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Cited by 14Mangiferin and Mango ExtractsMedicinal Plant ResearchBioactive natural compounds

Effects of Mangiferin on LPS-Induced Inflammation and SARS-CoV-2 Viral Adsorption in Human Lung Cells

Open access
Spampinato, Mariarita, Carota, Giuseppe, Sferrazzo, Giuseppe, Fuochi, Virginia, Distefano, Alfio, Ronsisvalle, Simone, Sipala, Federica, Giuffrida, Rosario +5 more·2022·Pharmaceutics
DOI 10.3390/pharmaceutics14122845PMC PMC9788116
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Abstract

The growing interest in natural bioactive molecules, as an approach to many pathological contexts, is widely justified by the necessity to overcome the disadvantageous benefit–risk ratio related to traditional therapies. Among them, mangiferin (MGF) shows promising beneficial properties such as antioxidant, anti-inflammatory, and immunomodulatory effects. In this study, we aimed to investigate the antioxidant and anti-inflammatory properties of MGF on lipopolysaccharide (LPS)-induced lung NCI-H292 cells, focusing on its role against COVID-19 adsorption. In order to obtain this information, cells treated with LPS, with or without MGF, were analyzed performing wound healing, gene expression of inflammatory cytokines, GSH quantification, and JC-1 staining. Moreover, the inhibition of viral adsorption was evaluated microbiologically and the results were further confirmed by molecular docking analysis. In this regard, MGF downregulates the expression of several inflammatory factors, enhances GSH levels, promotes the wound healing rate, and restores the mitochondrial dysfunction caused by LPS. In addition, MGF significantly inhibits SARS-CoV-2 adsorption as shown by the gene expression of ACE2 and TMPRSS-2, and furtherly confirmed by microbiological and molecular modeling evaluation. Although more investigations are still needed, all data obtained constitute a solid background, demonstrating the cytoprotective role of MGF in inflammatory mechanisms including COVID-19 infection.

AI snapshot

Written from the paper’s full text.

TL;DR

Mangiferin (MGF) reduced LPS-induced inflammatory markers, increased GSH, improved wound healing, and restored mitochondrial dysfunction in human lung NCI-H292 cells. It also inhibited SARS-CoV-2 pseudovirus adsorption in A549 cells and was predicted by docking/dynamics to bind at the spike–ACE2 interface.

Key findings

  • In LPS-stimulated NCI-H292 cells, MGF (20 μg/mL) significantly reduced expression of IL-6, COX-2, HO-1, TNF-α, and MCP-1, while increasing anti-inflammatory IL-10; MGF alone also increased GSH levels.
  • MGF improved wound closure from about 20% (CTRL) to about 90% at 6 h and from about 75% (CTRL) to about 100% at 24 h; LPS + MGF reached about 90% at 24 h.
  • LPS increased ACE2 and TMPRSS2 expression, whereas MGF significantly reduced them: ACE2 levels were halved and TMPRSS2 decreased to control level.
  • In the pseudovirus adsorption assay, fluorescence decrease versus K virus was 0% for LPS 10 µg/mL, 51% for MGF 20 µg/mL, and 77% for LPS + MGF; docking gave MGF dG −8948 and Vscore −10,115, with stable H-bonds to Asp406 and Asn492.

Methods

  • Human lung NCI-H292 cells were treated with LPS (10 μg/mL, 1 h) with or without MGF (20 μg/mL, 24 h) across four groups: CTRL, LPS, MGF, and MGF + LPS. Assays included MTT viability, RT-qPCR for inflammatory and viral-entry genes, GSH quantification, scratch wound healing, and JC-1 mitochondrial membrane potential staining.
  • Viral adsorption was tested in A549 cells transduced with ACE2 BacMam and exposed to Green Pseudo SARS-CoV-2, with fluorescence readout and microscopy. Molecular docking and dynamics used SARS-CoV-2 spike S1–ACE2 crystal structure PDB 6M0J, Flare 6.0, and NAMD simulations.
  • Statistical analysis used one-way ANOVA with Tukey multiple-comparison test; significance set at p < 0.05.

Limitations

  • The paper states that “more investigations are still needed” to obtain more biological details and further confirm the evidence, and that dose-dependent use might explain MGF binding to an accessory site and S1 disruption.
  • Evident from the text: all experiments are in vitro, using NCI-H292 and A549 cell lines and a pseudovirus rather than live SARS-CoV-2; no in vivo or clinical data are reported.
  • Evident from the text: several results are described qualitatively or as percentages without full statistical reporting, and the molecular modeling findings are computational predictions requiring experimental validation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/pharmaceutics14122845

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

10 of 22 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In vitro studies in macrophage cell lines showed that MGF treatment decreased proinflammatory factors and ROS promoted by LPS stress.

    “in vitro studies, suggesting that MGF treatment produced in decrease in proinflammatory factors and ROS promoted by LPS stress in different macrophage cell lines [42,43].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [42] Lei, 2021, Mangiferin inhibited neuroinflammation through regulating microglial polarization and suppressing NF-kappaB, NLRP3 pathway, Chin. J. Nat. Med. source
    • cites [43] Bulugonda, 2017, Mangiferin from Pueraria tuberosa reduces inflammation via inactivation of NLRP3 inflammasome, Sci. Rep. source

      The Results report that PT-mangiferin reduced LPS-induced ROS and inflammatory mediators in RAW 264.7 macrophages. The Cell culture and ROS methods identify only that macrophage cell line for these experiments, so this source does not establish the claim's reference to different macrophage cell lines. Page numbers were not provided in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Mitochondrial membrane potential increases following the pro-inflammatory effect of LPS.

    “the mitochondrial membrane potential (MMP) results increased following the pro-inflammatory effect of LPS [53].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Mills, 2016, Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages, Cell source
  • Findingown data

    Molecular docking showed MGF has excellent dG (−8948) and VSscore (−10,115).

    “MGF shows excellent dG (−8948) and VSscore (−10,115)”
    Quote in the paperSubstantial claim
  • Findingreasoning

    For the first MGF molecule at the first binding site, bonding between amino acids at the interface and the molecule was maintained for the duration of the dynamics.

    “for the first molecule of MGF at the first binding site, it was observed that the bonding between the amino acids at the interface and the molecule was maintained for the duration of the dynamics.”
    Quote in the paperSubstantial claim
  • Findingown data

    MGF establishes hydrogen and Ar-Ar bonds with His34 of the ACE2 protein.

    “The molecule also establishes hydrogen and Ar–Ar bonds with His34 of the ACE2 protein.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 12
  • May combine two claims. 11

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

    Premisecitation

    MGF offers a wide plethora of promising beneficial properties such as antioxidant, antiviral, anti-inflammatory, immunomodulatory, and cytoprotective effects.

    “It has been widely reported that MGF offers a wide plethora of promising beneficial properties such as antioxidant, antiviral, anti-inflammatory, immunomodulatory, and cytoprotective effects [20,21].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Imran, 2017, Mangiferin: A natural miracle bioactive compound against lifestyle related disorders, Lipids Health Dis. source
    • cites [21] Dar, 2005, Analgesic and antioxidant activity of mangiferin and its derivatives: The structure activity relationship, Biol. Pharm. Bull. source

      The Abstract reports antioxidant activity and protection against carbon-tetrachloride-induced liver injury. Results and Discussion reports an immune-related macrophage effect but found no acute anti-inflammatory activity in the rat-paw-edema test. It also reports that mangiferin was inactive as an anti-HIV agent; the anti-HIV result concerned a mangiferin derivative, so this paper does not support the antiviral claim for mangiferin itself. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Pathogenic microorganisms such as viruses are usually detected by specific cell protein complexes through recognition of pathogen-associated molecular patterns (PAMPs), including LPS.

    “pathogenic microorganisms such as viruses are usually detected by specific cell protein complexes through the recognition of pathogen-associated molecular patterns (PAMPs), including LPS [51].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [51] Andrieux, P., Chevillard, C., Cunha-Neto, E., and Nunes, J.P.S. (2021). Mitochondria as a Cellular Hub in Infection and Inflammation. Int. J. Mol. Sci., 22. source

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

    Premisecitation

    BacMam is a modified baculovirus produced using Sf9 insect cells and pseudotyped to infect mammalian cells.

    “BacMam is a modified baculovirus produced using Sf9 insect cells and it is pseudotyped to infect mammalian cells [54,55,56].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [54] Azali, 2022, Application of Baculovirus Expression Vector system (BEV) for COVID-19 diagnostics and therapeutics: A review, J. Genet. Eng. Biotechnol. source

      The Diagnostic applications section says Sf9 cells are used to make recombinant baculovirus and describes a SARS-CoV-2-spike-pseudotyped baculovirus. It does not identify that virus as BacMam or say that BacMam is pseudotyped to infect mammalian cells (page not available in our copy). (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [55] Chalfie, 1994, Green fluorescent protein as a marker for gene expression, Science source
    • cites [56] Kost, 2007, Implementation of BacMam virus gene delivery technology in a drug discovery setting, Drug Discov. Today source

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Premisecitation

    The use of natural compounds has been recommended in the recent health emergency of the COVID-19 pandemic.

    “the use of natural compounds has been recommended in the recent health emergency of the COVID-19 pandemic [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Parisi, G.F., Carota, G., Castruccio Castracani, C., Spampinato, M., Manti, S., Papale, M., Di Rosa, M., Barbagallo, I., and Leonardi, S. (2021). Nutraceuticals in the Prevention of Viral Infections, including COVID-19, among the Pediatric Population: A Review of the Literature. Int. J. Mol. Sci., 22. source

      The Conclusions (page unavailable) discuss possible use of nutraceuticals during the COVID-19 pandemic and say their use “could still be suggested,” especially in children. The claim overstates this tentative position as an established recommendation; the paper also says specific clinical evidence is lacking. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Relative gene expression levels were normalized with the housekeeping gene GAPDH using the comparative 2−ΔΔCt evaluation method.

    “The relative gene expression levels of each PCR product were obtained according to the threshold cycle (Ct) value and furtherly normalized with the housekeeping gene GAPDH (glyceraldeyde-3-phosphate dehydrogenase) using the comparative 2−ΔΔCt evaluation method [24].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Raffaele, 2018, N-Acetylcysteine (NAC) Ameliorates Lipid-Related Metabolic Dysfunction in Bone Marrow Stromal Cells-Derived Adipocytes, Evid. Based Complement. Altern. Med. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitochondria are involved both in recognition of pathogens and in many mechanisms of inflammatory response, inducing recruitment of proinflammatory cytokines.

    “mitochondria are involved both in the recognition of pathogens and in many mechanisms of inflammatory response, inducing the subsequent recruitment of several proinflammatory cytokines [52].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Dinarello, 2011, Interleukin-1 in the pathogenesis and treatment of inflammatory diseases, Blood source

      The Introduction (page unavailable) says mitochondrial reactive oxygen species may contribute to caspase-1 activation, a pathway involved in IL-1β secretion. It does not say mitochondria recognize pathogens or induce the recruitment of several proinflammatory cytokines; its account of pathogen-product recognition concerns TLRs instead. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The SARS-CoV-2 receptor-binding domain amino acid sequence extends from residue Thr333 to residue Gly526.

    “This amino acid sequence extends from residue Thr333 to residue Gly526 [28].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Lan, 2020, Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Nature source

      In the paper’s main text, the final structural model contains SARS-CoV-2 RBD residues Thr333–Gly526. But the authors say they expressed an RBD spanning Arg319–Phe541, so Thr333–Gly526 describes the residues included in the model, not the full amino acid sequence of the RBD. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The second MGF molecule is inserted into the accessory pocket, showing the same behavior as the first with formed bonds maintained for the duration of the dynamic.

    “The second molecule of MGF is inserted into this accessory pocket, showing the same behavior of the first one with the formed bonds maintained for the duration of the dynamic.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    LPS treatment enhanced wound healing rate in NCI-H292 cells, about 70% at 6 h and about 85% at 24 h, not reaching MGF rate.

    “According to the literature, the LPS treatment enhanced the wound healing rate as well, despite not reaching the MGF rate (about 70% at 6 h and about 85% at 24 h).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Combination with MGF significantly reduced LPS-induced ACE2 and TMPRSS2 expression in NCI-H292 cells; ACE2 levels were halved and TMPRSS2 expression decreased to control level.

    “whereas the combination with MGF significantly reduced their expression: in particular, the ACE2 levels were halved, while TMPRSS2 expression was decreased to the control level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In NCI-H292 cells, MGF at concentrations from 1 to 20 μg/mL did not show toxicity compared to control, while 30 μg/mL caused a slight and not significant decrease in cell viability.

    “With the only exception of the highest concentration, which resulted in a slight and not significant decrease of cell viability, the other concentrations did not show any toxicity compared to the control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MGF administration after LPS pre-treatment ameliorated repairing rate compared to LPS alone in NCI-H292 cells, reaching about 90% at 24 h, with no differences at 6 h.

    “Finally, the MGF administration after the pre-treatment with LPS ameliorated the repairing rate compared to LPS alone, reaching about 90% at 24 h, despite not providing differences at 6 h.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    MGF significantly prevents SARS-CoV-2 pseudovirus entrance into host cells both in the absence and presence of LPS.

    “The data obtained show a significant ability of MGF to prevent the virus entrance both in the absence or presence of LPS, as shown in Figure 7 (panels D and E, respectively)”
    • Also stated in: § 5. Conclusions · boosted
      “The significant inhibitory efficacy of MGF against SARS-CoV-2 adsorption in host cells was also confirmed by the results shown in vitro in A549 cells”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The pseudotyped BacMam SARS-CoV-2 enters host cells via ACE2 and does not replicate or integrate into the host cell genome, making it a valid surrogate for SARS-CoV-2 adsorption.

  • Classified as probably not a substantial claim.

    Premisecitation

    The SARS-CoV-2 spike protein facilitates binding of viral envelopes to ACE2 receptors expressed on host cell surfaces.

    “the S protein facilitates the binding of viral envelopes to angiotensin-converting enzyme 2 (ACE2) receptors expressed on host cells surfaces [15].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Mohamadian, 2021, COVID-19: Virology, biology and novel laboratory diagnosis, J. Gene Med. source

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

    Premisecitation

    LPS triggers massive inflammatory responses caused mainly by mitochondrial abnormalities.

    “it is already well established that LPS, the bacterial endotoxin par excellence, triggers massive inflammatory responses caused mainly by mitochondrial abnormalities [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Kielian, 1995, CD14 and other recognition molecules for lipopolysaccharide: A review, Immunopharmacology source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The viral adsorption assay included two internal controls: K cells as negative control and K virus as positive control.

    “The assay included two internal controls: K cells (cells not exposed to either pseudovirus or substances) and K virus (cells infected with pseudovirus, but not exposed to the substances) as negative and positive internal controls, respectively.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Every GSH measurement was performed in triplicate.

    “Every measurement was performed in triplicate using a spectrophotometer (Synergy 2 from BioTek) [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Spampinato, 2020, Non-competitive heme oxygenase-1 activity inhibitor reduces non-small cell lung cancer glutathione content and regulates cell proliferation, Mol. Biol. Rep. source

  • May combine two claims.

    Interpretationown data

    MGF exerts cytoprotective, antioxidant, and anti-inflammatory activities in an LPS-induced lung inflammation model.

    “MGF was shown to exert cytoprotective, antioxidant, and anti-inflammatory activities, as evidenced by the decreased gene expression of inflammatory markers, such as IL-6, COX-2, and TNF-α, and increased intracellular reduced GSH.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    SARS-CoV-2 promotes lung distress syndrome due to a serious chronic inflammatory pattern.

    “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which promotes lung distress syndrome due to a serious chronic inflammatory pattern [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Marin, 2021, COVID-19 and diabetes: A bidirectional relationship, Clin. Investig. Arterioscler.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In vivo studies in rats showed that MGF enhanced antioxidant enzyme levels and inhibited NF-κB p65 activation, reducing inflammation and cell proliferation.

    “in vivo studies demonstrated that MGF, administrated in rats, enhanced both antioxidant enzyme levels and inhibited NF-κB p65 activation, showing a significant reduction of inflammation and cell proliferation [40,41].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Wang, 2021, Mangiferin Inhibits Inflammation and Cell Proliferation, and Activates Proapoptotic Events via NF-kappaB Inhibition in DMBA-Induced Mammary Carcinogenesis in Rats, J. Environ. Pathol. Toxicol. Oncol. source
    • cites [41] Dong, 2020, Mangiferin protects against alcoholic liver injury via suppression of inflammation-induced adipose hyperlipolysis, Food Funct. source
20 of 20

  • The paper relies on this without support.

    LPS-induced inflammation in NCI-H292 cells adequately models the inflammatory mechanisms relevant to COVID-19.

    “In order to reproduce the phlogosis in vitro, the cells were incubated in the presence or absence of LPS (E. coli; Sigma L431-1MG) at the concentration of 10 μg/mL for 1 h.”

  • The paper relies on this without support.

    Molecular docking and molecular dynamics predictions of MGF binding to the SARS-CoV-2 spike/ACE2 interface reflect actual inhibition of viral adsorption.

    “the results were further confirmed by molecular docking analysis”

  • The paper relies on this without support.

    The Green Pseudo SARS-CoV-2 reporter assay in A549 cells measures SARS-CoV-2 viral adsorption.

    “Green Pseudo SARS-CoV-2 Reporter and Red Fluorescent ACE2 BacMam (Montana Molecular, Bozeman, MT, USA) were used to evaluate the viral adsorption inhibitory capacity of the substances under study.”

  • The paper relies on this without support.

    The pseudotyped BacMam SARS-CoV-2 enters host cells via ACE2 and does not replicate or integrate into the host cell genome, making it a valid surrogate for SARS-CoV-2 adsorption.

    “The pseudo SARS-CoV-2 enters host cells through interactions with ACE2, but once inside the cell, it does not replicate or integrate into the host cell genome.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • LPS wound-healing effect reverses between Results and Discussion

    Major

    The Results state that LPS increased wound closure relative to the control at both reported times. The Discussion instead says LPS reduced wound closure relative to the control.

  • Protective JC-1 effect is assigned the opposite red/green direction

    Major

    The methods associate red fluorescence with healthy cells and green fluorescence with damaged cells. The Results nevertheless describe a reduction in the red/green ratio after MGF co-treatment as evidence of protection against LPS-induced mitochondrial stress.

2 of 2

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Authors
Spampinato, M., Carota, G., Sferrazzo, G., Fuochi, V., Distefano, A., Ronsisvalle, S., Sipala, F., Giuffrida, R., Furneri, P. M., Di Rosa, M., Tibullo, D., Li Volti, G., & Barbagallo, I.
Affiliations
  • University of Catania (IT)
  • Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 87, 95125 Catania, Italy
Corresponding author
Barbagallo, Ignazio
ORCID
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2022-12-19
Volume
14
Issue
12
Pages
2845
ISSN
1999-4923 (ISSN-L)
DOI
10.3390/pharmaceutics14122845
PMC
PMC9788116
OpenAlex
W4312211391
Semantic Scholar
eaf817fcfb79e1e9da84c5c3f516e7897a12f9b0
Cited by
14
References
65
Citations by year
2026: 3 · 2025: 4 · 2024: 5 · 2023: 2
FWCI
2.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmaceutics (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
University of Catania (57722172123)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Mangiferin and Mango Extracts
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Medicinal Plant Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioactive natural compounds
Keywords
mangiferin, SARS-CoV-2, COVID-19 pandemic, lipopolysaccharide-induced inflammation, lung epithelial cells, NCI-H292 cells, antioxidant activity, mitochondrial dysfunction, reactive oxygen species, ACE2, TMPRSS2, viral attachment, anti-inflammatory activity, wound healing, natural bioactive compounds

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