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Anti-inflammatory effects of Athyrium yokoscense extract via inhibition of the Erk1/2 and NF-κB pathways in bisphenol A-stimulated A549 cells

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Abstract

Bisphenol A is an environmental endocrine disruptor that has similar functions to estrogen in humans. However, few studies have investigated pulmonary inflammation induced by BPA, and the effect of Athyrium yokoscense extract on this inflammatory response is unknown. In this study, we investigated this effect in A549 human alveolar epithelial cells. BPA at concentrations higher than 100 µM were cytotoxic to A549 cells at 24 and 48 h after treatment; however, AYE (100 µg/mL) had a protective effect against BPA-induced cytotoxicity. AYE also inhibited the generation of intracellular reactive oxygen species, expressions of cyclooxygenase-2 and extracellular signal-regulated kinase1/2 proteins, activities of phospholipase A2, COX-2, nuclear factor kappa-light-chain-enhancer of activated B cells, and proinflammatory mediators including prostaglandin E2, tumor necrosis factor-α, and interleukin-6 induced by BPA in A549 cells. This study demonstrated that BPA, which induces chronic lung disease, causes oxidative stress and inflammatory response in lung epithelial cell line, and found that AYE reduces BPA-induced oxidative stress and inflammatory response by down-regulating the Erk1/2 and NF-κB pathways.

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References

  1. Preethi S, Sandhya K, Lebonah DE, Prasad CV, Sreedevi B, Chandrasekhar K, Kumari JP (2014) Toxicity of Bisphenol A on humans: A review. Int Lett Nat Sci 27:32–46. https://doi.org/https://doi.org/10.18052/www.scipress.com/ILNS.27.32

    Google Scholar 

  2. Donohue KM, Miller RL, Perzanowski MS, Just AC, Hoepner LA, Arunajadai S, Canfield S, Resnick D, Calafat AM, Perera FP, Whyatt RM (2013) Prenatal and postnatal Bisphenol A exposure and asthma development among inner-city children. J Allergy Clin Immunol 131:736–742. https://doi.org/10.1016/j.jaci.2012.12.1573

    Article  CAS  Google Scholar 

  3. Bhatia M, Moochhala S (2004) Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 202:145–156. https://doi.org/10.1002/path.1491

    Article  CAS  Google Scholar 

  4. Tagami T, Ando Y, Ozeki T (2017) Fabrication of liposomal doxorubicin exhibiting ultrasensitivity against phospholipase A2 for efficient pulmonary drug delivery to lung cancers. Int J Pharm 517:35–41. https://doi.org/10.1016/j.ijpharm.2016.11.039

    Article  CAS  Google Scholar 

  5. Kim HG, Yoon DH, Kim CH, Shrestha B, Chang WC, Lim SY, Lee WH, Han SG, Lee JO, Lim MH, Kim GY, Choi S, Song WO, Sung JM, Hwang KC, Kim TW (2007) Ethanol extract of Inonotus obliquus inhibits lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells. J Med Food 10:80–89. https://doi.org/10.1089/jmf.2006.156

    Article  CAS  Google Scholar 

  6. Kwon DY, Koh SB, Lee JH, Park HK, Kim HJ, Shin HW, Youn J, Park KW, Choi SA, Kim SJ, Choi SM, Park JY, Jeon BS, Kim JY, Chung SJ, Lee CS, Park JH, Ahn TB, Kim WC, Kim HS, Cheon SM, Kim HT, Lee JY, Kim JS, Kim EJ, Kim JM, Lee KS, Kim JS, Kim MJ, Baik JS, Park KJ, Kim HJ, Park MY, Kang JH, Song SK, Kim YD, Yun JY, Lee HW, Oh HG, Cho J, Song IU, Sohn YH, Lee PH, Kim JW (2017) Erratum to: the KMDS-NATION study: Korean Movement Disorders Society multicenter assessment of non-motor symptoms and quality of life in parkinson’s disease NATION study group. J Clin Neurol 13:315. https://doi.org/10.3988/jcn.2017.13.3.315

    Article  Google Scholar 

  7. Hwang D, Byrne J, Scollard D, Levine E (1998) Expression of cyclooxygenase-1 and cyclooxygenase-2 in human breast cancer. J Natl Cancer Inst 90:455–460. https://doi.org/10.1093/jnci/90.6.455

    Article  CAS  Google Scholar 

  8. Christman JW, Lancaster LH, Blackwell TS (1998) Nuclear factor kB: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. Intensive Care Med 24:1131–1138. https://doi.org/10.1007/s001340050735

    Article  CAS  Google Scholar 

  9. Asehnoune K, Strassheim D, Mitra S, Kim JY, Abraham E (2004) Involvement of reactive oxygen species in toll-like receptor 4-dependent activation of NF-κB. J Immunol 172:2522–2529. https://doi.org/10.4049/jimmunol.172.4.2522

    Article  CAS  Google Scholar 

  10. Chao WW, Chung YC, Shih IP, Wang HY, Chou ST, Hsu CK (2015) Red bean extract inhibits lipopolysaccharide-induced inflammation and H(2)O(2)-induced oxidative stress in RAW 264.7 macrophages. J Med Food 18:724–730. https://doi.org/10.1089/jmf.2014.3353

    Article  CAS  Google Scholar 

  11. Van TK, Kang Y, Fukui T, Sakurai K, Iwasaki K, Aikawa Y, Phuong NM (2006) Arsenic and heavy metal accumulation by Athyrium yokoscense from contaminated soils. Soil Sci Plant Nutr 52:701–710. https://doi.org/10.1111/j.1747-0765.2006.00090.x

    Article  CAS  Google Scholar 

  12. Kamachi H, Komori I, Tamura H, Sawa Y, Karahara I, Honma Y, Wada N, Kawabata T, Matsuda K, Ikeno S, Noguchi M, Inoue H (2005) Lead tolerance and accumulation in the gametophytes of the fern Athyrium yokoscense. J Plant Res 118:137–145. https://doi.org/10.1007/s10265-005-0202-x

    Article  CAS  Google Scholar 

  13. Lee S, Oh D-G, Singh D, Lee JS, Lee S, Lee CH (2020) Exploring the metabolomic diversity of plant species across spatial (leaf and stem) components and phylogenic groups. BMC Plant Biol 20:39. https://doi.org/10.1186/s12870-019-2231-y

    Article  CAS  Google Scholar 

  14. Kang CH, Choi YH, Park SY, Kim GY (2012) Anti-inflammatory effects of methanol extract of Codium fragile in lipopolysaccharide-stimulated RAW 264.7 cells. J Med Food 15:44–50. https://doi.org/10.1089/jmf.2010.1540

    Article  CAS  Google Scholar 

  15. Kitanaka N, Nakano R, Sugiura K, Kitanaka T, Namba S, Konno T, Nakayama T, Sugiya H (2019) Interleukin-1β promotes interleulin-6 expression via ERK1/2 signaling pathway in canine dermal fibroblasts. PLoS One 14:e0220262. https://doi.org/10.1371/journal.pone.0220262

    Article  CAS  Google Scholar 

  16. Vellingiri B, Suriyanarayanan A, Selvaraj P, Abraham KS, Pasha MY, Winster H, Gopalakrishnan AV, Reddy GS, Ayyadurai JK, Kumar N, Giridharan N, Rao BPS, Nachimuthu KRSS, Narayanasamy SK, Mahalaxmi A, Venkatesan I D (2022) Role of heavy metals (copper (Cu), arsenic (As), cadmium (Cd), iron (Fe) and lithium (Li)) induced neurotoxicity. Chemosphere 301:134625. https://doi.org/10.1016/j.chemosphere.2022.134625

    Article  CAS  Google Scholar 

  17. Ma Y, Liu H, Wu J, Yuan L, Wang Y, Du X, Wang R, Marwa PW, Petlulu P, Chen X, Zhang H (2019) The adverse health effects of bisphenol A and related toxicity mechanisms. Environ Res 176:108575. https://doi.org/10.1016/j.envres.2019.108575

    Article  CAS  Google Scholar 

  18. Biswas SK (2016) Does the Interdependence between oxidative stress and inflammation explain the antioxidant paradox. Oxid Med Cell Longev. https://doi.org/10.1155/2016/5698931

    Article  Google Scholar 

  19. Martinez Useros J, Li W, Cabeza Morales M, Garcia Foncillas J (2017) Oxidative stress: a new target for pancreatic cancer prognosis and treatment. J Clin Med 6:29. https://doi.org/10.3390/jcm6030029

    Article  CAS  Google Scholar 

  20. Gill R, Tsung A, Billiar T (2010) Linking oxidative stress to inflammation: toll-like receptors. Free Radic Biol Med 48:1121–1132. https://doi.org/10.1016/j.freeradbiomed.2010.01.006

    Article  CAS  Google Scholar 

  21. Gassman NR (2017) Induction of oxidative stress by Bisphenol A and its pleiotropic effects. Environ Mol Mutagen 58:60–71. https://doi.org/10.1002/em.22072

    Article  CAS  Google Scholar 

  22. Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, Dong W (2016) ROS and ROS-mediated cellular signaling. Oxidative Med Cell Longev 2016:18. https://doi.org/10.1155/2016/4350965

    Article  CAS  Google Scholar 

  23. Singh S, Singh DK, Meena A, Dubey V, Masood N, Luqman S (2019) Rutin protects t–butyl hydroperoxide-induced oxidative impairment via modulating the Nrf2 and iNOS activity. Phytomedicine 55:92–104. https://doi.org/10.1016/j.phymed.2018.07.009

    Article  CAS  Google Scholar 

  24. Jung SH, Kim BJ, Lee EH, Osborne NN (2010) Isoquercitrin is the most effective antioxidant in the plant Thuja orientalis and able to counteract oxidative-induced damage to a transformed cell line (RGC-5 cells). Neurochem Int 57:713–721. https://doi.org/10.1016/j.neuint.2010.08.005

    Article  CAS  Google Scholar 

  25. Wang Y, Tang C, Zhang H (2015) Hepatoprotective effects of kaempferol 3-O-rutinoside and kaempferol 3-O-glucoside from Carthamus tinctorius L. on CCl4-induced oxidative liver injury in mice. J Food Drug Anal 23:310–317. https://doi.org/10.1016/j.jfda.2014.10.002

    Article  CAS  Google Scholar 

  26. Xu F, Xu Z, Zhang R, Wu Z, Lim JH, Koga T, Li JD, Shen H (2008) Nontypeable Haemophilus influenzae induces COX-2 and PGE2 expression in lung epithelial cells via activation of p38 MAPK and NF-kappa B. Respir Res 9:16. https://doi.org/10.1186/1465-9921-9-16

    Article  CAS  Google Scholar 

  27. Cho YJ, Park SB, Park JW, Oh SR, Han M (2018) Bisphenol A modulates inflammation and proliferation pathway in human endometrial stromal cells by inducing oxidative stress. Reprod Toxicol 81:41–49. https://doi.org/10.1016/j.reprotox.2018.06.016

    Article  CAS  Google Scholar 

  28. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50. https://doi.org/10.1128/MMBR.00031-10

    Article  CAS  Google Scholar 

  29. Laurent A, Nicco C, Chéreau C, Goulvestre C, Alexandre J, Alves A, Lévy E, Goldwasser F, Panis Y, Soubrane O, Weill B, Batteux F (2005) Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res 65:948–956. https://doi.org/10.1158/0008-5472.948.65.3

    Article  CAS  Google Scholar 

  30. Pu XJ, Li J, Zhou QL, Pan W, Li YQ, Zhang Y, Wang J, Jiao Z (2018) Rosiglitazone inhibits PM2.5-induced cytotoxicity in human lung epithelial A549 cells. Ann Transl Med 6:152–152. https://doi.org/10.21037/atm.2018.04.13

    Article  CAS  Google Scholar 

  31. Tian Y, Xiao Y, Wang B, Sun C, Tang K, Sun F (2018) Vitamin E and lycopene reduce coal burning fluorosis-induced spermatogenic cell apoptosis via oxidative stress-mediated JNK and ERK signaling pathways. Biosci Rep 38:BSR20171003. https://doi.org/10.1042/BSR20171003

    Article  Google Scholar 

  32. Martin LD, Krunkosky TM, Dye JA, Fischer BM, Jiang NF, Rochelle LG, Akley NJ, Dreher KL, Adler KB (1997) The role of reactive oxygen and nitrogen species in the response of airway epithelium to particulates. Environ Health Perspect 105:1301–1307. https://doi.org/10.1289/ehp.97105s51301

    Article  CAS  Google Scholar 

  33. Morgan MJ, Liu Z (2011) Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res 21:103–115. https://doi.org/10.1038/cr.2010.178

    Article  CAS  Google Scholar 

  34. Buhrmann C, Shayan P, Aggarwal BB, Shakibaei M (2013) Evidence that TNF-β (lymphotoxin α) can activate the inflammatory environment in human chondrocytes. Arthritis Res Therapy 15:R202–R202. https://doi.org/10.1186/ar4393

    Article  CAS  Google Scholar 

  35. Tian C, Liu X, Chang Y, Wang R, Yang M, Liu M (2020) Rutin prevents inflammation induced by lipopolysaccharide in RAW 264.7 cells via conquering the TLR4-MyD88-TRAF6-NF-κB signalling pathway. J Pharm Pharmacol 73:110–117. https://doi.org/10.1093/jpp/rgaa015

    Article  Google Scholar 

  36. Yoo H, Ku SK, Baek YD, Bae JS (2014) Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflamm Res 63:197–206. https://doi.org/10.1007/s00011-013-0689-x

    Article  CAS  Google Scholar 

  37. Hwang D, Kang MJ, Kang CW, Kim GD (2019) Kaempferol–3–O–β–rutinoside suppresses the inflammatory responses in lipopolysaccharide–stimulated RAW264.7 cells via the NF–κB and MAPK pathways. Int J Mol Med 44:2321–2328. https://doi.org/10.3892/ijmm.2019.4381

    Article  CAS  Google Scholar 

  38. Wang H, Xia W, Long G, Pei Z, Li Y, Wu M, Wang Q, Zhang Y, Jia Z, Chen H (2020) Isoquercitrin ameliorates cisplatin-induced nephrotoxicity via the inhibition of apoptosis, inflammation, and oxidative stress. Front Pharmacol 11:599416. https://doi.org/10.3389/fphar.2020.599416

    Article  CAS  Google Scholar 

  39. Nyau V, Prakash S, Rodrigues J, Farrant J (2015) HPLC-PDA-ESI-MS identification of polyphenolic phytochemicals in different market classes of common beans (Phaseolus vulgaris L.). Int J Biochem Res Rev 8:1–11. https://doi.org/10.9734/IJBCRR/2015/21608

    Article  CAS  Google Scholar 

  40. He W, Liu X, Xu H, Gong Y, Yuan F, Gao Y (2010) On-line HPLC-ABTS screening and HPLC-DAD-MS/MS identification of free radical scavengers in Gardenia (Gardenia jasminoides Ellis) fruit extracts. Food Chem 123:521–528. https://doi.org/10.1016/j.foodchem.2010.04.030

    Article  CAS  Google Scholar 

  41. Bystrom LM, Lewis BA, Brown DL, Rodriguez E, Obendorf RL (2008) Characterisation of phenolics by LC–UV/Vis, LC–MS/MS and sugars by GC in Melicoccus bijugatus Jacq. ‘Montgomery’ fruits. Food Chem 111:1017–1024. https://doi.org/10.1016/j.foodchem.2008.04.058

    Article  CAS  Google Scholar 

  42. Li X, Zhang Y, Zeng X, Yang L, Deng Y (2011) Chemical profiling of bioactive constituents in Sarcandra glabra and its preparations using ultra-high-pressure liquid chromatography coupled with LTQ Orbitrap mass spectrometry. Rapid Commun Mass Spectrom 25:2439–2447. https://doi.org/10.1002/rcm.5123

    Article  CAS  Google Scholar 

  43. Zengin G, Llorent-Martínez EJ, Sinan KI, Yıldıztugay E, Picot-Allain C, Mahomoodally MF (2019) Chemical profiling of Centaurea bornmuelleri Hausskn. aerial parts by HPLC-MS/MS and their pharmaceutical effects: from nature to novel perspectives. J Pharm Biomed Anal 174:406–413. https://doi.org/10.1016/j.jpba.2019.06.009

    Article  CAS  Google Scholar 

  44. Gobbo-Neto L, Lopes NP (2008) Online identification of chlorogenic acids, sesquiterpene lactones, and flavonoids in the Brazilian arnica Lychnophora ericoides Mart. (Asteraceae) leaves by HPLC-DAD-MS and HPLC-DAD-MS/MS and a validated HPLC-DAD Method for Their Simultaneous Analysis. J Agric Food Chem 56:1193–1204. https://doi.org/10.1021/jf072812l

    Article  CAS  Google Scholar 

  45. Olsen H, Aaby K, Borge GIA (2009) Characterization and quantification of flavonoids and hydroxycinnamic acids in curly kale (Brassica oleracea L. Convar. acephala Var. sabellica) by HPLC-DAD-ESI-MSn. J Agric Food Chem 57:2816–2825. https://doi.org/10.1021/jf803693t

    Article  CAS  Google Scholar 

  46. Kachlicki P, Einhorn J, Muth D, Kerhoas L, Stobiecki M (2008) Evaluation of glycosylation and malonylation patterns in flavonoid glycosides during LC/MS/MS metabolite profiling. J Mass Spectrom 43:572–586. https://doi.org/10.1002/jms.1344

    Article  CAS  Google Scholar 

  47. Harbaum B, Hubbermann EM, Wolff C, Herges R, Zhu Z, Schwarz K (2007) Identification of flavonoids and hydroxycinnamic acids in pak choi varieties (Brassica campestris L. ssp. chinensis var. communis) by HPLC–ESI-MS n and NMR and their quantification by HPLC–DAD. J Agric Food Chem 55:8251–8260. https://doi.org/10.1021/jf071314+

    Article  CAS  Google Scholar 

  48. Zhuang B, Bi Z-M, Wang Z-Y, Duan L, Lai C-J-S, Liu EH (2018) Chemical profiling and quantitation of bioactive compounds in Platycladi Cacumen by UPLC-Q-TOF-MS/MS and UPLC-DAD. J Pharm Biomed Anal 154:207–215. https://doi.org/10.1016/j.jpba.2018.03.005

    Article  CAS  Google Scholar 

  49. Bresciani L, Calani L, Cossu M, Mena P, Sayegh M, Ray S, Del Rio D (2015) (Poly)phenolic characterization of three food supplements containing 36 different fruits, vegetables and berries. PharmaNutrition 3:11–19. https://doi.org/10.1016/j.phanu.2015.01.001

    Article  CAS  Google Scholar 

  50. Aksay O, Selli S, Kelebek H (2021) LC-DAD‐ESI‐MS/MS-based assessment of the bioactive compounds in fresh and fermented caper (Capparis spinosa) buds and berries. Food Chem 337:127959. https://doi.org/10.1016/j.foodchem.2020.127959

    Article  CAS  Google Scholar 

  51. Schieber A, Berardini N, Carle R (2003) Identification of Flavonol and Xanthone Glycosides from Mango (Mangifera indica L. Cv. “Tommy Atkins”) Peels by High-Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry. J Agric Food Chem 51:5006–5011. https://doi.org/10.1021/jf030218f

    Article  CAS  Google Scholar 

  52. García-Villalba R, Espín JC, Tomás-Barberán FA, Rocha-Guzmán NE (2017) Comprehensive characterization by LC-DAD-MS/MS of the phenolic composition of seven Quercus leaf teas. J Food Compos Anal 63:38–46. https://doi.org/10.1016/j.jfca.2017.07.034

    Article  CAS  Google Scholar 

  53. Spínola V, Castilho PC (2016) Phytochemical profile, chemotaxonomic studies, and in vitro antioxidant activities of two endemisms from madeira archipelago: Melanoselinum decipiens and Monizia edulis (Apiaceae). Chem Biodivers 13:1290–1306. https://doi.org/10.1002/cbdv.201600039

    Article  CAS  Google Scholar 

  54. Patras MA, Milev BP, Vrancken G, Kuhnert N (2014) Identification of novel cocoa flavonoids from raw fermented cocoa beans by HPLC–MSn. Food Res Int 63:353–359. https://doi.org/10.1016/j.foodres.2014.05.031

    Article  CAS  Google Scholar 

  55. Rodrigues NP, Bragagnolo N (2013) Identification and quantification of bioactive compounds in coffee brews by HPLC–DAD–MSn. J Food Compos Anal 32:105–115. https://doi.org/10.1016/j.jfca.2013.09.002

    Article  CAS  Google Scholar 

  56. Choi SR, Lee MY, Reddy CK, Lee SJ, Lee CH (2021) Evaluation of metabolite profiles of ginseng berry pomace obtained after different pressure treatments and their correlation with the antioxidant activity. Molecules 26:284. https://doi.org/10.3390/molecules26020284

    Article  CAS  Google Scholar 

  57. Llorent-Martínez EJ, Zengin G, Lobine D, Molina-García L, Mollica A, Mahomoodally MF (2018) Phytochemical characterization, in vitro and in silico approaches for three Hypericum species. New J Chem 42:5204–5214. https://doi.org/10.1039/C8NJ00347E

    Article  Google Scholar 

  58. Napolitano A, Cerulli A, Pizza C, Piacente S (2018) Multi-class polar lipid profiling in fresh and roasted hazelnut (Corylus avellana cultivar “Tonda di Giffoni”) by LC-ESI/LTQOrbitrap/MS/MSn. Food Chemistry 269:125–135. https://doi.org/10.1016/j.foodchem.2018.06.121

    Article  CAS  Google Scholar 

  59. Fang N, Yu S, Badger TM (2003) LC-MS/MS analysis of lysophospholipids associated with soy protein isolate. J Agric Food Chem 51:6676–6682. https://doi.org/10.1021/jf034793v

    Article  CAS  Google Scholar 

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Acknowledgements

This research was supported by a grant from the National Institute of Biological Resources (NIBR) funded by the Ministry of Environment (MOE) of the Republic of Korea (NIBR201828101).

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This work was funded by National Institute of Biological Resources with Grant no (NIBR201828101).

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Conceptualization: JYL and JKL. Data curation: JKL, WSC, and JYL. Investigation: JKL, WSC, JYS, OSK, YJL, JSL, SL, SRC, CHL, and JYL. Formal analysis: JKL, WSC, JYS, OSK, SRC, CHL, and YJL. Supervision: JYL. Visualization: JKL, WSC, and JYL. Project administration: JYL. Resources: JSL, SL, and JYL. Writing—original draft: JKL. Writing—review and editing: WSC, JYS, and JYL. All authors read and approved the final version of the manuscript.

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Lee, JK., Choi, W.S., Song, J.Y. et al. Anti-inflammatory effects of Athyrium yokoscense extract via inhibition of the Erk1/2 and NF-κB pathways in bisphenol A-stimulated A549 cells. Toxicol Res. 39, 135–146 (2023). https://doi.org/10.1007/s43188-022-00154-0

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