellular regulated kinase 1/2 (ERK1/2) in the myocardium. Thus, mangiferin attenuated IR injury in diabetic rats by modulation of AGE-RAGE/MAPK pathways which further prevented oxidative stress, inflammation and apoptosis in the myocardium.
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MGF exerts protective effects across a broad spectrum of pathological conditions, including inflammatory, neurodegenerative, ocular, renal, cardiovascular, dermatological and infectious diseases.
“In addition to its well-characterized roles in diabetes and cancer, MGF exerts protective effects across a broad spectrum of pathological conditions. These include inflammatory, neurodegenerative, ocular, renal, cardiovascular, dermatological and infectious diseases (7,36,106,115-118).”
From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [117]
The Discussion (page not available) reports that mangiferin protected diabetic rat hearts from ischemia–reperfusion injury and cites evidence of benefit in diabetic nephropathy; the Results also report reduced inflammation. The paper does not establish protective effects in ocular, dermatological, or infectious diseases. Its mention of neurodegenerative disorders concerns RAGE, not mangiferin. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSeveral 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 [117]
The Discussion (page unavailable) reports that mangiferin reduced NF-κBp65 expression in diabetic rats with myocardial ischemia-reperfusion injury, supporting NF-κB modulation in that setting. It does not address MMP-9, G2/M arrest, or AMPK activation, and it does not assess variation across cell lines or strains or inconsistent replication under different stimuli or doses. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany studies rely on single models, small or unreported sample sizes, and pretreatment designs rather than therapeutic intervention after disease onset, reducing external validity.
“A number of studies rely on single models, small or unreported sample sizes, and pretreatment designs rather than therapeutic intervention after disease onset, which reduces external validity (117,188).”
From Mangiferin in human disease: Multifaceted mechanisms and applications (Review) (2026) · cites this paper as [117]
The Methods section, “Drug administration and animal model of myocardial IR injury” (page not available), describes one rat model with 10–12 animals per group and mangiferin given for 28 days before ischemia–reperfusion injury. It does report sample sizes, however, and does not assess a broader pattern across studies or state that these designs reduce external validity. The treatment also began in diabetic rats, so it was not solely pretreatment before disease onset. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMangiferin inhibits activation of the AGE-RAGE/MAPK, JNK and p38 pathways.
“Notably, mangiferin inhibits activation of the AGE-RAGE/mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 pathways (41).”
From Mangiferin: An effective therapeutic agent against several disorders (Review) (2018) · cites this paper as [41]
The Results sections on AGE-RAGE activation and MAPK phosphorylation report that mangiferin reduced AGE-RAGE expression and decreased p38 and JNK in diabetic rats with myocardial ischemia-reperfusion injury. But the paper reports increased ERK1/2 with treatment, so it supports modulation of MAPK signaling rather than inhibition of the entire MAPK pathway. The unqualified claim also omits the study’s specific rat model. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChronic treatment with mangiferin (20 mg/kg for 16 weeks) decreased myocardial enzymes CK-MB and LDH, and inflammatory mediators TNF-alpha and IL-1beta in serum and left ventricular myocardium.
“In addition, chronic treatment with mangiferin (20 mg/kg for 16 weeks) decreased the level of myocardial enzymes creatine kinase-MB and lactate dehydrogenase (LDH), as well as the inflammatory mediators tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the serum and left ventricular myocardium (41).”
From Mangiferin: An effective therapeutic agent against several disorders (Review) (2018) · cites this paper as [41]
The Results (‘Mangiferin normalized antioxidant status and cardiac enzymes levels’ and ‘Mangiferin inhibited inflammation’; pages unavailable) report reduced serum CK-MB and LDH release and reduced inflammatory markers, including serum TNF-α, after mangiferin treatment. However, the Methods specify 40 mg/kg/day for 28 days, not 20 mg/kg for 16 weeks. They report measuring serum IL-6 rather than IL-1β, and do not report reductions in all four named markers in left ventricular myocardium. (LLM, conf=0.90)
Experimental — accuracy not yet measured
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 [117]
The Material and Methods (Experimental preparation; page unavailable) describe experiments in Wistar rats, but no comparison across animal strains or cell lines. The Discussion addresses NF-κB and MAPK findings without reporting inconsistent replication across stimuli or dosing conditions. Searches for those comparisons found no supporting passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Mangiferin: An effective therapeutic agent against several disorders (Review)
Du, S., Liu, H., Lei, T., Xie, X., Wang, H., He, X., Tong, R., & Wang, Y. (2018) · Molecular Medicine Reports · doi:10.3892/mmr.2018.9529 · Cited by 139 · see citing works
“Notably, mangiferin inhibits activation of the AGE-RAGE/mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and p38 pathways (41).”
The management of diabetes mellitus by mangiferin: advances and prospects
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Mangiferin in human disease: Multifaceted mechanisms and applications (Review)
Dai, Y., Huang, Q., Tan, M., Wang, Z., Jiang, C., Liu, Z., Zhang, S., & Song, S. (2026) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2026.5736 · Cited by 3 · see citing works
“…cell lines and animal strains, and several mechanisms that are frequently cited (for example, NF‑ κ B or MMP‑9 modulation, G 2 /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).”
- Authors
- Suchal, K., Malik, S., Khan, S. I., Malhotra, R. K., Goyal, S. N., Bhatia, J., Kumari, S., Ojha, S., & Arya, D. S.
- Affiliations
- All India Institute of Medical Sciences (IN)
- Indian Agricultural Research Institute (IN)
- United Arab Emirates University (AE)
- Corresponding author
- Arya, Dharamvir Singh
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-02-09
- Volume
- 7
- Issue
- 1
- Pages
- 42027-42027
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5299420
- OpenAlex
- W2586342722
- Cited by
- 100
- References
- 4
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 13 · 2023: 10 · 2022: 11 · 2021: 9 · 2020: 15 · 2019: 11 · 2018: 7 · 2017: 9
- FWCI
- 17.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- mangiferin, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, streptozotocin-induced diabetes, AGE-RAGE signaling pathway, MAPK signaling, JNK, p38 MAPK, ERK1/2, oxidative stress, inflammation, apoptosis, cardioprotection
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Cardiovascular Agents, Diabetes Mellitus, Experimental, Disease Models, Animal, Male, Signal Transduction, Reperfusion Injury, Treatment Outcome, Glycation End Products, Advanced, Myocardial Ischemia, Rats, Wistar, MAP Kinase Signaling System, Xanthones
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