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Carica papaya leaf water extract promotes innate immune response via MAPK signaling pathways

  • Hyun, Su Bin (Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University) ;
  • Ko, Min Nyeong (Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University) ;
  • Hyun, Chang-Gu (Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University)
  • Received : 2021.07.08
  • Accepted : 2021.08.03
  • Published : 2021.09.30

Abstract

The emergence and rapid spread of the potentially fatal coronavirus disease 2019, caused due to infection by severe acute respiratory syndrome coronavirus-2, has led to worldwide interest in developing functional bioactive ingredients that act as immunomodulatory agents. In this study, we aimed to characterize Carica papaya extract and explore its potential as an immunomodulator by performing in vitro cell screening. Papaya leaf water extract (PLW) was found to significantly increase the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) by upregulating inducible nitric oxide synthase and cyclo-oxygenase-2 activity, respectively. Additionally, PLW increased the production of tumor necrosis factor-α and interleukin 1β in RAW 264.7 cells. Furthermore, PLW activated the expression of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) but not that of p38 mitogen-activated protein kinase. These results indicate that PLW increased the production of NO, PGE2, and pro-inflammatory cytokines by activating the JNK and ERK pathways in macrophages, thus demonstrating immunomodulatory properties. Finally, high-performance liquid chromatography fingerprint analysis indicated the presence of rutin, narirutin, and ρ-coumaric acid in PLW (6.30, 119.76, and 47.25 ppm, respectively). Treating cells with these compounds at non-toxic concentrations had no effect on NO production. Taken together, these results suggest that PLW may have potential as an immunity-enhancing supplement.

Keywords

Acknowledgement

This research was supported by the Ministry of Trade, Industry & Energy (MOTIE), Korea Institute for Advancement of Technology (KIAT) through Demand-Customized R&D Project for National Innovation Convergence Complex (P0015357).

References

  1. Gutierrez-Alvarez J, Honrubia JM, Fernandez-Delgado R, Wang L, Castano-Rodriguez C, Zuniga S, Sola I, Enjuanes L (2021) Genetically Engineered Live-Attenuated Middle East Respiratory Syndrome Coronavirus Viruses Confer Full Protection against Lethal Infection. mBio 12: e00103-121. doi: 10.1128/mBio.00103-21
  2. Chukwudozie OS, Gray CM, Fagbayi TA, Chukwuanukwu RC, Oyebanji VO, Bankole, TT, Adewole RA, Daniel EM (2021) Immuno-informatics Design of a Multimeric Epitope Peptide Based Vaccine Targeting SARS-CoV-2 Spike Glycoprotein. PLoS One 16: e0248061. doi: 10.1371/journal.pone.0248061
  3. Li Y, Renner DM, Comar CE, Whelan JN, Reyes HM, Cardenas-Diaz FL, Truitt R, Tan LH, Dong B, Alysandratos KD, Huang J, Palmer JN, Adappa ND, Kohanski MA, Kotton DN, Silverman RH, Yang W, Morrisey EE, Cohen NA, Weiss SR (2021) SARS-CoV-2 Induces Double-Stranded RNA-Mediated Innate Immune Responses in Respiratory Epithelial-Derived Cells and Cardiomyocytes. Proc Natl Acad Sci USA 118: e2022643118. doi: 10.1073/pnas.2022643118
  4. Jordan SC (2021) Innate and Adaptive Immune Responses to SARS-CoV-2 in Humans: Relevance to Acquired Immunity and Vaccine Responses. Clin Exp Immunol 204: 310-320. doi: 10.1111/cei.13582
  5. Wang X, Lin X, Zheng Z, Lu B, Wang J, Tan AH, Zhao M, Loh JT, Ng SW, Chen Q, Xiao F, Huang E, Ko KH, Huang Z, Li J, Kok KH, Lu G, Liu X, Lam KP, Liu W, Zhang Y, Yuen KY, Mak TW, Lu L (2021) Host-Derived Lipids Orchestrate Pulmonary γδ T Cell Response to Provide Early Protection Against Influenza Virus Infection. Nat Commun 12: 1914. doi: 10.1038/s41467-021-22242-9
  6. Dalboni LC, Alvares Saraiva AM, Konno FTC, Perez EC, Codeceira JF, Spadacci-Morena DD, Lallo MA (2021) Encephalitozoon cuniculi Takes Advantage of Efferocytosis to Evade the Immune Response. PLoS One 16: e0247658. doi: 10.1371/journal.pone.0247658
  7. Muniandy K, Gothai S, Badran KMH, Suresh Kumar S, Esa NM, Arulselvan P (2018) Suppression of Proinflammatory Cytokines and Mediators in LPS-Induced RAW 264.7 Macrophages by Stem Extract of Alternanthera sessilis via the Inhibition of the NF-κB Pathway. J Immunol Res 2018: 3430684. doi: 10.1155/2018/3430684
  8. Lim JH, Kim HY, Lee JS, Kim HM, Jeong HJ (2021) Dp44mT Regulates the Levels of Inflammatory Mediators through Blocking NF-κB Nuclear Translocation in LPS-stimulated RAW 264.7 Macrophages. In Vitro Cell Dev Biol Anim 57: 332-341. doi: 10.1007/s11626-021-00552-y
  9. Apostolova E, Lukova P, Baldzhieva A, Katsarov P, Nikolova M, Iliev I, Peychev L, Trica B, Oancea F, Delattre C, Kokova V (2020) Immunomodulatory and Anti-Inflammatory Effects of Fucoidan: A Review. Polymers (Basel) 12: 2338. doi: 10.3390/polym12102338
  10. Arango Duque G, Descoteaux A (2014) Macrophage Cytokines: Involvement in Immunity and Infectious Diseases. Front Immunol 5: 491. doi: 10.3389/fimmu.2014.00491
  11. Bocchetti M, Scrima M, Melisi F, Luce A, Sperlongano R, Caraglia M, Zappavigna S, Cossu AM (2021) LncRNAs and Immunity: Coding the Immune System with Noncoding Oligonucleotides. Int J Mol Sci 22: 1741. doi: 10.3390/ijms22041741
  12. Jacobson A, Yang D, Vella M, Chiu IM (2021) The Intestinal Neuroimmune Axis: Crosstalk Between Neurons, Immune Cells, and Microbes. Mucosal Immunol 14: 555-565. doi: 10.1038/s41385-020-00368-1
  13. Monmai C, Rod-In W, Jang AY, Lee SM, Jung SK, You S, Park WJ (2020) Immune-Enhancing Effects of Anionic Macromolecules Extracted from Codium fragile Coupled with Arachidonic Acid in RAW264.7 cells. PLoS One 15: e0239422. doi: 10.1371/journal.pone.0239422
  14. Li C, Dong Z, Zhang B, Huang Q, Liu G, Fu X (2020) Structural Characterization and Immune Enhancement Activity of a Novel Polysaccharide from Moringa oleifera leaves. Carbohydr Polym 234: 115897. doi: 10.1016/j.carbpol.2020.115897
  15. Lu H, Zhang L, Zhao H, Li J, You H, Jiang L, Hu J (2018) Activation of Macrophages in vitro by Phospholipids from Brain of Katsuwonus pelamis (Skipjack Tuna). J Oleo Sci 67: 327-333. doi: 10.5650/jos.ess17181
  16. Guo C, Bi J, Li X, Lyu J, Liu X, Wu X, Liu J (2021) Immunomodulation Effects of Polyphenols from Thinned Peach Treated by Different Drying Methods on RAW264.7 Cells Through the NF-κB and Nrf2 Pathways. Food Chem 340: 127931. doi: 10.1016/j.foodchem.2020.127931
  17. Sharma A, Bachheti A, Sharma P, Bachheti RK, Husen A (2020) Phytochemistry, Pharmacological Activities, Nanoparticle Fabrication, Commercial Products and Waste Utilization of Carica papaya L.: A comprehensive review. Curr Res Biotech 2: 145-160. doi: 10.1016/j.crbiot.2020.11.001
  18. Nugroho A, Heryani H, Choi JS, Park HJ (2017) Identification and Quantification of Flavonoids in Carica papaya Leaf and Peroxynitrite Scavenging Activity. Asian Pac J Trop Biomed 7: 208-213. doi: 10.1016/j.apjtb.2016.12.009
  19. Inam A, Shahzad M, Shabbir A, Shahid H, Shahid K, Javeed A (2017) Carica papaya Ameliorates Allergic Asthma via Down regulation of IL4, IL-5, Eotaxin, TNF-α, NF-ĸB, and iNOS Levels. Phytomedicine 32: 1-7. doi: 10.1016/j.phymed.2017.04.009
  20. Yap JY, Hii CL, Ong SP, Lim K, Abas F, Pin KY (2020) Effects of Drying on Total Polyphenols Content and Antioxidant Properties of Carica papaya leaves. J Sci Food Agric 100: 2932-2937. doi: 10.1002/jsfa.10320
  21. Teng WC, Chan W, Suwanarusk R, Ong A, Ho HK, Russell B, Renia L, Koh HL (2019) In vitro Antimalarial Evaluations and Cytotoxicity Investigations of Carica papaya Leaves and Carpaine. Nat Prod Commun 14: 33-36. doi: 10.1177/1934578X1901400110
  22. Adedayo BC, Oyeleye SI, Okeke BM, Oboh G (2021) AntiCholinesterase and Antioxidant Properties of Alkaloid and Phenolic-Rich Extracts from Pawpaw (Carica papaya) Leaf: A Comparative Study. Flavour Fragr J 36:47-54. doi: 10.1002/ffj.3615
  23. Kang JK, Hyun CG (2020) 4-Hydroxy-7-Methoxycoumarin Inhibits Inflammation in LPS-activated RAW264.7 Macrophages by Suppressing NF-κB and MAPK Activation. Molecules 25: 4424. doi: 10.3390/molecules25194424
  24. Kim MJ, Kim SS, Park KJ, An HJ, Choi YH, Lee NH, Hyun CG (2016) Methyl Jasmonate Inhibits Lipopolysaccharide-induced Inflammatory Cytokine Production via Mitogen-Activated Protein Kinase and Nuclear Factor-κB Pathways in RAW 264.7 Cells. Pharmazie 71: 540-543. doi: 10.1691/ph.2016.6647
  25. Yoon WJ, Ham YM, Yoo BS, Moon JY, Koh J, Hyun CG (2009) Oenothera laciniata Inhibits Lipopolysaccharide Induced Production of Nitric Oxide, Prostaglandin E2, and Proinflammatory Cytokines in RAW264.7 Macrophages. J Biosci Bioeng 107: 429-438. doi: 10.1016/j.jbiosc.2008.11.018
  26. Das D, Biswal S, Barhwal KK, Bhardwaj P, Kumar A, Hota SK, Chaurasia OP, Kumar B (2019) Methanolic Root Extract of Codonopsis clematidea Prevents Hypoxia Induced Procoagulant State by Inhibition of GPIb Receptor Regulated Lyn Kinase Activation. Phytomedicine 59: 152903. doi: 10.1016/j.phymed.2019.152903
  27. Chen X, Hu X, Liu L, Liang X, Xiao J (2019) Extracts Derived from a Traditional Chinese Herbal Formula Triggers Necroptosis in Ectocervical Ect1/E6E7 Cells through Activation of RIP1 Kinase. J Ethnopharmacol 15: 111922. doi: 10.1016/j.jep.2019.111922
  28. Chen Y, Lin L (2011) Study and Comparison on HPLC Fingerprints of Flavonoids of Frequently Used Chinese Materia Medica in Citrus. Zhongguo Zhong Yao Za Zhi 36: 2660-2665
  29. Lee K, Padzil A, Ahmad S, Abdullah N, Zuhainis S, Maziah M, Sulaiman M, Israf D, Shaari K, Lajis N (2011) Evaluation of Anti-inflammatory, Anti-oxidant and Anti-nociceptive Activities of Six Malaysian Medicinal Plants. J Med Plants Res 5: 5555-5563. doi: 10.5897/JMPR.9000612