Skip to main content

Advertisement

SpringerLink
Log in

Procyanidin alleviates ferroptosis and inflammation of LPS-induced RAW264.7 cell via the Nrf2/HO-1 pathway

  • Research
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Inflammation is a common occurrence in many medical conditions and is a natural defense mechanism of the human body. Ferroptosis, an iron-dependent form of cell death related to lipid peroxide build-up, has been found to be involved in inflammation. The anti-inflammatory effects of procyanidin, however, are not yet fully understood. Through network pharmacology and bioinformatics analysis, it was suggested that procyanidin could modulate ferroptosis and cause anti-inflammatory effects on RAW264.7 cells. This was further evidenced through molecular docking, molecular dynamics, and in vitro experiments. The results indicated that procyanidin could diminish inflammation in LPS-induced RAW264.7 cells by regulating ferroptosis via the Nrf2/HO-1/Keap-1 pathway. In conclusion, procyanidin supplementation might be an effective way to reduce inflammation by decreasing the release of inflammatory cytokines and suppressing ferroptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

Not applicable.

References

  • Alhouayek M, Muccioli GG (2014) COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci 35:284–292

    Article  CAS  PubMed  Google Scholar 

  • Arbiser JL, Bonner MY, Ward N, Elsey J, Rao S (2018) Selenium unmasks protective iron armor: a possible defense against cutaneous inflammation and cancer. Biochim Biophys Acta Gen Subj 1862:2518–2527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bagchi D, Garg A, Krohn RL, Bagchi M, Tran MX, Stohs SJ (1997) Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 95:179–189

    CAS  PubMed  Google Scholar 

  • Buendia I, Michalska P, Navarro E, Gameiro I, Egea J, León R (2016) Nrf2-ARE pathway: an emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol Ther 157:84–104

    Article  CAS  PubMed  Google Scholar 

  • Byun MW (2012) Effect of procyanidin C1 on nitric oxide production and hyperpolarization through Ca(2+)-dependent pathway in endothelial cells. J Med Food 15:1032–1037

    Article  CAS  PubMed  Google Scholar 

  • Byun EB, Sung NY, Byun EH, Song DS, Kim JK, Park JH, Song BS, Park SH, Lee JW, Byun MW, Kim JH (2013) The procyanidin trimer C1 inhibits LPS-induced MAPK and NF-κB signaling through TLR4 in macrophages. Int Immunopharmacol 15:450–456

    Article  CAS  PubMed  Google Scholar 

  • Cagiola M, Giulio S, Miriam M, Katia F, Paola P, Macrì A, Pasquali P (2006) In vitro down regulation of proinflammatory cytokines induced by LPS tolerance in pig CD14+ cells. Vet Immunol Immunopathol 112:316–320

    Article  CAS  PubMed  Google Scholar 

  • Čepelak I, Dodig S, Dodig D (2020) Ferroptosis: regulated cell death. Arh Hig Rada Toksikol 71:99–109

    PubMed  PubMed Central  Google Scholar 

  • Chacón MR, Ceperuelo-Mallafré V, Maymó-Masip E, Mateo-Sanz JM, Arola L, Guitiérrez C, Fernandez-Real JM, Ardèvol A, Simón I, Vendrell J (2009) Grape-seed procyanidins modulate inflammation on human differentiated adipocytes in vitro. Cytokine 47:137–142

    Article  PubMed  Google Scholar 

  • Chen S, Zou L, Li L, Wu T (2013) The protective effect of glycyrrhetinic acid on carbon tetrachloride-induced chronic liver fibrosis in mice via upregulation of Nrf2. PLoS ONE 8:e53662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Taeye C, Cibaka MK, Collin S (2017) Occurrence and antioxidant activity of C1 degradation products in cocoa. Foods (Basel, Switzerland) 6:18

  • Deng L, He S, Guo N, Tian W, Zhang W, Luo L (2023) Molecular mechanisms of ferroptosis and relevance to inflammation. Inflamm Res 72:281–299

    Article  CAS  PubMed  Google Scholar 

  • Ding Y, Li H, Li Y, Liu D, Zhang L, Wang T, Liu T, Ma L (2020) Protective effects of grape seed proanthocyanidins on the kidneys of diabetic rats through the Nrf2 signalling pathway. Evid Based Complement Alternat Med 2020:5205903

    Article  PubMed  PubMed Central  Google Scholar 

  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dodson M, Castro-Portuguez R, Zhang DD (2019) NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23:101107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dotan I, Allez M, Danese S, Keir M, Tole S, McBride J (2020) The role of integrins in the pathogenesis of inflammatory bowel disease: approved and investigational anti-integrin therapies. Med Res Rev 40:245–262

    Article  CAS  PubMed  Google Scholar 

  • Gai C, Yu M, Li Z, Wang Y, Ding D, Zheng J, Lv S, Zhang W, Li W (2020) Acetaminophen sensitizing erastin-induced ferroptosis via modulation of Nrf2/heme oxygenase-1 signaling pathway in non-small-cell lung cancer. J Cell Physiol 235:3329–3339

    Article  CAS  PubMed  Google Scholar 

  • Hambright WS, Fonseca RS, Chen L, Na R, Ran Q (2017) Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol 12:8–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han S, Gao H, Chen S, Wang Q, Li X, Du LJ, Li J, Luo YY, Li JX, Zhao LC, Feng J, Yang S (2019) Procyanidin A1 alleviates inflammatory response induced by LPS through NF-κB, MAPK, and Nrf2/HO-1 pathways in RAW264.7 cells. Sci Rep 9:15087

    Article  PubMed  PubMed Central  Google Scholar 

  • He L, Li P, Yu LH, Li L, Zhang Y, Guo Y, Long M, He JB, Yang SH (2018) Protective effects of proanthocyanidins against cadmium-induced testicular injury through the modification of Nrf2-Keap1 signal path in rats. Environ Toxicol Pharmacol 57:1–8

    Article  CAS  PubMed  Google Scholar 

  • Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol 1:45–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keuters MH, Keksa-Goldsteine V, Dhungana H, Huuskonen MT, Pomeshchik Y, Savchenko E, Korhonen PK, Singh Y, Wojciechowski S, Lehtonen Š, Kanninen KM, Malm T, Sirviö J, Muona A, Koistinaho M, Goldsteins G, Koistinaho J (2021) An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo. Sci Rep 11:3518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koppula P, Zhuang L, Gan B (2021) Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell 12:599–620

    Article  CAS  PubMed  Google Scholar 

  • Li J, Lu K, Sun F, Tan S, Zhang X, Sheng W, Hao W, Liu M, Lv W, Han W (2021) Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway. J Transl Med 19:96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long M, Yang SH, Han JX, Li P, Zhang Y, Dong S, Chen X, Guo J, Wang J, He JB (2016) The protective effect of grape-seed proanthocyanidin extract on oxidative damage induced by zearalenone in Kunming mice liver. Int J Mol Sci 17:808

  • Luo L, Huang F, Zhong S, Ding R, Su J, Li X (2022) Astaxanthin attenuates ferroptosis via Keap1-Nrf2/HO-1 signaling pathways in LPS-induced acute lung injury. Life Sci 311:121091

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi-Matsui M, Yano S, Matsumoto N, Futai M (2012) Lipopolysaccharide induces multinuclear cell from RAW264.7 line with increased phagocytosis activity. Biochem Biophys Res Commun 425:144–149

    Article  CAS  PubMed  Google Scholar 

  • Nie Y, Stürzenbaum SR (2019) Proanthocyanidins of natural origin: molecular mechanisms and implications for lipid disorder and aging-associated diseases. Adv Nutr (Bethesda, MD) 10:464–478

    Article  Google Scholar 

  • Nnah IC, Wessling-Resnick M (2018) Brain iron homeostasis: a focus on microglial iron. Pharmaceuticals (Basel, Switzerland) 11:129

  • Osburn WO, Wakabayashi N, Misra V, Nilles T, Biswal S, Trush MA, Kensler TW (2006) Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Arch Biochem Biophys 454:7–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rue EA, Rush MD, van Breemen RB (2018) Procyanidins: a comprehensive review encompassing structure elucidation via mass spectrometry. Phytochem Rev 17:1–16

    Article  CAS  PubMed  Google Scholar 

  • Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851

    Article  CAS  PubMed  Google Scholar 

  • Scally C, Abbas H, Ahearn T, Srinivasan J, Mezincescu A, Rudd A, Spath N, Yucel-Finn A, Yuecel R, Oldroyd K, Dospinescu C, Horgan G, Broadhurst P, Henning A, Newby DE, Semple S, Wilson HM, Dawson DK (2019) Myocardial and systemic inflammation in acute stress-induced (Takotsubo) cardiomyopathy. Circulation 139:1581–1592

    Article  PubMed  PubMed Central  Google Scholar 

  • Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171:273–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stockwell BR, Jiang X, Gu W (2020) Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol 30:478–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Y, Chen P, Zhai B, Zhang M, Xiang Y, Fang J, Xu S, Gao Y, Chen X, Sui X, Li G (2020) The emerging role of ferroptosis in inflammation. Biomed Pharmacother 127:110108

    Article  CAS  PubMed  Google Scholar 

  • Terra X, Valls J, Vitrac X, Mérrillon JM, Arola L, Ardèvol A, Bladé C, Fernandez-Larrea J, Pujadas G, Salvadó J, Blay M (2007) Grape-seed procyanidins act as antiinflammatory agents in endotoxin-stimulated RAW 264.7 macrophages by inhibiting NFkB signaling pathway. J Agric Food Chem 55:4357–4365

    Article  CAS  PubMed  Google Scholar 

  • Tsurusaki S, Tsuchiya Y, Koumura T, Nakasone M, Sakamoto T, Matsuoka M, Imai H, Yuet-Yin Kok C, Okochi H, Nakano H, Miyajima A, Tanaka M (2019) Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis. Cell Death Dis 10:449

    Article  PubMed  PubMed Central  Google Scholar 

  • Unver N, McAllister F (2018) IL-6 family cytokines: key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine Growth Factor Rev 41:10–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng YY, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang CC, Lin HL, Wey SP, Jan TR (2011) Areca-nut extract modulates antigen-specific immunity and augments inflammation in ovalbumin-sensitized mice. Immunopharmacol Immunotoxicol 33:315–322

    Article  CAS  PubMed  Google Scholar 

  • Wang H, An P, Xie E, Wu Q, Fang X, Gao H, Zhang Z, Li Y, Wang X, Zhang J, Li G, Yang L, Liu W, Min J, Wang F (2017) Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66:449–465

    Article  CAS  PubMed  Google Scholar 

  • Wang QQ, Gao H, Yuan R, Han S, Li XX, Tang M, Dong B, Li JX, Zhao LC, Feng J, Yang S (2020) Procyanidin A2, a polyphenolic compound, exerts anti-inflammatory and anti-oxidative activity in lipopolysaccharide-stimulated RAW264.7 cells. PloS one 15:e0237017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie LW, Cai S, Zhao TS, Li M, Tian Y (2020) Green tea derivative (-)-epigallocatechin-3-gallate (EGCG) confers protection against ionizing radiation-induced intestinal epithelial cell death both in vitro and in vivo. Free Radical Biol Med 161:175–186

    Article  CAS  Google Scholar 

  • Yan FJ, Wang X, Wang SE, Hong HT, Lu J, Ye Q, Zheng YL, Wang YJ (2020) C-Jun/C7ORF41/NF-κB axis mediates hepatic inflammation and lipid accumulation in NAFLD. Biochem J 477:691–708

    Article  CAS  PubMed  Google Scholar 

  • Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Mo J, Dai J, Ye C, Cen W, Zheng X, Jiang L, Ye L (2021) Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer. Cell Death Dis 12:1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Yin C, Zhang Z, Tang H, Shen W, Zha X, Gao M, Sun J, Xu X, Chen Q (2020) Proanthocyanidin promotes functional recovery of spinal cord injury via inhibiting ferroptosis. J Chem Neuroanat 107:101807

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Public Service Platform of South China Sea for R&D Marine Biomedicine Resources for support.

Funding

This study was supported by the Science and Technology Special Project of Zhanjiang (2022A01034), the Guangdong Provincial Department of Education Research Project (2022KTSCX), and the Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety (GDPLLAPPS2104).

Author information

Author notes

  1. Jiayan Zeng, Yanmin Weng, and Tianli Lai contributed equally to this work.

Authors and Affiliations

  1. The First Clinical College, Guangdong Medical University, Zhanjiang, 524023, Guangdong, China

    Jiayan Zeng, Yanmin Weng, Tianli Lai, Lan Chen, Ying Li & Qiqi Huang

  2. Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang, 524088, China

    Saiyi Zhong

  3. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA

    Shibiao Wan

  4. The Marine Biomedical Research Institute, Guangdong Medical University, No. 2 Wenming East Road, Xiashan District, Zhanjiang, 524023, Guangdong, China

    Lianxiang Luo

  5. The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong, 524023, China

    Lianxiang Luo

Authors
  1. Jiayan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanmin Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianli Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiqi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saiyi Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shibiao Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lianxiang Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LL conceived and designed the study. TL, YL, and JZ analyzed and interpreted the data. JZ, YW, and LC carried out the experiment. LL and JZ wrote the manuscript. LL, SZ, and SW reviewed the paper and provided comments, and all the authors reviewed the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Shibiao Wan or Lianxiang Luo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeng, J., Weng, Y., Lai, T. et al. Procyanidin alleviates ferroptosis and inflammation of LPS-induced RAW264.7 cell via the Nrf2/HO-1 pathway. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4055–4067 (2024). https://doi.org/10.1007/s00210-023-02854-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-023-02854-2

Keywords

Search

Navigation