Mangiferin in human disease: Multifaceted mechanisms and applications (Review)

May combine two claims.

In neuroblastoma SK-N-SH cells, MGF reduces ROS production and the activity of key antioxidants GSH, SOD, catalase and GSH-Px, pushing the redox balance toward apoptosis.

“In neuroblastoma SK-N-SH cells, MGF reduces ROS production and the activity of key antioxidants, such as glutathione (GSH), superoxide dismutase (SOD), catalase and GSH peroxidase (GSH-Px), pushing the redox balance toward apoptosis (9,76).”

• cites [9] Li HW Lan TJ Yun CX Yang KD Du ZC Luo XF Hao EW Deng JG Mangiferin exerts neuroprotective activity against lead-induced toxicity and oxidative stress via Nrf2 pathway Chin Herb Med 12 36 46 2020 36117559 PMC9476390 sourceDisputed

  The Results sections on rat brain homogenates report that mangiferin increased GSH content and the activities of SOD, catalase, and GSH-Px—not decreased them. The Discussion describes a favorable antioxidant balance and neuroprotection, not a shift toward apoptosis. The reported experiments were in lead-exposed rats, not SK-N-SH cells; page numbers are unavailable in our copy. (LLM, conf=0.89)

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• cites [76] Kavitha M Manivasagam T Essa MM Tamilselvam K Selvakumar GP Karthikeyan S Thenmozhi JA Subash S Mangiferin antagonizes rotenone: induced apoptosis through attenuating mitochondrial dysfunction and oxidative stress in SK-N-SH neuroblastoma cells Neurochem Res 39 668 676 2014 10.1007/s11064-014-1249-7 24493626 sourceNot checked — no full text of the source

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After uptake in the proximal small intestine, extensive first-pass metabolism and gut microbiota-mediated deglycosylation reduce parent MGF levels.

“After uptake in the proximal small intestine, extensive first-pass metabolism and gut microbiota-mediated deglycosylation (yielding norathyriol and downstream conjugates) further reduce parent drug levels (21,160-162).”

• cites [21] Tian X Gao Y Xu Z Lian S Ma Y Guo X Hu P Li Z Huang C Pharmacokinetics of mangiferin and its metabolite-norathyriol, part 1: Systemic evaluation of hepatic first-pass effect in vitro and in vivo Biofactors 42 533 544 2016 10.1002/biof.1291 27130074 sourceDisputed

  The Discussion (p. unavailable) concludes that hepatic first-pass metabolism plays a negligible role in MGF’s poor bioavailability, contrary to the claim of extensive first-pass metabolism. Results §3.3.2 (p. unavailable) reports that intestinal bacteria produced norathyriol slowly—only 0.1% of the added MGF after 72 hours—while parent MGF changed very little. The paper therefore does not support substantial depletion of parent MGF by either process. (LLM, conf=0.90)

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• cites [160] Bunt D Schwalbe M Hayeeawaema F El Aidy S Gut microbiota-mediated conversion of mangiferin to norathyriol alters short chain fatty acid and urate metabolism Gut Microbes 17 2508422 2025 10.1080/19490976.2025.2508422 40401774 PMC12101588 sourcePartly supported

  The Results section (‘Microbial conversion of MAN to NOR occurs in the colon, not the small intestine’; page unavailable) reports that fecal microbiota converted mangiferin to norathyriol, supporting the deglycosylation component. The Introduction instead attributes mangiferin’s poor oral bioavailability primarily to poor intestinal solubility and permeability; the cited passages do not establish proximal-small-intestinal uptake, extensive first-pass metabolism, or downstream conjugates as causes of reduced parent levels. (LLM, conf=0.87)

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• cites [161] Barakat S Nasr M Ahmed RF Badawy S Mortada N Recent formulation advances of mangiferin Rev Bras Farmacogn 32 871 882 2022 10.1007/s43450-022-00297-z sourcePartly supported

  The Bioavailability section reports greater mangiferin absorption in the duodenum and jejunum than farther along the intestine, and intensive hepatic first-pass metabolism that reduces the dose reaching circulation in normal rats. The Metabolism section describes deglycosylation to norathyriol followed by gut-microbiome-mediated conjugation, but does not specifically attribute the deglycosylation step to the microbiota. (LLM, conf=0.85)

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• cites [162] Guo X Cheng M Hu P Shi Z Chen S Liu H Shi H Xu Z Tian X Huang C Absorption, metabolism, and pharmacokinetics profiles of norathyriol, an aglycone of mangiferin, in rats by HPLC-MS/MS J Agric Food Chem 66 12227 12235 2018 10.1021/acs.jafc.8b03763 30298742 sourceNot checked — no full text of the source

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A nonclinical study reported favorable tolerability of MGF at pharmacologically relevant exposures, with adverse findings emerging at substantially higher doses.

“A nonclinical study has previously reported favorable tolerability at pharmacologically relevant exposures, with adverse findings emerging at substantially higher doses (180).”

• cites [180] Sellamuthu PS Muniappan BP Perumal SM Kandasamy M Antihyperglycemic effect of mangiferin in streptozotocin induced diabetic rats J Health Sci 55 206 214 2009 10.1248/jhs.55.206 sourceDisputed

  The Materials and Methods section identifies 40 mg/kg/day as the dose used in diabetic rats and 25–500 mg/kg/day as the toxicity-test range. Contrary to the claim that adverse findings emerged at higher doses, Acute Toxicity Studies reports no toxic reactions at any tested dose over 30 days. (LLM, conf=0.88)

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MGF has low water solubility (0.111 mg/ml) and poor oral bioavailability (~1.2%) due to limited lipophilicity and intestinal permeability.

“Despite its low water solubility (0.111 mg/ml) (1) and poor oral bioavailability (~1.2%) (2,3), due to its limited lipophilicity and intestinal permeability (4), MGF has been identified in 96 species, 28 genera and 19 families of angiosperms (5).”

• cites [1] Wang M Liang Y Chen K Wang M Long X Liu H Sun Y He B The management of diabetes mellitus by mangiferin: Advances and prospects Nanoscale 14 2119 2135 2022 10.1039/D1NR06690K 35088781 sourceNot checked — no full text of the source
• cites [2] Bhattacharyya S Ahmmed SM Saha BP Mukherjee PK Soya phospholipid complex of mangiferin enhances its hepatoprotectivity by improving its bioavailability and pharmacokinetics J Sci Food Agric 94 1380 1388 2014 10.1002/jsfa.6422 24114670 sourceNot checked — no full text of the source
• cites [3] Mei S Perumal M Battino M Kitts DD Xiao J Ma H Chen X Mangiferin: A review of dietary sources, absorption, metabolism, bioavailability, and safety Crit Rev Food Sci Nutr 63 3046 3064 2023 10.1080/10408398.2021.1983767 34606395 sourceNot checked — no full text of the source
• cites [4] Morozkina SN Nhung Vu TH Generalova YE Snetkov PP Uspenskaya MV Mangiferin as new potential anti-cancer agent and mangiferin-integrated polymer systems-a novel research direction Biomolecules 11 79 2021 10.3390/biom11010079 33435313 PMC7827323 sourceSupported

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In diabetic nephropathy, MGF downregulates PTEN/PI3K/Akt signaling and reduces expression of fibronectin, collagen I and α-SMA, along with decreases in renal fibrosis, inflammation and oxidative stress endpoints.

“This previous study reported downregulation of phosphatase and tensin homolog (PTEN)/PI3K/Akt signaling, and reduced expression of fibronectin, collagen I and α-smooth muscle actin (α-SMA), along with decreases in renal fibrosis, inflammation and oxidative stress endpoints (34).”

• cites [34] Song Y Liu W Tang K Zang J Li D Gao H Mangiferin alleviates renal interstitial fibrosis in streptozotocin-induced diabetic mice through regulating the PTEN/PI3k/Akt signaling pathway J Diabetes Res 2020 9481720 2020 10.1155/2020/9481720 32076626 PMC7016412 sourceSupported

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In diabetic pulmonary fibrosis, MGF inhibits endothelial-mesenchymal transition and modulates the AMPK/FoxO3/SIRT3 pathway, as evidenced by changes in pathway proteins and fibrosis markers.

“Reported effects include the inhibition of endothelial-mesenchymal transition and modulation of the AMPK/FoxO3/sirtuin (SIRT)3 pathway, as evidenced by changes in pathway proteins and fibrosis markers (33).”

• cites [33] Fu TL Li GR Li DH He RY Liu BH Xiong R Xu CZ Lu ZL Song CK Qiu HL Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis Acta Pharmacol Sin 45 1002 1018 2024 10.1038/s41401-023-01202-7 38225395 PMC11053064 sourceSupported

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In animal models of type 1 and type 2 diabetes, tail vein administration of MGF-loaded polymeric nanocarriers (5-10 mg/kg) increases β-cell proliferation, inhibits apoptosis and restores insulin secretion, thereby improving glycemic control.

“In animal models of type 1 and type 2 diabetes, tail vein administration of MGF-loaded polymeric nanocarriers (5-10 mg/kg) have been reported to increase β-cell proliferation, inhibit apoptosis and restored insulin secretion, thereby improving glycemic control (26).”

• cites [26] Kaur P Gupta RC Dey A Malik T Pandey DK Optimization of harvest and extraction factors by full factorial design for the improved yield of C-glucosyl xanthone mangiferin from swertia chirata Sci Rep 11 16346 2021 10.1038/s41598-021-95663-7 34381094 PMC8357827 sourceCould not verify

  Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.

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Under the reported analytical conditions, MGF is not detected in brain tissue, consistent with limited penetration across the blood-brain barrier in this model.

“Under the reported analytical conditions, MGF is not detected in brain tissue, which is consistent with limited penetration across the blood-brain barrier in this model (19).”

• cites [19] Gelabert-Rebato M Wiebe JC Martin-Rincon M Gericke N Perez-Valera M Curtelin D Galvan-Alvarez V Lopez-Rios L Morales-Alamo D Calbet JAL Mangifera indica l. Leaf extract in combination with luteolin or quercetin enhances VO2peak and peak power output, and preserves skeletal muscle function during ischemia-reperfusion in humans Front Physiol 9 740 2018 10.3389/fphys.2018.00740 29937737 PMC6002676 sourceCould not verify

  The Materials and methods section describes measurements of cerebral oxygenation and blood velocity, not an assay for mangiferin (MGF) in brain tissue. The Introduction says mangiferin can traverse the blood-brain barrier, but the paper reports no brain-tissue detection result or analytical conditions that could establish the claimed limited penetration. Searches for brain-tissue detection and blood-brain-barrier penetration found no such result. (LLM, conf=0.77)

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MGF isolated from indica rice leaves exhibits potent broad-spectrum antimicrobial activity against diverse fungal and bacterial pathogens, with MIC values of 1.95-62.5 and 1.95-31.25 μg/ml, respectively.

“MGF isolated from indica rice leaves has various pharmacological benefits; notably, it exhibits potent, broad-spectrum antimicrobial activity against diverse fungal and bacterial pathogens, with minimum inhibitory concentration (MIC) values of 1.95-62.5 and 1.95-31.25 μg/ml, respectively (7).”

• cites [7] Yehia RS Altwaim SA An insight into in vitro antioxidant, antimicrobial, cytotoxic, and apoptosis induction potential of mangiferin, a bioactive compound derived from mangifera indica Plants (Basel) 12 1539 2023 37050165 PMC10096949 sourcePartly supported

  The Conclusions report broad in vitro activity against bacteria and Candida species, but identify the source as Mangifera indica leaves, not indica rice leaves. They assign MIC ranges of 1.95–62.5 µg/mL to bacteria and 1.95–31.25 µg/mL to fungi—the reverse of the citing sentence. The Results (section 2.3) corroborate that assignment, although the paper’s abstract also reverses the ranges. (LLM, conf=0.89)

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Formation of M1 is well documented but should be considered a predominant rather than obligatory initial event in the overall metabolic scheme.

“Thus, while the formation of M1 is well documented (20,21), it should be considered a predominant rather than obligatory initial event in the overall metabolic scheme.”

• cites [20] Ehianeta TS Laval SP Yu B Bio- and chemical syntheses of mangiferin and congeners Biofactors 42 445 458 2016 10.1002/biof.1279 27774668 sourceNot checked — no full text of the source
• cites [21] Tian X Gao Y Xu Z Lian S Ma Y Guo X Hu P Li Z Huang C Pharmacokinetics of mangiferin and its metabolite-norathyriol, part 1: Systemic evaluation of hepatic first-pass effect in vitro and in vivo Biofactors 42 533 544 2016 10.1002/biof.1291 27130074 sourceCould not verify

  The citation is attached to the assertion that M1 formation is well documented; the qualification about a ‘predominant rather than obligatory’ event is the citing authors’ own framing. The Introduction and Discussion describe formation of norathyriol (NTR) from mangiferin, but our copy does not identify NTR as M1 or otherwise document formation of a metabolite called M1 (searched: M1, initial metabolite, metabolic scheme). (LLM, conf=0.76)

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MGF enhances phase II detoxifying enzymes, including GSH S-transferase, quinone reductase and UDP-glucuronosyltransferase, while reducing lipid peroxidation in lung cancer models.

“Additionally, MGF enhances phase II detoxifying enzymes, including GSH S-transferase, quinone reductase and UDP-glucuronosyltransferase, while reducing lipid peroxidation in lung cancer models (77,78).”

• cites [77] Walia V Chaudhary SK Kumar Sethiya N Therapeutic potential of mangiferin in the treatment of various neuropsychiatric and neurodegenerative disorders Neurochem Int 143 104939 2021 10.1016/j.neuint.2020.104939 33346032 sourceNot checked — no full text of the source
• cites [78] Rui R Zhou L He S Cancer immunotherapies: Advances and bottlenecks Front Immunol 14 1212476 2023 10.3389/fimmu.2023.1212476 37691932 PMC10484345 sourceCould not verify

  The Cancer cell vaccines and LAG-3 sections discuss immunotherapy mechanisms and studies, not MGF’s effects on detoxifying enzymes or lipid peroxidation. Searches for MGF, mangiferin, the named enzymes, and lipid peroxidation found no passage addressing the claim in our copy. (LLM, conf=0.76)

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In lung adenocarcinoma models, MGF reduces expression of miR-27b and miR-92a, thereby inhibiting tumor cell proliferation and promoting apoptosis.

“In lung adenocarcinoma models, MGF reduces the expression of miR-27b and miR-92a, two oncogenic miRNAs highly expressed in tumor tissues, thereby inhibiting tumor cell proliferation and promoting apoptosis (66).”

• cites [66] Chi XJ Meng JJ Lin CY Su QS Qin YY Wei RH Lan D Huang C Mangiferin inhibits human lung adenocarcinoma by suppressing MiR-27b and MiR-92a Evid Based Complement Alternat Med 2021 2822950 2021 10.1155/2021/2822950 34335801 PMC8292060 sourcePartly supported

  The Discussion reports that mangiferin lowered miR-27b and miR-92a in lung adenocarcinoma cells and that both miRNAs were elevated in tumor tissue. It also describes growth inhibition and apoptosis, but presents the proposed causal link to the miRNAs as an inference and says their biological functions still need in-vitro verification. The claim states that mechanism more definitively than the source supports. (LLM, conf=0.88)

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This Nrf2 activation suppresses intracellular ROS accumulation and induces apoptosis in leukemia HL-60 cells.

“This activity suppresses intracellular ROS accumulation and induces apoptosis in leukemia HL-60 cells (75).”

• cites [75] Zhao J Zhang B Li S Zeng L Chen Y Fang J Mangiferin increases nrf2 protein stability by inhibiting its ubiquitination and degradation in human HL60 myeloid leukemia cells Int J Mol Med 33 1348 1354 2014 10.3892/ijmm.2014.1696 24626801 sourcePartly supported

  The Results (p. 5) show that mangiferin inhibits Nrf2 ubiquitination in HL60 cells, and the Discussion (p. 6) links its increased stability to Nrf2 signaling. The paper does not report that this activity suppresses intracellular ROS accumulation or induces apoptosis in those cells; the Discussion instead describes a possible cytoprotective effect. (LLM, conf=0.85)

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MGF's anticancer mechanisms include induction of cell cycle arrest, promotion of apoptosis, inhibition of tumor invasion and metastasis, modulation of immune responses, and enhancement of radiosensitivity in glioblastoma.

“These include the induction of cell cycle arrest, the promotion of apoptosis through various intracellular pathways, the inhibition of tumor invasion and metastasis, the modulation of immune responses, and the enhancement of radiosensitivity in cancer such as glioblastoma (GBM) (36,37).”

• cites [36] Iqbal H Inam-Ur-Raheem M Munir S Rabail R Kafeel S Shahid A Mousavi Khaneghah A Aadil RM Therapeutic potential of mangiferin in cancer: unveiling regulatory pathways, mechanisms of action, and bioavailability enhancements-an updated review Food Sci Nutr 12 1413 1429 2024 10.1002/fsn3.3869 38455223 PMC10916574 sourcePartly supported

  The Introduction and Mechanism of Action sections describe cell-cycle arrest, apoptosis, reduced tumor invasion or migration, and immune modulation. The reviewed studies are in cells and animals, and the passages found on radiation and treatment sensitivity do not report enhanced radiosensitivity in glioblastoma. That part of the claim is unsupported by our copy (page numbers unavailable). (LLM, conf=0.88)

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• cites [37] Xiao J Liu L Zhong Z Xiao C Zhang J Mangiferin regulates proliferation and apoptosis in glioma cells by induction of microRNA-15b and inhibition of MMP-9 expression Oncol Rep 33 2815 2820 2015 10.3892/or.2015.3919 25901555 sourcePartly supported

  The Discussion (page unavailable) reports that mangiferin increased apoptosis and caspase activation in U87 glioma cells. The introductory passage also says mangiferin can arrest the cell cycle in a hepatoma cell line and has anti-inflammatory effects. This paper does not establish that mangiferin inhibits invasion or metastasis, modulates anticancer immune responses, or enhances radiosensitivity in glioblastoma; its U87 results concern proliferation, apoptosis, miR-15b and MMP-9. (LLM, conf=0.88)

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MAPK modulation by MGF is context dependent; a number of models show attenuation of ERK1/2, JNK and p38 phosphorylation, reduced AP-1 activity, and consequent decreases in proliferation and cytokine output.

“MAPK modulation is context dependent; a number of models show attenuation of ERK1/2, JNK and p38 phosphorylation, reduced activator protein (AP)-1 activity, and consequent decreases in proliferation and cytokine output (38,46).”

• cites [38] Gold-Smith F Fernandez A Bishop K Mangiferin and cancer: Mechanisms of action Nutrients 8 396 2016 10.3390/nu8070396 27367721 PMC4963872 sourcePartly supported

  Section 2.2.1 (page not provided) says mangiferin inhibits p38, ERK and JNK phosphorylation; Section 2.3.2 links it to reduced AP-1 binding in astroglioma cells. Section 2.1.1 reports reduced IL-6 and IL-8 production, but attributes that effect to NFκB downregulation. The paper does not establish the claimed chain from MAPK and AP-1 attenuation to reduced proliferation and cytokine output, or explicitly characterize MAPK modulation as context dependent. (LLM, conf=0.85)

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• cites [46] Pal PB Sinha K Sil PC Mangiferin attenuates diabetic nephropathy by inhibiting oxidative stress mediated signaling cascade, TNFα related and mitochondrial dependent apoptotic pathways in streptozotocin-induced diabetic rats PLoS One 9 e107220 2014 10.1371/journal.pone.0107220 25233093 PMC4169432 sourcePartly supported

  The Results section, “Mangiferin inhibits STZ-induced activation of MAPKs” (page unavailable), reports that mangiferin reversed increased p38, JNK and ERK1/2 phosphorylation in diabetic rat kidney. The Discussion also reports decreased TNFα with treatment, but the paper does not establish reduced AP-1 activity, decreased proliferation, or the claimed sequence linking those effects to MAPK attenuation. (LLM, conf=0.88)

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Across tumor cell systems, the functional consequence of MGF exposure remains G2/M arrest, with reduced proliferation and increased susceptibility to apoptosis.

“However, across tumor cell systems, the functional consequence remains G2/M arrest, with reduced proliferation and increased susceptibility to apoptosis.”

• cites [55] Żuryń A Krajewski A Szulc D Litwiniec A Grzanka A Activity of cyclin B1 in HL-60 cells treated with etoposide Acta Histochem 118 537 543 2016 10.1016/j.acthis.2016.05.010 27297620 sourceNot checked — no full text of the source
• cites [56] Shi W Deng J Tong R Yang Y He X Lv J Wang H Deng S Qi P Zhang D Wang Y Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells Mol Med Rep 13 3423 3432 2016 10.3892/mmr.2016.4947 26935347 PMC4805064 sourcePartly supported

  The Discussion reports G2/M arrest, growth inhibition and apoptosis after mangiferin treatment in A549 lung carcinoma cells. It does not establish that these effects occur across tumor cell systems. Page numbers are not provided in our copy. (LLM, conf=0.88)

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• cites [57] Pal-Ghosh R Xue D Warburton R Hill N Polgar P Wilson JL CDC2 is an important driver of vascular smooth muscle cell proliferation via FOXM1 and PLK1 in pulmonary arterial hypertension Int J Mol Sci 22 6943 2021 10.3390/ijms22136943 34203295 PMC8268698 sourceCould not verify

  The Discussion describes G2/M arrest with the CDC2 inhibitor RO-3306, not with MGF. The paper studies pulmonary-artery smooth muscle cells; searches for MGF and mangiferin found no passage addressing their effects on tumor-cell proliferation or apoptosis. The claimed outcome of MGF exposure therefore cannot be verified from this copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

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For PI3K/Akt, MGF changes Akt Thr308/Ser473 and downstream GSK3β and mTORC1, leading to reduced protein synthesis and survival signaling in tumor cells, whereas in metabolic tissues, they support GLUT4 translocation and glycogen synthesis.

“For PI3K/Akt, changes in Akt Thr308/Ser473, and downstream GSK3β and mTOR complex 1 lead to reduced protein synthesis and survival signaling in tumor cells, whereas in metabolic tissues, they support GLUT4 translocation and glycogen synthesis (16,47-54).”

• cites [16] Andreu GP Delgado R Velho JA Curti C Vercesi AE Iron complexing activity of mangiferin, a naturally occurring glucosylxanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate Eur J Pharmacol 513 47 55 2005 10.1016/j.ejphar.2005.03.007 15878708 sourceNot checked — no full text of the source
• cites [47] Du M Wen G Jin J Chen Y Cao J Xu A Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway Anticancer Drugs 29 167 175 2018 10.1097/CAD.0000000000000583 29215373 sourceNot checked — no full text of the source
• cites [48] Zou B Wang H Liu Y Qi P Lei T Sun M Wang Y Mangiferin induces apoptosis in human ovarian adenocarcinoma OVCAR3 cells via the regulation of Notch3 Oncol Rep 38 1431 1441 2017 10.3892/or.2017.5814 28714011 PMC5549032 sourcePartly supported

  The Results (page not provided) report that mangiferin decreased phosphorylation of Akt at Ser473 and mTOR at Ser2448 in OVCAR3 ovarian cancer cells; the Discussion links PI3K/Akt/mTOR inhibition to its antineoplastic effect. The paper does not establish changes at Akt Thr308 or in GSK3β, identify the mTOR complex as mTORC1, or report reduced protein synthesis. It also does not address GLUT4 translocation or glycogen synthesis in metabolic tissues. (LLM, conf=0.88)

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• cites [49] Xia J Li X Yao J Song D Gu Z Zheng G Tu C Mangiferin targets PFKFB3 to inhibit glioblastoma progression by suppressing glycolysis and PI3k/AKT/mTOR signaling Brain Res Bull 230 111520 2025 10.1016/j.brainresbull.2025.111520 40865736 sourceNot checked — no full text of the source
• cites [50] Girón MD Sevillano N Salto R Haidour A Manzano M Jiménez ML Rueda R López-Pedrosa JM Salacia oblonga extract increases glucose transporter 4-mediated glucose uptake in L6 rat myotubes: Role of mangiferin Clin Nutr 28 565 574 2009 10.1016/j.clnu.2009.04.018 19477051 sourceNot checked — no full text of the source
• cites [51] Apontes P Liu Z Su K Benard O Youn DY Li X Li W Mirza RH Bastie CC Jelicks LA Mangiferin stimulates carbohydrate oxidation and protects against metabolic disorders induced by high-fat diets Diabetes 63 3626 3636 2014 10.2337/db14-0006 24848064 PMC4207399 sourcePartly supported

  The Results section on carbohydrate utilization reports increased GLUT4 mRNA and glucose utilization in muscle with MGF treatment. It does not establish GLUT4 translocation or glycogen synthesis, and the passages found do not link these effects to Akt Thr308/Ser473, GSK3β, or mTORC1. They also do not address protein synthesis or survival signaling in tumor cells. (LLM, conf=0.78)

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• cites [52] Singh AK Raj V Keshari AK Rai A Kumar P Rawat A Maity B Kumar D Prakash A De A Isolated mangiferin and naringenin exert antidiabetic effect via PPAR(γ)/GLUT4 dual agonistic action with strong metabolic regulation Chem Biol Interact 280 33 44 2018 10.1016/j.cbi.2017.12.007 29223569 sourceNot checked — no full text of the source
• cites [53] Mistry J Biswas M Sarkar S Ghosh S Antidiabetic activity of mango peel extract and mangiferin in alloxan-induced diabetic rats Future J Pharm 9 22 2023 10.1186/s43094-023-00472-6 sourcePartly supported

  The section on liver and muscle glycogen reports that mangiferin increased glycogen levels in alloxan-induced diabetic rats, supporting the glycogen portion of the claim. It does not address Akt phosphorylation, GSK3β, mTORC1, GLUT4 translocation, or protein synthesis and survival signaling in tumor cells (no page number available in our copy). (LLM, conf=0.88)

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• cites [54] Alsaedi AQ Nader MA El-Kashef DH Abdelmageed ME Mangiferin mitigates dexamethasone-induced insulin resistance in rats: Insight into vascular dysfunction and hepatic steatosis Front Pharmacol 16 1572758 2025 10.3389/fphar.2025.1572758 40406487 PMC12095298 sourcePartly supported

  The Introduction links PI3K/Akt to glycogen synthesis and glucose transport, while the Discussion reports that mangiferin reversed dexamethasone-associated hepatic changes and induced glycogen synthesis in rats. The paper does not report Akt Thr308/Ser473 or mTORC1 changes, GLUT4 translocation, or reduced protein synthesis and survival signaling in tumor cells; it discusses GLUT4 expression in relation to AMPK instead. (LLM, conf=0.87)

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For NF-κB, MGF engagement is inferred from reduced IKKα/IKKβ phosphorylation, stabilization of IκBα, and reduced nuclear p65 DNA binding, with downstream decreases in BCL2L1, BIRC5 and MMP-9.

“For NF-κB, typical engagement is inferred from reduced IKKα/IKKβ phosphorylation, stabilization of IκBα, and reduced nuclear p65 DNA binding, with downstream decreases in pro-survival and invasive effectors, such as BCL2L1, BIRC5 and MMP-9 (40-43).”

• cites [40] Takeda T Tsubaki M Sakamoto K Ichimura E Enomoto A Suzuki Y Itoh T Imano M Tanabe G Muraoka O Mangiferin, a novel nuclear factor kappa b-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model Toxicol Appl Pharmacol 306 105 112 2016 10.1016/j.taap.2016.07.005 27417526 sourceNot checked — no full text of the source
• cites [41] Jung JS Jung K Kim DH Kim HES Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: involvement of PI3k/akt and MAPK signaling pathways Pharmacol Res 66 95 103 2012 10.1016/j.phrs.2012.02.013 22465218 sourceNot checked — no full text of the source
• cites [42] Dilshara MG Kang CH Choi YH Kim GY Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity BMB Rep 48 559 564 2015 10.5483/BMBRep.2015.48.10.003 25739392 PMC4911182 sourcePartly supported

  The Results section, ‘Inhibition of TNF-α-induced NF-κB activity by mangiferin’ (page not specified in the indexed copy), reports reduced NF-κB DNA binding after mangiferin treatment; the Introduction and Discussion link NF-κB suppression to reduced MMP-9 expression in TNF-α-stimulated LNCaP cells. The copy does not report reduced IKKα/IKKβ phosphorylation, IκBα stabilization, or decreases in BCL2L1 or BIRC5. Its DNA-binding assay measures NF-κB binding, not p65 binding specifically. (LLM, conf=0.88)

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• cites [43] Shoji K Tsubaki M Yamazoe Y Satou T Itoh T Kidera Y Tanimori Y Yanae M Matsuda H Taga A Mangiferin induces apoptosis by suppressing Bcl-xL and XIAP expressions and nuclear entry of NF-κB in HL-60 cells Arch Pharm Res 34 469 475 2011 10.1007/s12272-011-0316-8 21547680 sourceNot checked — no full text of the source

May combine two claims.

MGF reduces mitochondrial membrane potential in HT29 colon cancer cells, leading to mitochondrial outer membrane permeabilization and apoptosis.

“MGF reduces the mitochondrial membrane potential in HT29 colon cancer cells, leading to mitochondrial outer membrane permeabilization and apoptosis (69).”

• cites [69] Rodriguez-Gonzalez JC Hernández-Balmaseda I Declerck K Pérez-Novo C Logie E Theys C Jakubek P Quiñones-Maza OL Dantas-Cassali G Carlos Dos Reis D Antiproliferative, antiangiogenic, and antimetastatic therapy response by mangiferin in a syngeneic immunocompetent colorectal cancer mouse model involves changes in mitochondrial energy metabolism Front Pharmacol 12 670167 2021 10.3389/fphar.2021.670167 34924998 PMC8678272 sourceCould not verify

  The Results section, “Mangiferin Targets Fatty Acid β-oxidation Metabolism in Human HT29 Colon Cancer Cells” (page unavailable), reports that MGF reverses free-fatty-acid-induced changes in β-hydroxybutyrate and CPT1 expression. Searches for mitochondrial membrane potential, outer membrane permeabilization, and apoptosis found no passage establishing the claimed sequence in HT29 cells. (LLM, conf=0.76)

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MGF decreases CDK1/cyclin B1 activity, alters CDK1 phosphorylation, and engages ATR-dependent Chk1 activation in other tumor cell lines.

“This outcome is consistent with reports of decreased CDK1/cyclin B1 activity, altered phosphorylation of CDK1 with reduced activating phosphorylation and increased inhibitory phosphorylation, and engagement of checkpoint signaling, including ATR-dependent Chk1 activation, in other tumor cell lines exposed to MGF (56,57).”

• cites [56] Shi W Deng J Tong R Yang Y He X Lv J Wang H Deng S Qi P Zhang D Wang Y Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells Mol Med Rep 13 3423 3432 2016 10.3892/mmr.2016.4947 26935347 PMC4805064 sourcePartly supported

  The Results section reports reduced CDK1 (cdc2) and cyclin B1 protein expression after mangiferin treatment in A549 cells, supporting downregulation of that pathway. It does not report a direct activity measurement, CDK1 phosphorylation changes, or ATR-dependent Chk1 activation; those terms were also searched in our copy. The study’s cell-line finding cannot by itself establish those mechanisms in other tumor cell lines. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [57] Pal-Ghosh R Xue D Warburton R Hill N Polgar P Wilson JL CDC2 is an important driver of vascular smooth muscle cell proliferation via FOXM1 and PLK1 in pulmonary arterial hypertension Int J Mol Sci 22 6943 2021 10.3390/ijms22136943 34203295 PMC8268698 sourceCould not verify

  The Introduction describes activating and inhibitory phosphorylation of CDC2/cyclin B, but not changes caused by MGF. The paper’s Results concern pulmonary artery smooth muscle cells; searches for MGF, mangiferin, and ATR-dependent Chk1 activation found no passage addressing the claimed effects in tumor cell lines. No page numbers are available in our copy. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

May combine two claims.

For Nrf2, MGF evidence includes diminished KEAP1-mediated ubiquitination, increased nuclear Nrf2, and induction of HO-1, NQO1 and other phase II enzymes, aligning with decreased ROS and lipid peroxidation.

“For Nrf2, evidence includes diminished Kelch-like ECH-associated protein 1-mediated ubiquitination, increased nuclear Nrf2, and the induction of heme oxygenase (HO)-1, NAD(P)H quinone dehydrogenase 1 (NQO1) and other phase II enzymes, aligning with decreased ROS and lipid peroxidation (44,45).”

• cites [44] Gong M Li Y Ye X Zhang L Wang Z Xu X Shen Y Zheng C Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation Cell Commun Signal 18 98 2020 10.1186/s12964-020-00568-z 32576270 PMC7310414 sourcePartly supported

  The Results section on KEAP1-mutant lung cancer cell lines reports increased nuclear NRF2, higher HO-1 and NQO1 expression, reduced NRF2 degradation, and lower ROS. It does not report MGF treatment, directly measure KEAP1-mediated ubiquitination, or address lipid peroxidation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [45] DeBlasi JM Falzone A Caldwell S Prieto-Farigua N Prigge JR Schmidt EE Chio IIC Karreth FA DeNicola GM Distinct nrf2 signaling thresholds mediate lung tumor initiation and progression Cancer Res 83 1953 1967 2023 10.1158/0008-5472.CAN-22-3848 37062029 PMC10267679 sourcePartly supported

  The Introduction describes KEAP1-mediated NRF2 ubiquitination and NRF2’s role in detoxifying reactive oxygen species. The Results report that the studied KEAP1 and NRF2 mutations prevent ubiquitination and increase transcription of Nrf2 targets including Nqo1. This lung-cancer study does not establish the claimed MGF effects or report HO-1 induction, decreased lipid peroxidation, or the full set of changes as a linked response. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

MGF has a selective inhibitory effect on MMP-9, making it a promising candidate for antimetastatic therapy.

“MGF has been demonstrated to have a selective inhibitory effect on MMP-9, making it a promising candidate for antimetastatic therapy (87).”

• cites [87] Chen J Liu Z Fang H Su Q Fan Y Song L He S Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas J Transl Med 22 395 2024 10.1186/s12967-024-05151-5 38685028 PMC11057130 sourceCould not verify

  The Results section discusses mitochondrial membrane potential (MMP) in glioma cells, not MMP-9 inhibition. The Conclusions concern an immunostimulatory siRNA. Searches for MGF, selective MMP-9 inhibition, and antimetastatic therapy found no passage addressing the claim in our copy. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

May combine two claims.

MGF's therapeutic actions converge on several core molecular pathways, particularly suppression of oxidative stress and NF-κB-mediated inflammation, and activation of AMPK and SIRT1 signaling.

“Its therapeutic actions converge on several core molecular pathways, particularly the suppression of oxidative stress and NF-κB-mediated inflammation, and the activation of AMPK and SIRT1 signaling (119-121).”

• cites [119] Pal PB Sinha K Sil PC Mangiferin, a natural xanthone, protects murine liver in Pb(II) induced hepatic damage and cell death via MAP kinase, NF-κB and mitochondria dependent pathways PLoS One 8 e56894 2013 10.1371/journal.pone.0056894 23451106 PMC3581562 sourcePartly supported

  The Results section ('Effect on intracellular ROS production') reports that mangiferin reduced Pb(II)-induced ROS in murine liver, and the Discussion reports suppression of phosphorylated NF-κB in liver and hepatocytes. The paper frames the NF-κB finding as part of protection against hepatic damage and apoptosis, rather than demonstrating reduced NF-κB-mediated inflammation. Searches for AMPK and SIRT1 found no support for activation of either pathway in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [120] Chen X Huang J Mangiferin inhibits hypoxia/reoxygenation-induced alveolar epithelial cell injury via the SIRT1/AMPK signaling pathway Exp Ther Med 22 1220 2021 10.3892/etm.2021.10654 34603517 PMC8453333 sourcePartly supported

  The Results (page unavailable) show that mangiferin reduced inflammatory markers in hypoxia/reoxygenation-treated A549 cells and increased SIRT1 and AMPK signaling. The Introduction describes mangiferin as antioxidative, but this study does not establish suppression of oxidative stress or NF-κB-mediated inflammation as mechanisms of its protective effect. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [121] Sadhukhan P Saha S Dutta S Sil PC 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 9 638 2018 10.3389/fphar.2018.00638 29967581 PMC6015878 sourcePartly supported

  The Results (page unavailable) report that mangiferin restored renal NF-κB levels and pro-inflammatory cytokines after cisplatin exposure; the Discussion also describes attenuation of oxidative stress. The paper instead identifies PI3K–Nrf-2 signaling as a protective pathway and does not report activation of AMPK or SIRT1 by mangiferin. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

In HeLa and HT29 cells, MGF suppression of NF-κB coincides with improved responses to oxaliplatin and reduced drug resistance.

“In HeLa and HT29 cells, this suppression coincides with improved responses to oxaliplatin and reduced drug resistance.”

• cites [56] Shi W Deng J Tong R Yang Y He X Lv J Wang H Deng S Qi P Zhang D Wang Y Molecular mechanisms underlying mangiferin-induced apoptosis and cell cycle arrest in A549 human lung carcinoma cells Mol Med Rep 13 3423 3432 2016 10.3892/mmr.2016.4947 26935347 PMC4805064 sourcePartly supported

  The Discussion (page not provided) reports that mangiferin suppresses PKC–NF-κB signaling in A549 lung carcinoma cells. The Results (page not provided) report enhanced antiproliferative effects when mangiferin is combined with cisplatin in A549 cells. The paper does not support the claimed findings in HeLa or HT29 cells, improved responses to oxaliplatin, or reduced drug resistance. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

In MDA-MB-231 breast cancer cells, MGF disrupts Rac1/WAVE2 signaling and inhibits cytokine secretion (IL-6 and IL-8), thereby reducing invasive capacity and inflammatory crosstalk.

“In MDA-MB-231 breast cancer cells, MGF disrupts Rac1/WAVE2 signaling and inhibits cytokine secretion (for example, IL-6 and IL-8), thereby reducing invasive capacity and inflammatory crosstalk (104).”

• cites [104] Deng Q Tian YX Liang J Mangiferin inhibits cell migration and invasion through Rac1/WAVE2 signalling in breast cancer Cytotechnology 70 593 601 2018 10.1007/s10616-017-0140-1 29455393 PMC5851954 sourcePartly supported

  The Discussion and invasion results (page numbers unavailable) support that mangiferin suppresses Rac1/WAVE2 signalling and reduces invasion in MDA-MB-231 cells. The copy does not report inhibited IL-6 or IL-8 secretion or reduced inflammatory crosstalk; searches for cytokine secretion and interleukins found no supporting passage. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

In acute lung injury models, MGF reduces inflammatory cytokine production and ameliorates pulmonary pathology.

“This results in reduced inflammatory cytokine production and amelioration of pulmonary pathology (126).”

• cites [126] Li N Xiong R He R Liu B Wang B Geng Q Mangiferin mitigates lipopolysaccharide-induced lung injury by inhibiting NLRP3 inflammasome activation J Inflamm Res 14 2289 2300 2021 10.2147/JIR.S304492 34103962 PMC8178744 sourceSupported

May combine two claims.

MGF induces cytoskeletal rearrangement in macrophages, alters their morphology and enhances their phagocytic capacity.

“MGF induces cytoskeletal rearrangement in macrophages, alters their morphology and enhances their phagocytic capacity (102).”

• cites [102] Chen Q Wang S Bao R Wang D Wu Y Zhang Y Liu M Wang T Combination of mangiferin and T0901317 targeting autophagy promotes cholesterol efflux from macrophage foam cell in atherosclerosis Chin Med 19 5 2024 10.1186/s13020-023-00876-9 38183139 PMC10770909 sourceCould not verify

  The Results sections on foam-cell formation and autophagic flux report changes in lipid accumulation and cholesterol efflux, not cytoskeletal rearrangement, macrophage morphology, or phagocytic capacity. Searches for those terms and for actin, cell shape, and phagocytosis found no passage addressing the claim. Page numbers are unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

In intervertebral disc degeneration, MGF attenuates mitochondrial dysfunction and reduces ROS in human nucleus pulposus cells.

“In intervertebral disc degeneration, MGF has been shown to attenuate mitochondrial dysfunction and reduce ROS in human nucleus pulposus cells.”

• cites [122] Li W Wang K Liu Y Wu H He Y Li C Wang Q Su X Yan S Su W A novel drug combination of mangiferin and cinnamic acid alleviates rheumatoid arthritis by inhibiting TLR4/NFκB/NLRP3 activation-induced pyroptosis Front Immunol 13 912933 2022 10.3389/fimmu.2022.912933 35799788 PMC9253268 sourceCould not verify

  The Results and Materials and Methods passages concern rheumatoid arthritis models, RAW264.7 macrophages, and MH7A synoviocytes. Searches for intervertebral disc degeneration, nucleus pulposus cells, mitochondrial dysfunction, and ROS found no passage in our copy addressing the claimed effect. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

By sensitizing tumor cells to radiation-induced DNA damage, MGF improves therapeutic outcomes without necessitating an increase in radiation dose.

“By sensitizing tumor cells to radiation-induced DNA damage, MGF improves therapeutic outcomes without necessitating an increase in radiation dose (36).”

• cites [36] Iqbal H Inam-Ur-Raheem M Munir S Rabail R Kafeel S Shahid A Mousavi Khaneghah A Aadil RM Therapeutic potential of mangiferin in cancer: unveiling regulatory pathways, mechanisms of action, and bioavailability enhancements-an updated review Food Sci Nutr 12 1413 1429 2024 10.1002/fsn3.3869 38455223 PMC10916574 sourcePartly supported

  The Mechanism of Action section (page unavailable) reports that MGF may cause ROS-mediated DNA damage and inhibit cancer-cell growth. The review does not link that damage to radiation or report improved radiotherapy outcomes at an unchanged radiation dose; its discussion of treatment sensitization concerns chemotherapy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

In arthritic rats, MGF promotes inflammatory apoptosis and attenuates the pathogenic activity of fibroblast-like synoviocytes.

“MGF also promotes inflammatory apoptosis and attenuates the pathogenic activity of fibroblast-like synoviocytes in arthritic rats (123).”

• cites [123] Radu AF Bungau SG Management of rheumatoid arthritis: An overview Cells 10 2857 2021 10.3390/cells10112857 34831081 PMC8616326 sourceCould not verify

  The Pathophysiology of RA section describes the pathogenic activity of fibroblast-like synoviocytes, but does not discuss MGF or its effects on those cells. Searches for MGF, mangiferin, apoptosis, and arthritic rats found no passage establishing the claimed effect. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

May combine two claims.

In a rat model of rheumatoid arthritis, MGF (15-45 mg/kg, 2-week administration) inhibits the MAPK and NF-κB pathways, reducing inflammatory cell proliferation, migration and cytokine secretion.

“In a rat model of rheumatoid arthritis, MGF (15-45 mg/kg, 2-week administration) inhibits the MAPK and NF-κB pathways, thereby reducing inflammatory cell proliferation, migration and cytokine secretion.”

• cites [123] Radu AF Bungau SG Management of rheumatoid arthritis: An overview Cells 10 2857 2021 10.3390/cells10112857 34831081 PMC8616326 sourceCould not verify

  Section 6 (page unavailable) mentions p38 MAPK as a potential therapeutic target, but does not discuss MGF treatment. Searches for MGF, mangiferin, the 15–45 mg/kg dose, and the proposed MAPK/NF-κB effects found no passage addressing the claimed rat experiment. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

May combine two claims.

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).”

• cites [124] Yong Z Ruiqi W Hongji Y Ning M Chenzuo J Yu Z Zhixuan X Qiang L Qibing L Weiying L Xiaopo Z Mangiferin ameliorates HFD-induced NAFLD through regulation of the AMPK and NLRP3 inflammasome signal pathways J Immunol Res 2021 4084566 2021 10.1155/2021/4084566 34734090 PMC8560285 sourceSupported

May combine two claims.

In an azoxymethane-induced colorectal cancer rat model, MGF improves antioxidant enzyme activity, reduces aberrant crypt foci formation, and modulates apoptotic proteins Bax, Bcl-2 and caspase-3.

“In colorectal cancer, an azoxymethane-induced rat model treated with MGF has been shown to exhibit improved antioxidant enzyme activity, reduced aberrant crypt foci formation and modulation of apoptotic proteins, such as Bax, Bcl-2 and caspase-3, have been reported, linking redox control to tumor suppression in colon tissue (80).”

• cites [80] Abdul-Aziz Ahmed K Jabbar AAJ Abdulla MA Zuhair Alamri Z Ain Salehen N Abdel Aziz Ibrahim I Almaimani G Bamagous GA Almaimani RA Almasmoum HA Mangiferin (mango) attenuates AOM-induced colorectal cancer in rat's colon by augmentation of apoptotic proteins and antioxidant mechanisms Sci Rep 14 813 2024 10.1038/s41598-023-50947-y 38191592 PMC10774405 sourcePartly supported

  The Abstract and Results report fewer aberrant crypt foci, higher antioxidant enzyme activity, and increased Bax expression in mangiferin-treated AOM rats. The Results and Methods identify β-catenin, not Bcl-2 or caspase-3, as the other protein examined in their colon tissue. The Discussion mentions Bcl-2 and caspase-3 only when describing findings in cardiomyocytes, not this rat colon model; page numbers are unavailable in our copy. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

May combine two claims.

MGF selectively inhibits the nonhomologous end joining pathway, a major DNA repair mechanism in GBM cells, thereby impairing DNA repair following radiation and enhancing radiotherapeutic efficacy.

“Notably, MGF selectively inhibits the nonhomologous end joining pathway, a major DNA repair mechanism in GBM cells, thereby impairing DNA repair following radiation and enhancing radiotherapeutic efficacy.”

• cites [36] Iqbal H Inam-Ur-Raheem M Munir S Rabail R Kafeel S Shahid A Mousavi Khaneghah A Aadil RM Therapeutic potential of mangiferin in cancer: unveiling regulatory pathways, mechanisms of action, and bioavailability enhancements-an updated review Food Sci Nutr 12 1413 1429 2024 10.1002/fsn3.3869 38455223 PMC10916574 sourceCould not verify

  The Mechanism of Action section (page unavailable) says MGF-induced ROS may damage cancer-cell DNA, but it does not discuss inhibition of DNA repair. A separate section mentions a glioblastoma cell line in nanoparticle assays. Searches for nonhomologous end joining, GBM DNA repair, radiation, and radiosensitization found no passage supporting the claimed mechanism or radiotherapeutic benefit. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

May combine two claims.

In intervertebral disc degeneration, MGF suppresses TNF-α-induced NF-κB activation and downregulates apoptosis-related markers, including pro-apoptotic caspases and Bcl-2 family proteins.

“It suppresses TNF-α-induced NF-κB activation and downregulates the expression of apoptosis-related markers, including pro-apoptotic caspases and Bcl-2 family proteins, indicating its therapeutic potential for treating degenerative disc disorders (122).”

• cites [122] Li W Wang K Liu Y Wu H He Y Li C Wang Q Su X Yan S Su W A novel drug combination of mangiferin and cinnamic acid alleviates rheumatoid arthritis by inhibiting TLR4/NFκB/NLRP3 activation-induced pyroptosis Front Immunol 13 912933 2022 10.3389/fimmu.2022.912933 35799788 PMC9253268 sourcePartly supported

  The Results (Figures 4–6; page unavailable) report reduced NF-κB signaling and caspase-1 in rheumatoid-arthritis models treated with mangiferin, alone or with cinnamic acid. They do not establish suppression of TNF-α-induced NF-κB activation in intervertebral disc degeneration, or downregulation of apoptosis-related Bcl-2 family proteins; the measured caspase-1 is discussed in relation to pyroptosis. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

MGF impairs the nuclear translocation and DNA-binding activity of p65 in response to TNF-α stimulation, thereby disrupting NF-κB-driven transcription and weakening the survival response in tumor cells.

“Furthermore, MGF impairs the nuclear translocation and DNA-binding activity of p65 in response to TNF-α stimulation (100), thereby disrupting NF-κB-driven transcription and weakening the survival response in tumor cells (101).”

• cites [100] Dai C Yu L Wang Z Deng P Li L Gu Z He X Wang J Yuan J Mangiferin and taurine ameliorate MSRV infection by suppressing NF-κB signaling Microbiol Spectr 11 e0514622 2023 10.1128/spectrum.05146-22 37255471 PMC10434205 sourcePartly supported

  The Results section (page unavailable in our copy) reports that mangiferin reduced p65 nuclear translocation in MSRV-infected fish brain cells. It does not report p65 DNA-binding activity or TNF-α stimulation. The later claim about tumor-cell survival carries a different citation and is not assessed here. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [101] Gálvez-Rodríguez A Ferino-Pérez A Rodríguez-Riera Z Rodeiro Guerra I řeha D Minofar B Jáuregui-Haza UJ Explaining the interaction of mangiferin with MMP-9 and NF-κβ: A computational study J Mol Model 28 266 2022 10.1007/s00894-022-05260-2 35987945 sourceNot checked — no full text of the source

May combine two claims.

In streptozotocin-induced diabetic mice, MGF (15, 30, or 60 mg/kg) suppresses inflammation and oxidative stress by modulating the PTEN/PI3K/Akt pathway, reducing expression of collagen I, fibronectin, and α-SMA.

“In streptozotocin-induced diabetic mice, MGF (15, 30 or 60 mg/kg) suppresses inflammation and oxidative stress by modulating the PTEN/PI3K/Akt pathway, leading to reduced expression of fibrotic markers such as collagen I, fibronectin and α-SMA (34).”

• cites [34] Song Y Liu W Tang K Zang J Li D Gao H Mangiferin alleviates renal interstitial fibrosis in streptozotocin-induced diabetic mice through regulating the PTEN/PI3k/Akt signaling pathway J Diabetes Res 2020 9481720 2020 10.1155/2020/9481720 32076626 PMC7016412 sourceSupported

May combine two claims.

In a placebo-controlled human study, acute MGF administration enhances attention, long-term memory, and cognitive performance in healthy adults.

“A placebo-controlled human study demonstrated that acute MGF administration enhances attention, long-term memory and cognitive performance in healthy adults (136).”

• cites [136] Arora MK Kisku A Jangra A Mangiferin ameliorates intracerebroventricular-quinolinic acid-induced cognitive deficits, oxidative stress, and neuroinflammation in wistar rats Indian J Pharmacol 52 296 305 2020 10.4103/ijp.IJP_699_19 33078731 PMC7722907 sourcePartly supported

  The Results report that MGF improved memory deficits, but only in rats given quinolinic acid. The Experimental design describes treatment over 21 days, not acute administration. The paper does not support a placebo-controlled human study or improvements in attention, long-term memory, and cognitive performance in healthy adults; no page numbers are available in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

May combine two claims.

MGF enhances hippocampal neuronal excitability and cognitive processing.

“Furthermore, it enhances hippocampal neuronal excitability and cognitive processing, supporting its potential as a neurocognitive enhancer (139).”

• cites [139] López-Ríos L Wiebe JC Vega-Morales T Gericke N Central nervous system activities of extract mangifera indica L J Ethnopharmacol 260 112996 2020 10.1016/j.jep.2020.112996 32473365 sourcePartly supported

  Section 4.1 reports that mangiferin increased hippocampal pyramidal-cell excitability in rat hippocampal slices and may enhance memory. The paper does not establish that mangiferin enhances cognitive processing: the clinical tests used mango leaf extract, and Section 3.3.2 reports no statistically significant improvement in psychometric performance versus placebo. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

In mouse models of Parkinson's disease, MGF reduces neuroinflammation and oxidative stress by inhibiting NF-κB signaling, improving motor coordination and neuronal survival in the substantia nigra.

“In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse models and α-synuclein overexpression transgenic mouse models of Parkinson's disease, MGF reduces neuroinflammation and oxidative stress by inhibiting NF-κB signaling, resulting in improved motor coordination and neuronal survival in the substantia nigra (133).”

• cites [133] Li Y Xia Y Yin S Wan F Hu J Kou L Sun Y Wu J Zhou Q Huang J Targeting microglial α-synuclein/TLRs/NF-kappaB/NLRP3 inflammasome axis in Parkinson's disease Front Immunol 12 719807 2021 10.3389/fimmu.2021.719807 34691027 PMC8531525 sourceCould not verify

  Section 3.3 discusses reduced inflammation, NF-κB activity, and motor deficits in Parkinson’s mouse models, but attributes those effects to compounds such as hypoestoxide and lenalidomide, not MGF. Searches for MGF, mangiferin, and the claimed combination of mouse models and outcomes found no passage addressing MGF’s effects. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

In high-fat diet-induced hyperlipidemic rats, MGF (50, 100, or 150 mg/kg orally for 6 weeks) activates hepatic AMPK, improving lipid metabolism and reducing circulating free fatty acids.

“In high-fat diet-induced hyperlipidemic rats, MGF (50, 100 or 150 mg/kg, orally administered for 6 weeks) has been shown to activate hepatic AMPK, resulting in improved lipid metabolism and reduced circulating free fatty acids (147).”

• cites [147] Han J Yang N Zhang F Zhang C Liang F Xie W Chen W Rhizoma anemarrhenae extract ameliorates hyperglycemia and insulin resistance via activation of AMP-activated protein kinase in diabetic rodents J Ethnopharmacol 172 368 376 2015 10.1016/j.jep.2015.05.016 26162543 sourcePartly supported

  The Discussion (page unavailable) reports that mangiferin activated hepatic AMPK in hyperlipidemic rats, citing Niu et al. (2012); the References list describes that study as finding decreased plasma free fatty acids through hepatic AMPK activation. Our copy does not give the claimed 50, 100, or 150 mg/kg doses, oral administration, six-week duration, or high-fat-diet condition for those rats. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

In aging mice, MGF improves memory, reduces hippocampal pathology, and decreases β-amyloid burden and lipid peroxidation.

“In aging mice, MGF improves memory, reduces hippocampal pathology, and decreases the β-amyloid burden and lipid peroxidation (138).”

• cites [138] Du Z Fanshi F Lai YH Chen JR Hao E Deng J Hsiao CD Mechanism of anti-dementia effects of mangiferin in a senescence accelerated mouse (SAMP8) model Biosci Rep 39 BSR20190488 2019 10.1042/BSR20190488 31484797 PMC6753319 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Diabetic nephropathy is a common microvascular complication of type 1 and type 2 diabetes.

“Diabetic nephropathy is a common microvascular complication of type 1 and type 2 diabetes (143).”

• cites [143] Samsu N Diabetic nephropathy: Challenges in pathogenesis, diagnosis, and treatment Biomed Res Int 2021 1497449 2021 10.1155/2021/1497449 34307650 PMC8285185 sourceSupported

May combine two claims.

Orally administered MGF has low aqueous solubility and limited intestinal permeability, resulting in poor systemic exposure at conventional doses.

“Orally administered MGF shows low aqueous solubility and limited intestinal permeability, resulting in poor systemic exposure at conventional doses (157-160).”

• cites [157] Ma H Chen H Sun L Tong L Zhang T Improving permeability and oral absorption of mangiferin by phospholipid complexation Fitoterapia 93 54 61 2014 10.1016/j.fitote.2013.10.016 24220727 sourceNot checked — no full text of the source
• cites [158] Pacheco-Ordaz RN Antunes-Ricardo M Gutiérrez-Uribe JA González-Aguilar GA Intestinal permeability and cellular antioxidant activity of phenolic compounds from mango (mangifera indica cv. Ataulfo) peels Int J Mol Sci 19 514 2018 10.3390/ijms19020514 29419800 PMC5855736 sourcePartly supported

  Results §2.3 reports mangiferin transport across an intestinal cell monolayer, including 28.84% basolateral recovery from one mango-peel fraction and an apparent permeability coefficient for the mangiferin standard. This provides some support for limited intestinal permeability, but the paper does not establish low aqueous solubility or poor systemic exposure after oral administration at conventional doses. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [159] Hou S Wang F Li Y Li Y Wang M Sun D Sun C Pharmacokinetic study of mangiferin in human plasma after oral administration Food Chem 132 289 294 2012 10.1016/j.foodchem.2011.10.079 26434292 sourceNot checked — no full text of the source
• cites [160] Bunt D Schwalbe M Hayeeawaema F El Aidy S Gut microbiota-mediated conversion of mangiferin to norathyriol alters short chain fatty acid and urate metabolism Gut Microbes 17 2508422 2025 10.1080/19490976.2025.2508422 40401774 PMC12101588 sourcePartly supported

  The Introduction attributes mangiferin’s negligible oral bioavailability in rats to poor intestinal solubility and permeability, and says it was undetectable in rat plasma even at relatively high oral doses of 50–500 mg/kg. This supports poor systemic exposure after oral administration, but the passage does not establish the claim for populations beyond rats or define exposure at “conventional doses.” (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

In rodents, MGF tissue distribution shows measurable concentrations in liver, kidney, and lung with delayed plasma peaks, but limited brain penetration under standard conditions.

“The tissue distribution in rodents indicates measurable concentrations in the liver, kidney and lung with delayed plasma peaks, whereas brain penetration appears limited under standard conditions (107,163).”

• cites [107] Kammalla AK Ramasamy MK Inampudi J Dubey GP Agrawal A Kaliappan I Comparative pharmacokinetic study of mangiferin after oral administration of pure mangiferin and US patented polyherbal formulation to rats AAPS PharmSciTech 16 250 258 2015 10.1208/s12249-014-0206-8 25273025 PMC4370957 sourcePartly supported

  The Tissue Distribution Studies and Discussion report detectable mangiferin in rat liver, kidney, and lung, with brain levels below the quantification limit. Table III in the Discussion shows a later plasma peak for the polyherbal formulation than for pure mangiferin (3.00 versus 0.67 hours). The claim omits that this delay was formulation-specific and that tissue distribution was measured after administration of the formulation, not under general ‘standard conditions.’ (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [163] Lin A Li J Li D Jin H Liu Y Tissue distribution study of mangiferin after intragastric administration of mangiferin monomer, rhizoma anemarrhenae, and rhizoma anemarrhenae-phellodendron decoctions in normal or type 2 diabetic rats by LC-MS/MS J Chromatogr B Analyt Technol Biomed Life Sci 1122-1123 18 28 2019 10.1016/j.jchromb.2019.05.019 31129356 sourceNot checked — no full text of the source

May combine two claims.

Human evidence remains sparse, with a lack of standardized endpoints, validated translational biomarkers, and prospective trials incorporating randomization, blinding, and predefined primary outcomes.

“Human evidence remains sparse, with a lack of standardized endpoints, validated translational biomarkers, and prospective trials that incorporate randomization, blinding and predefined primary outcomes (184,191).”

• cites [184] Shang Y Tian J Zhang Z Luo L Saeheng S Qiu S Zhou R Chen J Li L Mangiferin: Sources, anti-inflammatory activities, and molecular mechanisms J Agric Food Chem 73 27145 27160 2025 10.1021/acs.jafc.5c06234 41108271 sourceNot checked — no full text of the source
• cites [191] Minniti G Laurindo LF Machado NM Duarte LG Guiguer EL Araujo AC Dias JA Lamas CB Nunes YC Bechara MD Mangifera indica L., By-products, and mangiferin on cardio-metabolic and other health conditions: A systematic review Life (Basel) 13 2270 2023 38137871 PMC10744517 sourcePartly supported

  The Results (section 3; page unavailable) report only 12 clinical trials, and the Discussion (section 4.2; page unavailable) identifies limitations including small samples and limited outcome measurement. These passages support the characterization of human evidence as limited, but they do not establish a lack of standardized endpoints, validated translational biomarkers, or trials combining randomization, blinding, and predefined primary outcomes. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Safety reporting is inconsistent, with limited long-term toxicity, immunomodulatory risk, and drug-drug interaction data.

“Furthermore, safety reporting is inconsistent, with limited long-term toxicity, immunomodulatory risk and drug-drug interaction data, and with few studies that stratify patients by sex or age (184,185,190).”

• cites [184] Shang Y Tian J Zhang Z Luo L Saeheng S Qiu S Zhou R Chen J Li L Mangiferin: Sources, anti-inflammatory activities, and molecular mechanisms J Agric Food Chem 73 27145 27160 2025 10.1021/acs.jafc.5c06234 41108271 sourceNot checked — no full text of the source
• cites [185] Na L Zhang Q Jiang S Du S Zhang W Li Y Sun C Niu Y Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: A double-blind randomized controlled trial Sci Rep 5 10344 2015 10.1038/srep10344 25989216 PMC4437311 sourcePartly supported

  The Discussion (page unavailable) says there had been no reports of long-duration mangiferin intervention in humans, supporting the concern about limited long-term safety data. It also reports no observed side effects during this 12-week trial. The paper does not assess whether safety reporting is inconsistent across studies or discuss immunomodulatory risks or drug–drug interaction data. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [190] Ren K Li H Zhou HF Liang Y Tong M Chen L Zheng XL Zhao GJ Mangiferin promotes macrophage cholesterol efflux and protects against atherosclerosis by augmenting the expression of ABCA1 and ABCG1 Aging (Albany NY) 11 10992 11009 2019 10.18632/aging.102498 31790366 PMC6932905 sourceCould not verify

  The Discussion reports effects on cholesterol efflux and atherosclerosis, while Materials and Methods describes experiments in male mice; neither section assesses safety reporting across studies. Searches for long-term toxicity, immunomodulatory risk, drug–drug interactions, and sex- or age-stratified patient data found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

Early human data on MGF are limited, heterogeneous, and not definitive for purified MGF.

“Early human data are limited, heterogeneous (often extract-based) and not yet definitive for purified MGF.”

• cites [139] López-Ríos L Wiebe JC Vega-Morales T Gericke N Central nervous system activities of extract mangifera indica L J Ethnopharmacol 260 112996 2020 10.1016/j.jep.2020.112996 32473365 sourceSupported
• cites [166] Fuentes-Rios D Sanchez-Rodriguez A Lopez-Rios L Garcia-Gonzalez E Martinez-Canton M Galvan-Alvarez V Gallego-Selles A Martin-Rincon M Calbet JAL Vega-Morales T Human pharmacokinetic profiling and comparative analysis of mangiferin and its monosodium derivative from mangifera indica extracts using UHPLC-MS/MS with (1)h NMR and MALDI-TOF confirmation Molecules 30 461 2025 10.3390/molecules30030461 39942566 PMC11820055 sourceSupported
• cites [185] Na L Zhang Q Jiang S Du S Zhang W Li Y Sun C Niu Y Mangiferin supplementation improves serum lipid profiles in overweight patients with hyperlipidemia: A double-blind randomized controlled trial Sci Rep 5 10344 2015 10.1038/srep10344 25989216 PMC4437311 sourcePartly supported

  The Discussion says no long-term human mangiferin intervention had previously been reported, supporting the description of early human evidence as limited. But the Methods describe this trial’s intervention as 98%-pure mangiferin, and the Discussion reports significant lipid-profile improvements after 12 weeks. The paper does not establish that human studies were often extract-based or characterize the evidence for purified mangiferin as not definitive. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

PK constraints remain under-characterized, including oral exposure at clinically relevant doses, relative contribution of metabolites such as norathyriol, tissue penetration in target organs, and variability introduced by different formulations.

“PK constraints remain under-characterized, including oral exposure at clinically relevant doses, the relative contribution of metabolites such as norathyriol, tissue penetration in target organs and the variability introduced by different formulations (21,159,162).”

• cites [21] Tian X Gao Y Xu Z Lian S Ma Y Guo X Hu P Li Z Huang C Pharmacokinetics of mangiferin and its metabolite-norathyriol, part 1: Systemic evaluation of hepatic first-pass effect in vitro and in vivo Biofactors 42 533 544 2016 10.1002/biof.1291 27130074 sourcePartly supported

  The Introduction reports very low oral bioavailability, and the Abstract says norathyriol’s exposure and possible effects after repeated dosing require further study. The Discussion reports limited accumulation in the liver. These passages concern rat dosing and liver measurements; they do not establish uncertainty about exposure at clinically relevant doses, penetration into other target organs, or variability between formulations. Page numbers are unavailable in the indexed passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [159] Hou S Wang F Li Y Li Y Wang M Sun D Sun C Pharmacokinetic study of mangiferin in human plasma after oral administration Food Chem 132 289 294 2012 10.1016/j.foodchem.2011.10.079 26434292 sourceNot checked — no full text of the source
• cites [162] Guo X Cheng M Hu P Shi Z Chen S Liu H Shi H Xu Z Tian X Huang C Absorption, metabolism, and pharmacokinetics profiles of norathyriol, an aglycone of mangiferin, in rats by HPLC-MS/MS J Agric Food Chem 66 12227 12235 2018 10.1021/acs.jafc.8b03763 30298742 sourceNot checked — no full text of the source

May combine two claims.

Many 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).”

• cites [117] Suchal K Malik S Khan SI Malhotra RK Goyal SN Bhatia J Kumari S Ojha S Arya DS Protective effect of mangiferin on myocardial ischemia-reperfusion injury in streptozotocin-induced diabetic rats: Role of AGE-RAGE/MAPK pathways Sci Rep 7 42027 2017 10.1038/srep42027 28181586 PMC5299420 sourcePartly supported

  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 measured
• cites [188] Bhatia J Suchal K Bhargava P Malik S Arya D Evaluation of the cardioprotective effect of mangiferin in an experimental model of ischemia reperfusion injury J Hypertens 39 e280 2021 10.1097/01.hjh.0000747668.48915.20 sourceNot checked — no full text of the source

May combine two claims.

MGF mitigates chronic inflammation and oxidative stress in diabetes through inhibition of HIF-1α and NF-κB signaling, suppression of JNK phosphorylation, and reduction in endoplasmic reticulum stress, collectively restoring insulin signaling.

“Given that chronic inflammation and oxidative stress are central to the development of diabetes (29), MGF mitigates these processes through the inhibition of HIF-1α and NF-κB signaling, the suppression of JNK phosphorylation, and the reduction in endoplasmic reticulum stress, collectively restoring insulin signaling (30).”

• cites [29] Mao X Liu L Cheng L Cheng R Zhang L Deng L Sun X Zhang Y Sarmento B Cui W Adhesive nanoparticles with inflammation regulation for promoting skin flap regeneration J Control Release 297 91 101 2019 10.1016/j.jconrel.2019.01.031 30690104 sourceNot checked — no full text of the source
• cites [30] Yang CQ Xu JH Yan DD Liu BL Liu K Huang F Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition Chin J Nat Med 15 664 673 2017 28991527 sourceNot checked — no full text of the source

May combine two claims.

In metabolic disorders, MGF improves insulin sensitivity, supports mitochondrial function and reduces diabetic complications.

“In metabolic disorders, MGF has been shown to improve insulin sensitivity, support mitochondrial function and reduce diabetic complications.”

May combine two claims.

M1 is dehydroxylated to form M2 and M4, with M2 being the predominant urinary metabolite in rodents.

“Specifically, M1 is dehydroxylated to form 1,3,7-trihydroxyxanthone (M2) and 1,7-dihydroxyxanthone (M4), with M2 being the predominant urinary metabolite in rodents (22).”

• cites [22] Hasanah U Miki K Nitoda T Kanzaki H Aerobic bioconversion of c-glycoside mangiferin into its aglycone norathyriol by an isolated mouse intestinal bacterium Biosci Biotechnol Biochem 85 989 997 2021 10.1093/bbb/zbaa121 33710320 sourceNot checked — no full text of the source

May combine two claims.

MGF exerts wide-ranging pharmacological effects by modulating glycolysis, the TCA cycle, and lipid and amino acid metabolism, supporting its potential use in treating hyperlipidemia and hyperglycemia.

“In addition, it exerts wide-ranging pharmacological effects by modulating key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and lipid and amino acid metabolism, supporting its potential use in treating metabolic disorders such as hyperlipidemia and hyperglycemia (8).”

• cites [8] Xiang G Guo S Xing N Du Q Qin J Gao H Zhang Y Wang S Mangiferin, a potential supplement to improve metabolic syndrome: Current status and future opportunities Am J Chin Med 52 355 386 2024 10.1142/S0192415X24500150 38533569 sourceNot checked — no full text of the source

May combine two claims.

Microbial or enzymatic deglycosylation of MGF's C-glucoside generates the aglycone norathyriol (M1), which has greater membrane permeability than the parent compound.

“A frequently observed pathway is microbial or enzymatic deglycosylation of C-glucoside, generating the aglycone norathyriol (metabolite M1), which has greater membrane permeability than the parent compound (20).”

• cites [20] Ehianeta TS Laval SP Yu B Bio- and chemical syntheses of mangiferin and congeners Biofactors 42 445 458 2016 10.1002/biof.1279 27774668 sourceNot checked — no full text of the source

May combine two claims.

Only 1.15% of orally administered MGF (30 mg/kg) is bioavailable in mice, whereas intraperitoneal administration results in markedly increased systemic levels.

“A previous in vivo study demonstrated that only 1.15% of orally administered MGF (30 mg/kg) is bioavailable in mice, whereas intraperitoneal administration results in markedly increased systemic levels.”

• cites [17] Gu PC Wang L Han MN Peng J Shang JC Pan YQ Han WL Comparative pharmacokinetic study of mangiferin in normal and alloxan-induced diabetic rats after oral and intravenous administration by UPLC-MS/MS Pharmacology 103 30 37 2019 10.1159/000493364 30359985 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

References were screened by title, abstract and full text, and only those meeting the inclusion criteria were included in the final review.

“References were screened by title, abstract and full text, and only those meeting the inclusion criteria were included in the final review.”

May combine two claims.

Anti-inflammatory actions of MGF include decreased cytokine release and regulation of the NLR family pyrin domain-containing 3 inflammasome.

“Anti-inflammatory actions include decreased cytokine release and regulation of the NLR family pyrin domain-containing 3 inflammasome.”

May combine two claims.

The stability of MGF's C-glycosidic bond prevents enzymatic cleavage and reduces transmembrane transport, thereby restricting passive absorption across the intestinal epithelium.

“The stability of its C-glycosidic bond prevents enzymatic cleavage and reduces transmembrane transport, thereby restricting passive absorption across the intestinal epithelium (16).”

• cites [16] Andreu GP Delgado R Velho JA Curti C Vercesi AE Iron complexing activity of mangiferin, a naturally occurring glucosylxanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate Eur J Pharmacol 513 47 55 2005 10.1016/j.ejphar.2005.03.007 15878708 sourceNot checked — no full text of the source

May combine two claims.

MGF reverses high glucose-induced impairment of GLUT4 translocation and glucose uptake, partly via AMPK activation and Akt phosphorylation, improving hepatic energy metabolism and insulin responsiveness.

“Furthermore, MGF reverses high glucose-induced impairment of GLUT4 translocation and glucose uptake, partly via AMPK activation and Akt phosphorylation, thereby improving hepatic energy metabolism and overall insulin responsiveness (31).”

• cites [31] Fan X Jiao G Pang T Wen T He Z Han J Zhang F Chen W Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3k/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes Phytomedicine 114 154740 2023 10.1016/j.phymed.2023.154740 36965373 sourceNot checked — no full text of the source

May combine two claims.

MGF complies with Lipinski's rule of five, suggesting favorable drug-like properties despite its absorption limitations.

“Moreover, MGF complies with Lipinski's rule of five, suggesting favorable drug-like properties despite its absorption limitations (6).”

• cites [6] Akkewar AS Mishra KA Sethi KK Mangiferin: A natural bioactive immunomodulating glucosylxanthone with potential against cancer and rheumatoid arthritis J Biochem Mol Toxicol 38 e23765 2024 10.1002/jbt.23765 38967724 sourceNot checked — no full text of the source

May combine two claims.

Compound X-3, a semi-synthetic derivative prepared from MGF, markedly reduces hyperglycemia and obesity in mice after 8 weeks of oral treatment (40-120 mg/kg), primarily through AMPK pathway activation.

“For example, compound X-3, a semi-synthetic derivative prepared from MGF, has been reported to markedly reduce hyperglycemia and obesity in mice after 8 weeks of oral treatment (40-120 mg/kg), primarily through AMPK pathway activation (32).”

• cites [32] Han J Yi J Liang F Jiang B Xiao Y Gao S Yang N Hu H Xie WF Chen W X-3, a mangiferin derivative, stimulates AMP-activated protein kinase and reduces hyperglycemia and obesity in db/db mice Mol Cell Endocrinol 405 63 73 2015 10.1016/j.mce.2015.02.008 25681564 sourceNot checked — no full text of the source

May combine two claims.

In cancer models, MGF suppresses proliferation, invasion and angiogenesis, and can influence antitumor immunity in the tumor microenvironment.

“In cancer models, MGF suppresses proliferation, invasion and angiogenesis, and can influence antitumor immunity in the tumor microenvironment.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

MGF has neuroprotective, anti-inflammatory and anticancer effects by reducing oxidative stress, inhibiting proinflammatory signaling, and suppressing tumor proliferation and metastasis.

“Additionally, MGF has neuroprotective, anti-inflammatory and anticancer effects by reducing oxidative stress, inhibiting proinflammatory signaling, and suppressing tumor proliferation and metastasis.”

May combine two claims.

Activation of the PPARα/γ axis by MGF enhances fatty acid β-oxidation and upregulates GLUT4, thereby improving insulin sensitivity.

“Activation of the peroxisome proliferator-activated receptor (PPAR)α/γ axis enhances fatty acid β-oxidation and upregulates glucose transporter 4 (GLUT4), thereby improving insulin sensitivity (28).”

• cites [28] Shimada T Nagai E Harasawa Y Watanabe M Negishi K Akase T Sai Y Miyamoto K Aburada M Salacia reticulata inhibits differentiation of 3T3-l1 adipocytes J Ethnopharmacol 136 67 74 2011 10.1016/j.jep.2011.04.012 21511020 sourceNot checked — no full text of the source

May combine two claims.

MGF is a natural C-glucosyl xanthone with multitarget activity relevant to metabolic, inflammatory and cancer diseases.

“Mangiferin (MGF) is a natural C-glucosyl xanthone with multitarget activity relevant to metabolic, inflammatory and cancer diseases.”

Classified as probably not a substantial claim. May combine two claims.

The review excluded non-peer-reviewed materials, conference abstracts or duplicated data; studies using complex herbal mixtures without quantifiable MGF content; and articles lacking sufficient methodological detail or outcome data.

“The exclusion criteria were as follows: i) Non-peer-reviewed materials, conference abstracts or duplicated data; ii) studies using complex herbal mixtures without quantifiable MGF content; and iii) articles lacking sufficient methodological detail or outcome data.”

May combine two claims.

MGF promotes glycolysis and glycogen synthesis while inhibiting gluconeogenesis by modulating GSK3β, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.

“It promotes glycolysis and glycogen synthesis while inhibiting gluconeogenesis by modulating key enzymes such as glycogen synthase kinase 3β (GSK3β), glucose-6-phosphatase and phosphoenolpyruvate carboxykinase.”

• cites [31] Fan X Jiao G Pang T Wen T He Z Han J Zhang F Chen W Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3k/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes Phytomedicine 114 154740 2023 10.1016/j.phymed.2023.154740 36965373 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The review included original research or review articles investigating the pharmacological, biochemical or clinical properties of MGF; studies providing mechanistic, pharmacokinetic or toxicological data; and publications written in English and indexed in peer-reviewed journals.

“The inclusion criteria were as follows: i) Original research or review articles investigating the pharmacological, biochemical or clinical properties of MGF; ii) studies providing mechanistic, pharmacokinetic (PK) or toxicological data; and iii) publications written in English and indexed in peer-reviewed journals.”

May combine two claims.

Safety signals in animals are favorable at relevant doses, but clinical evidence remains limited.

“Furthermore, safety signals in animals are favorable at relevant doses, but clinical evidence remains limited.”

May combine two claims.

Benefits of nanocarrier delivery, structural optimization and combination therapy have been reported, which may improve exposure and efficacy in experimental systems.

“However, benefits of nanocarrier delivery, structural optimization and combination therapy have been reported, which may improve exposure and efficacy in experimental systems.”

Classified as probably not a substantial claim.

The review's literature search was conducted in PubMed, Web of Science, Scopus and Google Scholar for studies published between January 2000 and June 2025.

“To ensure the comprehensiveness and reliability of the present review, a structured literature search was conducted in the PubMed (https://pubmed.ncbi.nlm.nih.gov/), Web of Science (http://www.webofscience.com/), Scopus (http://www.scopus.com/) and Google Scholar (http://scholar.google.com/) databases. The search included studies published between January 2000 and June 2025.”

May combine two claims.

In rats, apparent permeability is greater in the duodenum than in the jejunum, and greater in the jejunum than in the ileum, suggesting that the upper small intestine is the principal site of MGF uptake.

“In situ perfusion experiments have indicated greater apparent permeability in the duodenum compared with that in the jejunum, and greater permeability in the jejunum than in the ileum, which suggests that the upper small intestine is the principal site of uptake (18).”

• cites [18] Liu H Wu B Pan G He L Li Z Fan M Jian L Chen M Wang K Huang C Metabolism and pharmacokinetics of mangiferin in conventional rats, pseudo-germ-free rats, and streptozotocin-induced diabetic rats Drug Metab Dispos 40 2109 2118 2012 10.1124/dmd.112.045849 22859782 sourceNot checked — no full text of the source

May combine two claims.

MGF is biotransformed by the human intestinal microbiota, with deglycosylation to norathyriol a key step.

“Metabolic investigations have indicated that MGF is biotransformed by the human intestinal microbiota, with deglycosylation to norathyriol a key step (8).”

• cites [8] Xiang G Guo S Xing N Du Q Qin J Gao H Zhang Y Wang S Mangiferin, a potential supplement to improve metabolic syndrome: Current status and future opportunities Am J Chin Med 52 355 386 2024 10.1142/S0192415X24500150 38533569 sourceNot checked — no full text of the source

May combine two claims.

In lung cancer mouse models, MGF alters mitochondrial metabolism by increasing lipid peroxidation and suppressing key TCA cycle and electron transport enzymes, including isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and α-ketoglutarate dehydrogenase.

“In lung cancer mouse models, MGF alters mitochondrial metabolism by increasing lipid peroxidation and suppressing key TCA cycle and electron transport enzymes, including isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase and α-ketoglutarate dehydrogenase (70).”

• cites [70] Rajendran P Ekambaram G Sakthisekaran D Effect of mangiferin on benzo(a)pyrene induced lung carcinogenesis in experimental swiss albino mice Nat Prod Res 22 672 680 2008 10.1080/14786410701824973 18569708 sourceNot checked — no full text of the source

May combine two claims.

In HeLa cervical cancer cells, ethanolic mango peel extract enriched with MGF downregulates Bid, Bcl-2 and pro-caspase-3 and -8, while activating caspases-3, -7, -8 and -9, and cleaving PARP.

“In HeLa cervical cancer cells, ethanolic mango peel extract enriched with MGF downregulates Bid, Bcl-2 and pro-caspase-3 and -8, while activating caspases-3, -7, -8 and -9, and cleaving poly(ADP-ribose) polymerase (PARP)-hallmarks of caspase-mediated apoptosis (62).”

• cites [62] Kim H Kim H Mosaddik A Gyawali R Ahn KS Cho SK Induction of apoptosis by ethanolic extract of mango peel and comparative analysis of the chemical constitutes of mango peel and flesh Food Chem 133 416 422 2012 10.1016/j.foodchem.2012.01.053 25683414 sourceNot checked — no full text of the source

May combine two claims.

In diabetic peripheral neuropathy models, MGF enhances antioxidant defenses and upregulates nerve growth factor, thereby promoting nerve regeneration and functional recovery.

“Concurrently, it enhances antioxidant defenses and upregulates nerve growth factor, thereby promoting nerve regeneration and functional recovery (35).”

• cites [35] Shivam Gupta AK Neuroprotective effects of isolated mangiferin from swertia chirayita leaves regulating oxidative pathway on streptozotocin-induced diabetic neuropathy in experimental rats Cent Nerv Syst Agents Med Chem 24 182 195 2024 10.2174/0118715249255977231213053039 38305392 sourceNot checked — no full text of the source

May combine two claims.

In SGC-7901 gastric cancer cells, MGF suppresses Bcl-2, Bcl-xL and Mcl-1 expression, and increases Bax, Bad, and cleaved caspase-3 and -9 levels.

“In SGC-7901 gastric cancer cells, MGF suppresses Bcl-2, Bcl-xL and Mcl-1 expression, and increases Bax, Bad, and cleaved caspase-3 and -9 levels.”

• cites [47] Du M Wen G Jin J Chen Y Cao J Xu A Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway Anticancer Drugs 29 167 175 2018 10.1097/CAD.0000000000000583 29215373 sourceNot checked — no full text of the source

May combine two claims.

AMPK activation by MGF can suppress NF-κB priming and MAPK activity, whereas redox shifts through Nrf2 dampen inflammasome priming, converging on MMP-9 and invasion programs.

“Notably, crosstalk is evident: AMPK activation can suppress NF-κB priming and MAPK activity, whereas redox shifts through Nrf2 dampen inflammasome priming, which converges on MMP-9 and invasion programs.”

May combine two claims.

MGF activates the Nrf2 pathway, stabilizing Nrf2 protein levels by inhibiting its ubiquitination, leading to increased transcription of antioxidant enzymes such as NQO1.

“MGF activates the Nrf2 pathway, stabilizing Nrf2 protein levels by inhibiting its ubiquitination, which leads to increased transcription of antioxidant enzymes, such as NQO1 (73,74).”

• cites [73] Ren J Su D Li L Cai H Zhang M Zhai J Li M Wu X Hu K Anti-inflammatory effects of aureusidin in LPS-stimulated RAW264.7 macrophages via suppressing NF-κB and activating ROS- and MAPKs-dependent Nrf2/HO-1 signaling pathways Toxicol Appl Pharmacol 387 114846 2020 10.1016/j.taap.2019.114846 31790703 sourceNot checked — no full text of the source
• cites [74] Qin ZZ Ruan J Lee MR Sun K Chen P Chen Y Hong M Xia LH Fang J Tang H Mangiferin promotes bregs level, activates Nrf2 antioxidant signaling, and inhibits proinflammatory cytokine expression in murine splenic mononuclear cells in vitro Curr Med Sci 41 454 464 2021 10.1007/s11596-021-2371-9 34129203 sourceNot checked — no full text of the source

May combine two claims.

In SGC-7901 gastric cancer cells, MGF inhibits the PI3K/Akt/mTOR signaling axis, further promoting apoptosis and suppressing cell survival.

“Additionally, it inhibits the PI3K/Akt/mTOR signaling axis, further promoting apoptosis and suppressing cell survival (47).”

• cites [47] Du M Wen G Jin J Chen Y Cao J Xu A Mangiferin prevents the growth of gastric carcinoma by blocking the PI3K-Akt signalling pathway Anticancer Drugs 29 167 175 2018 10.1097/CAD.0000000000000583 29215373 sourceNot checked — no full text of the source

May combine two claims.

In murine models, low concentrations of MGF (5-40 mg/ml) enhance the proliferation of splenocytes and thymocytes, whereas higher doses inhibit tumor cell proliferation.

“Dose-dependent immunostimulatory effects have also been observed in murine models; low concentrations (5-40 mg/ml) enhance the proliferation of splenocytes and thymocytes, whereas higher doses inhibit tumor cell proliferation.”

• cites [105] Shang HS Chen CJ Shih YL Peng SF Chen YL Liu KC Huang HC Hsueh SC Chen KW Lu HF Mangiferin induces immune responses and evaluates the survival rate in WEHI-3 cell generated mouse leukemia in vivo Environ Toxicol 36 77 85 2021 10.1002/tox.23013 32889744 sourceNot checked — no full text of the source
• cites [106] Jeong JJ Jang SE Hyam SR Han MJ Kim DH Mangiferin ameliorates colitis by inhibiting IRAK1 phosphorylation in NF-κB and MAPK pathways Eur J Pharmacol 740 652 661 2014 10.1016/j.ejphar.2014.06.013 24972244 sourceNot checked — no full text of the source

May combine two claims.

MGF activates splenocytes, facilitates plant lectin agglutination and stimulates NK-resistant tumor cell killing by macrophages.

“MGF activates splenocytes, facilitates plant lectin agglutination and stimulates NK-resistant tumor cell killing by macrophages (105,106).”

• cites [105] Shang HS Chen CJ Shih YL Peng SF Chen YL Liu KC Huang HC Hsueh SC Chen KW Lu HF Mangiferin induces immune responses and evaluates the survival rate in WEHI-3 cell generated mouse leukemia in vivo Environ Toxicol 36 77 85 2021 10.1002/tox.23013 32889744 sourceNot checked — no full text of the source
• cites [106] Jeong JJ Jang SE Hyam SR Han MJ Kim DH Mangiferin ameliorates colitis by inhibiting IRAK1 phosphorylation in NF-κB and MAPK pathways Eur J Pharmacol 740 652 661 2014 10.1016/j.ejphar.2014.06.013 24972244 sourceNot checked — no full text of the source

May combine two claims.

In metastatic melanoma models, low-dose MGF enhances the antitumor activity of citrus-derived glycosides, partly by increasing TNF-α expression and inhibiting metastasis.

“In metastatic melanoma models, low-dose MGF enhances the antitumor activity of citrus-derived glycosides, partly by increasing TNF-α expression and inhibiting metastasis (89).”

• cites [89] 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 Anti-angiogenic effects of mangiferin and mechanism of action in metastatic melanoma Melanoma Res 30 39 51 2020 10.1097/CMR.0000000000000647 31651714 sourceNot checked — no full text of the source

May combine two claims.

MGF suppresses RelA and RelB expression, reduces NF-κB transcriptional activity, and induces apoptosis in malignancies such as multiple myeloma.

“MGF suppresses RelA and RelB expression, reduces NF-κB transcriptional activity, and induces apoptosis in malignancies such as multiple myeloma (95).”

• cites [95] Wu Y Yao X Shi X Xu Z Ren J Shi M Li M Liu J Du X Myeloma extracellular vesicle-derived RAGE increases inflammatory responses and myotube atrophy in multiple myeloma through activation of the TLR4/NF-κB p65 pathway Apoptosis 29 849 864 2024 10.1007/s10495-023-01920-7 38117373 sourceNot checked — no full text of the source

May combine two claims.

MGF upregulates proapoptotic markers including cleaved caspase-3, cleaved PARP-1, p53, phosphorylated-p53 and PUMA, while downregulating antiapoptotic proteins such as survivin and Bcl-xL.

“MGF upregulates proapoptotic markers, including cleaved caspase-3, cleaved PARP-1, p53, phosphorylated-p53 and p53-upregulated modulator of apoptosis, while downregulating antiapoptotic proteins, such as survivin and Bcl-xL (40).”

• cites [40] Takeda T Tsubaki M Sakamoto K Ichimura E Enomoto A Suzuki Y Itoh T Imano M Tanabe G Muraoka O Mangiferin, a novel nuclear factor kappa b-inducing kinase inhibitor, suppresses metastasis and tumor growth in a mouse metastatic melanoma model Toxicol Appl Pharmacol 306 105 112 2016 10.1016/j.taap.2016.07.005 27417526 sourceNot checked — no full text of the source

May combine two claims.

In human glioma models, MGF reduces PMA-induced MMP-9 without materially affecting other MMP family members, consistent with decreased NF-κB and AP-1 binding to the MMP-9 promoter, and upstream attenuation of Akt and MAPK signaling.

“In human glioma models, MGF reduces phorbol 12-myristate 13-acetate-induced MMP-9 without materially affecting other MMP family members, which is consistent with decreased NF-κB and AP-1 binding to the MMP-9 promoter, and with upstream attenuation of Akt and MAPK signaling (41).”

• cites [41] Jung JS Jung K Kim DH Kim HES Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: involvement of PI3k/akt and MAPK signaling pathways Pharmacol Res 66 95 103 2012 10.1016/j.phrs.2012.02.013 22465218 sourceNot checked — no full text of the source

May combine two claims.

In NAFLD mouse models, MGF inhibits the NF-κB and JNK pathways, with reduced body weight and plasma triglyceride and cholesterol levels.

“An additional study has confirmed the ability of MGF to inhibit the NF-κB and JNK pathways, with reduced body weight and plasma triglyceride and cholesterol levels in NAFLD mouse models (125).”

• cites [125] Wang H Zhu YY Wang L Teng T Zhou M Wang SG Tian YZ Du L Yin XX Sun Y Mangiferin ameliorates fatty liver via modulation of autophagy and inflammation in high-fat-diet induced mice Biomed Pharmacother 96 328 335 2017 10.1016/j.biopha.2017.10.022 29024899 sourceNot checked — no full text of the source

May combine two claims.

In a diethylnitrosamine-induced hepatocellular carcinoma rat model, MGF reduces MDA content, elevates SOD activity and GSH levels, and attenuates tumor formation.

“In a diethylnitrosamine-induced hepatocellular carcinoma rat model, treatment with MGF has been shown to improve hepatic oxidative stress markers, as follows: Malondialdehyde (MDA) content was reduced, whereas SOD activity and GSH levels were elevated, and tumor formation was attenuated (79).”

• cites [79] Yang G Shang X Cui G Zhao L Zhao H Wang N Mangiferin attenuated diethynitrosamine-induced hepatocellular carcinoma in sprague-dawley rats via alteration of oxidative stress and apoptotic pathway J Environ Pathol Toxicol Oncol 38 1 12 2019 10.1615/JEnvironPatholToxicolOncol.2018027392 30806285 sourceNot checked — no full text of the source

May combine two claims.

MGF suppresses NF-κB-inducing kinase, reinforcing the blockade of both canonical and noncanonical NF-κB pathways, ultimately limiting cancer cell proliferation, metastasis and survival.

“Additionally, MGF suppresses NF-κB-inducing kinase, further reinforcing the blockade of both the canonical and noncanonical NF-κB pathways, ultimately limiting cancer cell proliferation, metastasis and survival.”

May combine two claims.

A computational study supports direct interactions between MGF derivatives and the MMP-9 catalytic site, which may contribute to enzymatic inhibition.

“A Computational study has provided support for direct interactions between MGF derivatives and the MMP-9 catalytic site, which may contribute to enzymatic inhibition (88).”

• cites [88] Gálvez-Rodríguez A Ferino-Pérez A Rodríguez-Riera Z Guerra IR Jáuregui-Haza UJ In silico evaluation of new mangiferin-based positron emission tomography radiopharmaceuticals through the inhibition of metalloproteinase-9 J Mol Graph Model 124 108569 2023 10.1016/j.jmgm.2023.108569 37487370 sourceNot checked — no full text of the source

May combine two claims.

MGF's neuroprotective mechanisms include modulation of oxidative stress, mitochondrial protection, and anti-inflammatory signaling.

“Its mechanisms include the modulation of oxidative stress, mitochondrial protection and anti-inflammatory signaling (132).”

• cites [132] Hayes MT Parkinson's disease and parkinsonism Am J Med 132 802 807 2019 10.1016/j.amjmed.2019.03.001 30890425 sourceNot checked — no full text of the source

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In D(+)-galactosamine-induced nephrotoxicity, MGF inhibits inducible nitric oxide synthase and downregulates NF-κB signaling, improving renal function and histology.

“Similarly, in D(+)-galactosamine-induced nephrotoxicity, MGF exhibits antioxidant properties by inhibiting inducible nitric oxide synthase and downregulating NF-κB signaling, leading to improved renal function and histology (142).”

• cites [142] Zhang D Han S Zhou Y Qi B Wang X 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 152 105400 2020 10.1016/j.ejps.2020.105400 32540472 sourceNot checked — no full text of the source

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In streptozotocin-induced diabetic rats, MGF increases antioxidant enzyme activity (SOD, GSH-Px), reduces lipid peroxidation (MDA), and decreases advanced glycation end-products and sorbitol levels in the lens and serum, contributing to prevention of diabetic ocular complications.

“In streptozotocin-induced diabetic rats, biochemical analysis has revealed that MGF increases antioxidant enzyme activity (SOD, GSH-Px), reduces lipid peroxidation (MDA), and decreases advanced glycation end-products (AGEs) and sorbitol levels in the lens and serum, thereby contributing to the prevention of diabetic ocular complications (131).”

• cites [131] Li X Cui X Wang J Yang J Sun X Li X Zhu Q Li W Rhizome of Anemarrhena asphodeloides counteracts diabetic ophthalmopathy progression in streptozotocin-induced diabetic rats Phytother Res 27 1243 1250 2013 10.1002/ptr.4866 23148017 sourceNot checked — no full text of the source

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In mouse models of ischemic retinal injury, MGF downregulates HIF-1α and glial fibrillary acidic protein, upregulates SIRT1, and protects retinal ganglion cells from oxidative damage.

“In ischemic retinal injury, MGF downregulates HIF-1α and glial fibrillary acidic protein while upregulating SIRT1, thereby protecting retinal ganglion cells from oxidative damage in mouse models (128).”

• cites [128] Kim SJ Sung MS Heo H Lee JH Park SWO Mangiferin protects retinal ganglion cells in ischemic mouse retina via SIRT1 Curr Eye Res 41 844 855 2016 10.3109/02713683.2015.1050736 26200953 sourceNot checked — no full text of the source

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In a murine periodontitis model, oral administration of MGF (50 mg/kg for 8 weeks) suppresses Porphyromonas gingivalis-induced alveolar bone loss, downregulates TNF-α production, and inhibits NF-κB and JAK1/STAT1/3 phosphorylation in gingival epithelium.

“In a murine periodontitis model, oral administration of MGF (50 mg/kg for 8 weeks) has been reported to suppress Porphyromonas gingivalis-induced alveolar bone loss, downregulate TNF-α production and inhibit NF-κB and JAK1/STAT1/3 phosphorylation in the gingival epithelium (155).”

• cites [155] Li H Wang Q Ding Y Bao C Li W Mangiferin ameliorates porphyromonas gingivalis-induced experimental periodontitis by inhibiting phosphorylation of nuclear factor-κB and janus kinase 1-signal transducer and activator of transcription signaling pathways J Periodontal Res 52 1 7 2017 10.1111/jre.12360 26825585 sourceNot checked — no full text of the source

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MGF (12.5, 25, or 50 mg/kg) enhances autophagic flux via AMPK-mTOR signaling, delaying progression of diabetic nephropathy.

“Moreover, MGF (12.5, 25 or 50 mg/kg) enhances autophagic flux via AMPK-mTOR signaling, delaying the progression of diabetic nephropathy (145).”

• cites [145] Wang X Gao L Lin H Song J Wang J Yin Y Zhao J Xu X Li Z Li L Mangiferin prevents diabetic nephropathy progression and protects podocyte function via autophagy in diabetic rat glomeruli Eur J Pharmacol 824 170 178 2018 10.1016/j.ejphar.2018.02.009 29444469 sourceNot checked — no full text of the source

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Purified MGF has MIC values ranging from 1.95 to 62.5 μg/ml for fungi and from 1.95 to 31.25 μg/ml for bacteria.

“Purified MGF has MIC values ranging from 1.95 to 62.5 μg/ml for fungi and from 1.95 to 31.25 μg/ml for bacteria, with a time-kill study confirming its bactericidal and fungicidal efficacy (1).”

• cites [1] Wang M Liang Y Chen K Wang M Long X Liu H Sun Y He B The management of diabetes mellitus by mangiferin: Advances and prospects Nanoscale 14 2119 2135 2022 10.1039/D1NR06690K 35088781 sourceNot checked — no full text of the source

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In Alzheimer's disease models, MGF protects against β-amyloid-induced oxidative damage, restoring redox balance and preserving mitochondrial integrity.

“MGF also protects against β-amyloid-induced oxidative damage, restoring redox balance and preserving mitochondrial integrity in Alzheimer's disease models, such as amyloid β-treated neuronal cultures and APP/PS1 transgenic mice (137).”

• cites [137] Liu T Song Y Hu A Neuroprotective mechanisms of mangiferin in neurodegenerative diseases Drug Dev Res 82 494 502 2021 10.1002/ddr.21783 33458836 sourceNot checked — no full text of the source

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In an LPS-induced sepsis mouse model, MGF (20, 50, or 100 mg/kg) protects against acute kidney injury by preserving syndecan-1, reducing ROS and MDA, enhancing tight junction integrity, and limiting vascular leakage and inflammation.

“MGF (20, 50 or 100 mg/kg) also protects against sepsis-induced acute kidney injury in an LPS-induced sepsis mouse model by preserving the endothelial glycocalyx component syndecan-1, reducing ROS and MDA production, enhancing tight junction integrity, and limiting vascular leakage and inflammation (142).”

• cites [142] Zhang D Han S Zhou Y Qi B Wang X 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 152 105400 2020 10.1016/j.ejps.2020.105400 32540472 sourceNot checked — no full text of the source

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In rat models of diabetic cardiomyopathy, MGF (20 mg/kg for 16 weeks) decreases ROS production and AGE accumulation partly through inhibition of NF-κB signaling, preserving myocardial function and delaying cardiomyopathic remodeling.

“In rat models of diabetic cardiomyopathy, MGF (20 mg/kg for 16 weeks) has been shown to notably decrease ROS production and AGE accumulation, partly through the inhibition of NF-κB signaling. This preserves myocardial function and delays cardiomyopathic remodeling (149).”

• cites [149] Hou J Zheng D Fung G Deng H Chen L Liang J Jiang Y Hu Y Mangiferin suppressed advanced glycation end products (AGEs) through NF-κB deactivation and displayed anti-inflammatory effects in streptozotocin and high fat diet-diabetic cardiomyopathy rats Can J Physiol Pharmacol 94 332 340 2016 10.1139/cjpp-2015-0073 26751764 sourceNot checked — no full text of the source

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MGF derivatives are efficacious against K. pneumoniae by disrupting biofilms, impairing virulence factor expression, and increasing antibiotic susceptibility.

“Furthermore, MGF derivatives have demonstrated efficacy against K. pneumoniae by disrupting biofilms, impairing virulence factor expression and increasing antibiotic susceptibility (154).”

• cites [154] Saifi S Ashraf A Hasan GM Shamsi A Hassan MI Insights into the preventive actions of natural compounds against klebsiella pneumoniae infections and drug resistance Fitoterapia 173 105811 2024 10.1016/j.fitote.2023.105811 38168570 sourceNot checked — no full text of the source

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In oxazolone-induced murine contact dermatitis, MGF suppresses TNF-α-stimulated macrophage activation and inhibits NF-κB pathway activation, decreasing production of inflammatory mediators and oxidative stress markers.

“In murine models of contact dermatitis induced by oxazolone, MGF suppresses TNF-α-stimulated macrophage activation and inhibits NF-κB pathway activation, resulting in decreased production of inflammatory mediators and oxidative stress markers (150).”

• cites [150] Zhao Y Wang W Wu X Ma X Qu R Chen X Liu C Liu Y Wang X Yan P Mangiferin antagonizes TNF-α-mediated inflammatory reaction and protects against dermatitis in a mice model Int Immunopharmacol 45 174 179 2017 10.1016/j.intimp.2017.02.014 28222357 sourceNot checked — no full text of the source

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In high-fat diet-induced hyperlipidemic rats, MGF-loaded N-succinyl-chitosan-grafted alginate nanoparticles increase hepatic expression of PPARα, carnitine palmitoyltransferase I, and FAT/CD36 while suppressing lipogenic genes SREBP-1c, ACC, DGAT2, and MTP, enhancing therapeutic efficacy.

“Furthermore, in high-fat diet-induced hyperlipidemic rats, MGF-loaded N-succinyl-chitosan-grafted alginate nanoparticles enhance therapeutic efficacy by increasing the hepatic expression of PPARα, carnitine palmitoyltransferase I and FAT/CD36, while suppressing lipogenic genes, such as SREBP-1c, ACC, DGAT2 and MTP (148).”

• cites [148] Wang Y Karmakar T Ghosh N Basak S Gopal Sahoo N Targeting mangiferin loaded n-succinyl chitosan-alginate grafted nanoparticles against atherosclerosis-a case study against diabetes mediated hyperlipidemia in rat Food Chem 370 131376 2022 10.1016/j.foodchem.2021.131376 34662793 sourceNot checked — no full text of the source

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Clinical use of MGF is limited by poor solubility and low oral bioavailability.

“Notably, the clinical use of MGF is limited by poor solubility and low oral bioavailability.”

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Preclinical findings regarding MGF are promising, but the evidence base shows important gaps that limit translation.

“Preclinical findings regarding MGF are promising; however, the evidence base shows important gaps that limit translation.”

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MGF has broad pharmacological effects, including antidiabetic, anticancer, anti-inflammatory, antioxidant, and neuroprotective activities, with low toxicity and good biocompatibility.

“MGF, a natural C-glucosylxanthone, has broad pharmacological effects, including antidiabetic, anticancer, anti-inflammatory, antioxidant and neuroprotective activities, with low toxicity and good biocompatibility, making it a promising therapeutic candidate.”