Skip to content
2000
image of The Anti-PEDV Effects and Mechanisms of Forsythia Essential Oil Based on Network Pharmacology and Experimental Validation

Abstract

Objective

Porcine epidemic diarrhea virus (PEDV), a member of the Coronaviridae, is responsible for acute diarrhea, vomiting, and dehydration, which can lead to high mortality in neonatal piglets. Previous research has indicated the antiviral potential of forsythia essential oil (FEO); however, its active components and mechanisms of action remain inadequately defined. This study aims to investigate the antiviral effects of FEO and elucidate its potential mechanisms for treating PEDV.

Methods

The primary components of FEO were identified using gas chromatography-mass spectrometry (GC/MS) in conjunction with the National Institute of Standards and Technology Standard Spectrum (NIST) Database. Network pharmacology and weighting coefficients were employed to determine the key signaling pathways associated with PEDV-related diseases. Molecular docking simulations were conducted to explore the interactions between the active ingredients and their corresponding targets. The safety profile of FEO was assessed through cell viability assays utilizing the CCK8 method. Subsequently, immunofluorescence assays (IFA) and reverse transcription-quantitative polymerase chain reaction (RT-Q-PCR) were performed to provide evidence of the anti-PEDV effects. Additionally, the viral replication cycle was analyzed to identify the stages at which FEO exerts its antiviral effects. Finally, key targets were validated through RT-Q-PCR to further investigate the anti-PEDV mechanisms of FEO.

Results

The IL-17 signaling pathway was identified as a critical pathway for the treatment of PEDV with FEO based on network pharmacology and weighting coefficient analyses. Furthermore, results from RT-Q-PCR and IFA demonstrated that FEO influenced the replication of PEDV during the attachment and internalization phases. Specifically, during the viral attachment phase, FEO significantly upregulated the expression of HSP90AA1 while downregulating MAPK14 expression, leading to a reduction in associated inflammatory factors. At the high dose of FEO, the expression of HSP90AA1 was higher than that of the model group by about 5-fold, and the expression of MAPK14 was lower than that of the model group by about 2-fold. Cell viability assay showed no significant cytotoxicity of FEO at 0.63 µL/mL, thus confirming its safety.

Conclusion

The findings of this study suggest that FEO possesses potential antiviral properties against PEDV. Its novel mechanisms of action warrant further investigation, which may contribute to the development of effective therapeutic strategies for managing PEDV infections.

Loading

Article metrics loading...

/content/journals/cchts/10.2174/0113862073358217250225052414
2025-03-10
2025-06-21
Loading full text...

Full text loading...

References

  1. Pijpers A. van Nieuwstadt A. Terpstra C. Verheijden J. Porcine epidemic diarrhoea virus as a cause of persistent diarrhoea in a herd of breeding and finishing pigs. Vet. Rec. 1993 132 6 129 131 10.1136/vr.132.6.129 8383370
    [Google Scholar]
  2. Pensaert M. B. de Bouck P. A new coronavirus-like particle associated with diarrhea in swine. Arch. Virol. 1978 58 3 243 247 10.1007/BF01317606
    [Google Scholar]
  3. Jung K. Saif L.J. Wang Q. Porcine epidemic diarrhea virus (PEDV): An update on etiology, transmission, pathogenesis, and prevention and control. Virus Res. 2020 286 198045 10.1016/j.virusres.2020.198045 32502552
    [Google Scholar]
  4. Hanke D. Pohlmann A. Sauter-Louis C. Höper D. Stadler J. Ritzmann M. Steinrigl A. Schwarz B.A. Akimkin V. Fux R. Blome S. Beer M. Porcine epidemic diarrhea in Europe: In-detail analyses of disease dynamics and molecular epidemiology. Viruses 2017 9 7 177 10.3390/v9070177 28684708
    [Google Scholar]
  5. Hu Y. Xie X. Yang L. Wang A. A comprehensive view on the host factors and viral proteins associated with porcine epidemic diarrhea virus infection. Front. Microbiol. 2021 12 762358 10.3389/fmicb.2021.762358 34950116
    [Google Scholar]
  6. He W.T. Bollen N. Xu Y. Zhao J. Dellicour S. Yan Z. Gong W. Zhang C. Zhang L. Lu M. Lai A. Suchard M.A. Ji X. Tu C. Lemey P. Baele G. Su S. Phylogeography reveals association between swine trade and the spread of porcine epidemic diarrhea virus in China and across the World. Mol. Biol. Evol. 2022 39 2 msab364 10.1093/molbev/msab364 34951645
    [Google Scholar]
  7. Yang X.N. Khan I. Kang S.C. Chemical composition, mechanism of antibacterial action and antioxidant activity of leaf essential oil of Forsythia koreana deciduous shrub. Asian Pac. J. Trop. Med. 2015 8 9 694 700 10.1016/j.apjtm.2015.07.031 26433652
    [Google Scholar]
  8. Dong Z. Lu X. Tong X. Dong Y. Tang L. Liu M. Forsythiae fructus: A review on its phytochemistry, quality control, pharmacology and pharmacokinetics. Molecules 2017 22 9 1466 10.3390/molecules22091466 28869577
    [Google Scholar]
  9. Wang Z. Xia Q. Liu X. Liu W. Huang W. Mei X. Luo J. Shan M. Lin R. Zou D. Ma Z. Phytochemistry, pharmacology, quality control and future research of Forsythia suspensa (Thunb.) Vahl: A review. J. Ethnopharmacol. 2018 210 318 339 10.1016/j.jep.2017.08.040 28887216
    [Google Scholar]
  10. Commission C.P. Pharmacopoeia of the People’s Republic of China 2010 China Medical Science and Technology Press Beijing 2020
    [Google Scholar]
  11. Gai Q.Y. Jiao J. Wei F.Y. Luo M. Wang W. Zu Y-G. Fu Y-J. Enzyme-assisted aqueous extraction of oil from Forsythia suspense seed and its physicochemical property and antioxidant activity. Ind. Crops Prod. 2013 51 274 278 10.1016/j.indcrop.2013.09.014
    [Google Scholar]
  12. Jue D. An Y. Lin L. Antipyretic effect of forsythia suspense extract and forsythia oil on yeast-induced fever rats and its mechanism. Nat. Prod. Res. Dev. 2017 29 9 1542 1545 10.16333/j.1001‑6880.2017.9.015
    [Google Scholar]
  13. Yuan A. Gong L. Luo L. Revealing anti-inflammation mechanism of water-extract and oil of forsythiae fructus on carrageenan-Induced edema rats by serum metabolomics. Biomed Pharmacother 2017 95 929 937 10.1016/j.biopha.2017.09.009
    [Google Scholar]
  14. Yang Zhiwei. Comparative anti-infectious bronchitis virus (IBV) activity of (-)-pinene: Effect on nucleocapsid (N) protein. Molecules 2011 16 2 1044 1054 2011 10.3390/molecules16021044
    [Google Scholar]
  15. Ding T. Meng-Qi S. Yun W. Volatile Oil from Forsythia suspense: Chemical constituents and pharmacological effects. Nat. Prod. Res. Dev. 2018 30 10 1834 1842 10.16333/j.1001‑6880.2018.10.029
    [Google Scholar]
  16. Wang X. Wang P. Ding X. Prediction of the active components and mechanism of forsythia suspensa leaf against respiratory syncytial virus based on network pharmacology. Evid. Based Complement Alternat Med. 2022 2022 5643345 10.1155/2022/5643345
    [Google Scholar]
  17. Mohamed M.E. Tawfeek N. Elbaramawi S.S. Fikry E. Agathis robusta bark essential oil effectiveness against COVID-19: Chemical composition, in silico and in vitro approaches. Plants 2022 11 5 663 10.3390/plants11050663 35270131
    [Google Scholar]
  18. Mieres-Castro D. Ahmar S. Shabbir R. Mora-Poblete F. Antiviral activities of Eucalyptus Essential Oils: Their effectiveness as therapeutic targets against human viruses. Pharmaceuticals 2021 14 12 1210 10.3390/ph14121210 34959612
    [Google Scholar]
  19. Astani A. Reichling J. Schnitzler P. Comparative study on the antiviral activity of selected monoterpenes derived from essential oils. Phytother. Res. 2010 24 5 673 679 10.1002/ptr.2955 19653195
    [Google Scholar]
  20. Ginting B. Chiari W. Duta T.F. Hudaa S. Purnama A. Harapan H. Rizki D.R. Puspita K. Idroes R. Meriatna M. Iqhrammullah M. COVID-19 pandemic sheds a new research spotlight on antiviral potential of essential oils – A bibliometric study. Heliyon 2023 9 7 e17703 10.1016/j.heliyon.2023.e17703 37456016
    [Google Scholar]
  21. Li T. Wang W. Guo Q. Li J. Tang T. Wang Y. Liu D. Yang K. Li J. Deng K. Wang F. Li H. Wu Z. Guo J. Guo D. Shi Y. Zou J. Sun J. Zhang X. Yang M. Rosemary (Rosmarinus officinalis L.) hydrosol based on serotonergic synapse for insomnia. J. Ethnopharmacol. 2024 318 Pt B 116984 10.1016/j.jep.2023.116984 37532071
    [Google Scholar]
  22. Zhou P. Yu S. Wang X. Zhang X. Guo D. Zhao C. Cheng J. Wang J. Sun J. Ferulic acid methyl ester attenuates cerebral ischemia-reperfusion injury in rats by modulating PI3K/HIF-1α/VEGF signaling pathway. J. Inflamm. Res. 2024 17 5741 5762 10.2147/JIR.S473665 39224659
    [Google Scholar]
  23. Wang X. Zhou P. Shi H. Wang W. Li T. Tang T. Duan J. Li J. Xia N. Wang J. Chen C. Wang J. Zou J. Shi Y. Guo D. Wu Z. Yang M. Zhang X. Sun J. Cinnamon essential oil based on NLRP3 inflammasome and renal uric acid transporters for hyperuricemia. Food Biosci. 2023 56 103285 10.1016/j.fbio.2023.103285
    [Google Scholar]
  24. Zhou P. Zhang B. Wang X. Duan J. Li J. Wang J. Xia N. Zhang S. Wang J. Guo D. Zhao C. Shi H. Cheng J. Xie Y. Sun J. Zhang X. Spike lavender essential oil attenuates hyperuricemia and induced renal injury by modulating the TLR4/NF-κB/NLRP3 signalling pathway. Arab. J. Chem. 2024 17 9 105897 10.1016/j.arabjc.2024.105897
    [Google Scholar]
  25. Zhao Y. Xiao D. Zhang L. Song D. Chen R. Li S. Liao Y. Wen Y. Liu W. Yu E. Wen Y. Wu R. Zhao Q. Du S. Wen X. Cao S. Huang X. HSP90 inhibitors 17-AAG and VER-82576 inhibit porcine deltacoronavirus replication in vitro. Vet. Microbiol. 2022 265 109316 10.1016/j.vetmic.2021.109316 34954542
    [Google Scholar]
  26. Xu X. Zhang W. Wu X. Yang H. Sun Y. Pu Y. Wang B. Peng W. Sun L. Guo Q. Zhou S. Fang B. Analysis of mechanisms of Shenhuang Granule in treating severe COVID-19 based on network pharmacology and molecular docking. J. Integr. Med. 2022 20 6 561 574 10.1016/j.joim.2022.07.005 35934629
    [Google Scholar]
  27. Kang Z. Wu Q. Peng Q. Deng Y. Xu H. Xiao Y. Li J. Li S. Li J. Chen Y. Deciphering the potential therapeutic targets and mechanisms of jaranol for the treatment of COVID-19 and lung adenocarcinoma. Arab. J. Chem. 2024 17 3 105648 10.1016/j.arabjc.2024.105648
    [Google Scholar]
  28. Wang J. Tian W.J. Li C.C. Zhang X.Z. Fan K. Li S.L. Wang X.J. Small-molecule RAF265 as an antiviral therapy acts against PEDV infection. Viruses 2022 14 10 2261 10.3390/v14102261 36298816
    [Google Scholar]
  29. Rao H. Su W. Zhang X. Wang Y. Li T. Li J. Zeng X. Li P. Hypericum japonicum extract inhibited porcine epidemic diarrhea virus in vitro and in vivo. Front. Pharmacol. 2023 14 1112610 10.3389/fphar.2023.1112610 37138845
    [Google Scholar]
  30. Xu Z. Liu Y. Peng P. Aloe extract inhibits porcine epidemic diarrhea virus in vitro and in vivo Vet. Microbiol. 2020 249 108849 10.1016/j.vetmic.2020.108849
    [Google Scholar]
  31. Hu Y. Li Y. Zhu H. Wang D. Zhou J. Ni Y. Guo R. Fan B. Li B. In vitro suppression of porcine epidemic diarrhea virus by Panax notoginseng saponins: assessing antiviral potential. Arch. Virol. 2024 169 5 89 89 10.1007/s00705‑024‑06020‑8 38565720
    [Google Scholar]
  32. Kim J.I. Anti-porcine epidemic diarrhea Virus (PEDV) activity and antimicrobial activities of artemisia dubia essential oil. Han’guk Misaengmul, Saengmyong Konghakhoe Chi. 2012 40 4 396 402 10.4014/kjmb.1208.08011
    [Google Scholar]
  33. So J. Kim J.H. Lee S. Kim C. Park R. Park J. Arctigenin from Forsythia viridissima fruit inhibits the replication of human coronavirus. Int. J. Mol. Sci. 2024 25 13 7363 10.3390/ijms25137363 39000469
    [Google Scholar]
  34. Temajo N.O. Howard N. The virus-induced HSPs regulate the apoptosis of operatus APCs that results in autoimmunity, not in homeostasis. Autoimmun. Rev. 2014 13 10 1013 1019 10.1016/j.autrev.2014.08.030 25183243
    [Google Scholar]
  35. Xu Q. Qiao H. Xu Y. Zhao Y. He N. Zhao J. Liu Y. HSP90 and Noncoding RNAs. DNA Cell Biol. 2023 42 10 585 593 10.1089/dna.2023.0172 37638805
    [Google Scholar]
  36. Yu D.S. Wu X.X. Weng T.H. Cheng L.F. Liu F.M. Wu H.B. Lu X.Y. Wu N.P. Sun S.L. Yao H.P. Host proteins interact with viral elements and affect the life cycle of highly pathogenic avian influenza A virus H7N9. Heliyon 2024 10 7 e28218 10.1016/j.heliyon.2024.e28218 38560106
    [Google Scholar]
  37. Xu Y. Liu F. Liu J. Wang D. Yan Y. Ji S. Zan J. Zhou J. The co-chaperone Cdc37 regulates the rabies virus phosphoprotein stability by targeting to Hsp90AA1 machinery. Sci. Rep. 2016 6 1 27123 10.1038/srep27123 27251758
    [Google Scholar]
  38. Wang X. Zheng T. Lin L. Zhang Y. Peng X. Yan Y. Lei J. Zhou J. Hu B. Influenza A virus induces autophagy by its hemagglutinin binding to cell surface heat shock protein 90AA1. Front. Microbiol. 2020 11 566348 566348 10.3389/fmicb.2020.566348 33117314
    [Google Scholar]
  39. Liu C. Zhao W. Su J. Chen X. Zhao F. Fan J. Li X. Liu X. Zou L. Zhang M. Zhang Z. Zhang L. Fan S. Li Y. Zhao M. Chen J. Yi L. HSP90AA1 interacts with CSFV NS5A protein and regulates CSFV replication via the JAK/STAT and NF-κB signaling pathway. Front. Immunol. 2022 13 1031868 10.3389/fimmu.2022.1031868 36405689
    [Google Scholar]
  40. Choi M.S. Heo J. Yi C.M. Ban J. Lee N.J. Lee N.R. Kim S.W. Kim N.J. Inn K.S. A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation. Biochem. Biophys. Res. Commun. 2016 477 3 311 316 10.1016/j.bbrc.2016.06.111 27346133
    [Google Scholar]
  41. Cheng Y. Jiao L. Chen J. Chen P. Zhou F. Zhang J. Wang M. Wu Q. Cao S. Lu H. Wu Z. Wang A. Qian Y. Zhu S. Duck Tembusu virus infection activates the MKK3/6-p38 MAPK signaling pathway to promote virus replication. Vet. Microbiol. 2024 288 109951 10.1016/j.vetmic.2023.109951 38101078
    [Google Scholar]
  42. Zhong M. Wang H.Q. Yan H.Y. Wu S. Gu Z.Y. Li Y.H. Santin inhibits influenza A virus replication through regulating MAPKs and NF-κB pathways. J. Asian Nat. Prod. Res. 2019 21 12 1205 1214 10.1080/10286020.2018.1520221 30417663
    [Google Scholar]
  43. Kundlacz C. Pourcelot M. Fablet A. Amaral Da Silva Moraes R. Léger T. Morlet B. Viarouge C. Sailleau C. Turpaud M. Gorlier A. Breard E. Lecollinet S. van Rijn P.A. Zientara S. Vitour D. Caignard G. Novel function of bluetongue virus NS3 protein in regulation of the MAPK/ERK signaling pathway. J. Virol. 2019 93 16 e00336-19 10.1128/JVI.00336‑19 31167915
    [Google Scholar]
  44. Chen X. Chen Y. Yin Z. Wang R. Hu H. Liang X. He C. Yin L. Ye G. Zou Y. Li L. Tang H. Jia R. Song X. Kaempferol inhibits Pseudorabies virus replication in vitro through regulation of MAPKs and NF-κB signaling pathways. J. Integr. Agric. 2021 20 8 2227 2239 10.1016/S2095‑3119(20)63477‑3
    [Google Scholar]
  45. De S. Mamidi P. Ghosh S. Keshry S.S. Mahish C. Pani S.S. Laha E. Ray A. Datey A. Chatterjee S. Singh S. Mukherjee T. Khamaru S. Chattopadhyay S. Subudhi B.B. Chattopadhyay S. Telmisartan restricts chikungunya virus infection in vitro and in vivo through the AT1/PPAR-γ/MAPKs pathways. Antimicrob. Agents Chemother. 2022 66 1 e01489-21 10.1128/AAC.01489‑21 34748384
    [Google Scholar]
  46. Qiao W.T. Yao X. Lu W.H. Zhang Y.Q. Malhi K.K. Li H.X. Li J.L. Matrine exhibits antiviral activities against PEDV by directly targeting Spike protein of the virus and inducing apoptosis via the MAPK signaling pathway. Int. J. Biol. Macromol. 2024 270 Pt 2 132408 10.1016/j.ijbiomac.2024.132408 38754683
    [Google Scholar]
  47. Li K. Wang H. Chen T. Wang X. Wang X. Zhong M. Gao X. Hao Z. Dehydroevodiamine inhibits PEDV through regulateing ERK1/2 MAPK pathway in Vero cells. Virology 2024 598 110166 110166 10.1016/j.virol.2024.110166 39024722
    [Google Scholar]
/content/journals/cchts/10.2174/0113862073358217250225052414
Loading
/content/journals/cchts/10.2174/0113862073358217250225052414
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test