Skip to main content
Top
Published in: Virology Journal 1/2015

Open Access 01-12-2015 | Research

Formononetin inhibits enterovirus 71 replication by regulating COX- 2/PGE2 expression

Authors: Huiqiang Wang, Dajun Zhang, Miao Ge, Zhuorong Li, Jiandong Jiang, Yuhuan Li

Published in: Virology Journal | Issue 1/2015

Login to get access

Abstract

Background

The activation of ERK, p38 and JNK signal cascade in host cells has been demonstrated to up-regulate of enterovirus 71 (EV71)-induced cyclooxygenase-2 (COX-2)/ prostaglandins E2 (PGE2) expression which is essential for viral replication. So, we want to know whether a compound can inhibit EV71 infection by suppressing COX-2/PGE2 expression.

Methods

The antiviral effect of formononetin was determined by cytopathic effect (CPE) assay and the time course assays. The influence of formononetin for EV71 replication was determined by immunofluorescence assay, western blotting assay and qRT-PCR assay. The mechanism of the antiviral activity of formononetin was determined by western blotting assay and ELISA assay.

Results

Formononetin could reduce EV71 RNA and protein synthesis in a dose-dependent manner. The time course assays showed that formononetin displayed significant antiviral activity both before (24 or 12 h) and after (0–6 h) EV71 inoculation in SK-N-SH cells. Formononetin was also able to prevent EV71-induced cytopathic effect (CPE) and suppress the activation of ERK, p38 and JNK signal pathways. Furthermore, formononetin could suppress the EV71-induced COX-2/PGE2 expression. Also, formononetin exhibited similar antiviral activities against other members of Picornaviridae including coxsackievirus B2 (CVB2), coxsackievirus B3 (CVB3) and coxsackievirus B6 (CVB6).

Conclusions

Formononetin could inhibit EV71-induced COX-2 expression and PGE2 production via MAPKs pathway including ERK, p38 and JNK. Formononetin exhibited antiviral activities against some members of Picornaviridae. These findings suggest that formononetin could be a potential lead or supplement for the development of new anti-EV71 agents in the future.
Literature
1.
go back to reference Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH, et al. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10(11):778–90.CrossRefPubMed Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH, et al. Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis. 2010;10(11):778–90.CrossRefPubMed
2.
go back to reference McMinn PC. Recent advances in the molecular epidemiology and control of human enterovirus 71 infection. Curr Opin Virol. 2012;2(2):199–205.CrossRefPubMed McMinn PC. Recent advances in the molecular epidemiology and control of human enterovirus 71 infection. Curr Opin Virol. 2012;2(2):199–205.CrossRefPubMed
3.
go back to reference Wang X, Zhu C, Bao W, Zhao K, Niu J, Yu XF, et al. Characterization of full-length enterovirus 71 strains from severe and mild disease patients in northeastern China. PLoS One. 2012;7(3):e32405.CrossRefPubMedCentralPubMed Wang X, Zhu C, Bao W, Zhao K, Niu J, Yu XF, et al. Characterization of full-length enterovirus 71 strains from severe and mild disease patients in northeastern China. PLoS One. 2012;7(3):e32405.CrossRefPubMedCentralPubMed
4.
go back to reference Weng KF, Chen LL, Huang PN, Shih SR. Neural pathogenesis of enterovirus 71 infection. Microbes Infect. 2010;12(7):505–10.CrossRefPubMed Weng KF, Chen LL, Huang PN, Shih SR. Neural pathogenesis of enterovirus 71 infection. Microbes Infect. 2010;12(7):505–10.CrossRefPubMed
5.
go back to reference Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7(6):735–42.CrossRefPubMed Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7(6):735–42.CrossRefPubMed
6.
go back to reference Tung WH, Hsieh HL, Yang CM. Enterovirus 71 induces COX-2 expression via MAPKs, NF-kappaB, and AP-1 in SK-N-SH cells: Role of PGE(2) in viral replication. Cell Signal. 2010;22(2):234–46.CrossRefPubMed Tung WH, Hsieh HL, Yang CM. Enterovirus 71 induces COX-2 expression via MAPKs, NF-kappaB, and AP-1 in SK-N-SH cells: Role of PGE(2) in viral replication. Cell Signal. 2010;22(2):234–46.CrossRefPubMed
7.
go back to reference Tung WH, Hsieh HL, Lee IT, Yang CM. Enterovirus 71 modulates a COX-2/PGE2/cAMP-dependent viral replication in human neuroblastoma cells: role of the c-Src/EGFR/p42/p44 MAPK/CREB signaling pathway. J Cell Biochem. 2011;112(2):559–70.CrossRefPubMed Tung WH, Hsieh HL, Lee IT, Yang CM. Enterovirus 71 modulates a COX-2/PGE2/cAMP-dependent viral replication in human neuroblastoma cells: role of the c-Src/EGFR/p42/p44 MAPK/CREB signaling pathway. J Cell Biochem. 2011;112(2):559–70.CrossRefPubMed
8.
go back to reference Steer SA, Corbett JA. The role and regulation of COX-2 during viral infection. Viral Immunol. 2003;16(4):447–60.CrossRefPubMed Steer SA, Corbett JA. The role and regulation of COX-2 during viral infection. Viral Immunol. 2003;16(4):447–60.CrossRefPubMed
9.
go back to reference Tung WH, Lee IT, Hsieh HL, Yang CM. EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. J Cell Physiol. 2010;224(2):376–86.CrossRefPubMed Tung WH, Lee IT, Hsieh HL, Yang CM. EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. J Cell Physiol. 2010;224(2):376–86.CrossRefPubMed
10.
go back to reference Zhang G, Zhou F, Gu B, Ding C, Feng D, Xie F, et al. In vitro and in vivo evaluation of ribavirin and pleconarilantiviral activity against enterovirus 71 infection. Arch Virol. 2012;157(4):669–79.CrossRefPubMed Zhang G, Zhou F, Gu B, Ding C, Feng D, Xie F, et al. In vitro and in vivo evaluation of ribavirin and pleconarilantiviral activity against enterovirus 71 infection. Arch Virol. 2012;157(4):669–79.CrossRefPubMed
11.
go back to reference Chen TC, Liu SC, Huang PN, Chang HY, Chern JH, Shih SR. Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants. J Biomed Sci. 2008;15(3):291–300.CrossRefPubMed Chen TC, Liu SC, Huang PN, Chang HY, Chern JH, Shih SR. Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants. J Biomed Sci. 2008;15(3):291–300.CrossRefPubMed
12.
go back to reference Zhang W, Tao J, Yang X, Yang Z, Zhang L, Liu H, et al. Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection. Biochem Biophys Res Commun. 2014;449(3):307–12.CrossRefPubMed Zhang W, Tao J, Yang X, Yang Z, Zhang L, Liu H, et al. Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection. Biochem Biophys Res Commun. 2014;449(3):307–12.CrossRefPubMed
13.
go back to reference Pu X, Wang H, Li Y, Fan W, Yu S. Antiviral activity of GuiQi polysaccharides against enterovirus 71 in vitro. Virol Sin. 2013;28(6):352–9.CrossRefPubMed Pu X, Wang H, Li Y, Fan W, Yu S. Antiviral activity of GuiQi polysaccharides against enterovirus 71 in vitro. Virol Sin. 2013;28(6):352–9.CrossRefPubMed
14.
go back to reference Wang J, Su H, Zhang T, Du J, Cui S, Yang F, et al. Inhibition of Enterovirus 71 replication by 7-hydroxyflavone and diisopropyl-flavon7-yl Phosphate. PLoS One. 2014;9(3):e92565.CrossRefPubMedCentralPubMed Wang J, Su H, Zhang T, Du J, Cui S, Yang F, et al. Inhibition of Enterovirus 71 replication by 7-hydroxyflavone and diisopropyl-flavon7-yl Phosphate. PLoS One. 2014;9(3):e92565.CrossRefPubMedCentralPubMed
15.
go back to reference Yang Y, Xiu J, Liu J, Zhang L, Li X, Xu Y, et al. Chebulagic acid, a hydrolyzable tannin, exhibited antiviral activity in vitro and in vivo against human enterovirus 71. Int J Mol Sci. 2013;14(5):9618–27.CrossRefPubMedCentralPubMed Yang Y, Xiu J, Liu J, Zhang L, Li X, Xu Y, et al. Chebulagic acid, a hydrolyzable tannin, exhibited antiviral activity in vitro and in vivo against human enterovirus 71. Int J Mol Sci. 2013;14(5):9618–27.CrossRefPubMedCentralPubMed
16.
go back to reference Li X, Liu Y, Hou X, Peng H, Zhang L, Jiang Q, et al. Chlorogenic acid inhibits the replication and viability of enterovirus 71 in vitro. PLoS One. 2013;8(9):e76007.CrossRefPubMedCentralPubMed Li X, Liu Y, Hou X, Peng H, Zhang L, Jiang Q, et al. Chlorogenic acid inhibits the replication and viability of enterovirus 71 in vitro. PLoS One. 2013;8(9):e76007.CrossRefPubMedCentralPubMed
17.
go back to reference Ho HY, Cheng ML, Weng SF, Leu YL, Chiu DT. Antiviral effect of epigallocatechingallate on enterovirus 71. J Agric Food Chem. 2009;57(14):6140–7.CrossRefPubMed Ho HY, Cheng ML, Weng SF, Leu YL, Chiu DT. Antiviral effect of epigallocatechingallate on enterovirus 71. J Agric Food Chem. 2009;57(14):6140–7.CrossRefPubMed
18.
go back to reference Zhu QC, Wang Y, Liu YP, Zhang RQ, Li X, Su WH, et al. Inhibition of enterovirus 71 replication by chrysosplenetin and penduletin. Eur J Pharm Sci. 2011;44(3):392–8.CrossRefPubMed Zhu QC, Wang Y, Liu YP, Zhang RQ, Li X, Su WH, et al. Inhibition of enterovirus 71 replication by chrysosplenetin and penduletin. Eur J Pharm Sci. 2011;44(3):392–8.CrossRefPubMed
19.
go back to reference Wang HQ, Meng S, Li ZR, Peng ZG, Han YX, Guo SS, et al. The antiviral effect of 7-hydroxyisoflavone against Enterovirus 71 in vitro. J Asian Nat Prod Res. 2013;15(4):382–9.CrossRefPubMed Wang HQ, Meng S, Li ZR, Peng ZG, Han YX, Guo SS, et al. The antiviral effect of 7-hydroxyisoflavone against Enterovirus 71 in vitro. J Asian Nat Prod Res. 2013;15(4):382–9.CrossRefPubMed
21.
go back to reference Barnard DL, Hubbard VD, Smee DF, Sidwell RW, Watson KG, Tucker SP, et al. In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity. Antimicrob Agents Chemother. 2004;48(5):1766–72.CrossRefPubMedCentralPubMed Barnard DL, Hubbard VD, Smee DF, Sidwell RW, Watson KG, Tucker SP, et al. In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity. Antimicrob Agents Chemother. 2004;48(5):1766–72.CrossRefPubMedCentralPubMed
22.
go back to reference Lai PK, Chan JY, Cheng L, Lau CP, Han SQ, Leung PC, et al. Isolation of anti-inflammatory fractions and compounds from the root of Astragalus membranaceus. Phytother Res. 2013;27(4):581–7.CrossRefPubMed Lai PK, Chan JY, Cheng L, Lau CP, Han SQ, Leung PC, et al. Isolation of anti-inflammatory fractions and compounds from the root of Astragalus membranaceus. Phytother Res. 2013;27(4):581–7.CrossRefPubMed
23.
go back to reference Krenn L, Paper DH. Inhibition of angiogenesis and inflammation by an extract of red clover Trifolium pratense L.). Phytomedicine. 2009;16(12):1083–8.CrossRefPubMed Krenn L, Paper DH. Inhibition of angiogenesis and inflammation by an extract of red clover Trifolium pratense L.). Phytomedicine. 2009;16(12):1083–8.CrossRefPubMed
24.
go back to reference Mu H, Bai YH, Wang ST, Zhu ZM, Zhang YW. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine. 2009;16(4):314–9.CrossRefPubMed Mu H, Bai YH, Wang ST, Zhu ZM, Zhang YW. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine. 2009;16(4):314–9.CrossRefPubMed
25.
go back to reference Huh JE, Nam DW, Baek YH, Kang JW, Park DS, Choi DY, et al. Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways. Int Immunopharmacol. 2011;11(1):46–54.CrossRefPubMed Huh JE, Nam DW, Baek YH, Kang JW, Park DS, Choi DY, et al. Formononetin accelerates wound repair by the regulation of early growth response factor-1 transcription factor through the phosphorylation of the ERK and p38 MAPK pathways. Int Immunopharmacol. 2011;11(1):46–54.CrossRefPubMed
26.
go back to reference Auyeung KK, Law PC, Ko JK. Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. Oncol Rep. 2012;28(6):2188–94.PubMed Auyeung KK, Law PC, Ko JK. Novel anti-angiogenic effects of formononetin in human colon cancer cells and tumor xenograft. Oncol Rep. 2012;28(6):2188–94.PubMed
27.
go back to reference Chen J, Zeng J, Xin M, Huang W, Chen X. Formononetin induces cell cycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo. Horm Metab Res. 2011;43(10):681–6.CrossRefPubMed Chen J, Zeng J, Xin M, Huang W, Chen X. Formononetin induces cell cycle arrest of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo. Horm Metab Res. 2011;43(10):681–6.CrossRefPubMed
28.
go back to reference Sun T, Liu R, Cao YX. Vasorelaxant and antihypertensive effects of formononetin through endothelium-dependent and -independent mechanisms. Acta Pharmacol Sin. 2011;32(8):1009–18.CrossRefPubMedCentralPubMed Sun T, Liu R, Cao YX. Vasorelaxant and antihypertensive effects of formononetin through endothelium-dependent and -independent mechanisms. Acta Pharmacol Sin. 2011;32(8):1009–18.CrossRefPubMedCentralPubMed
29.
go back to reference Zhang S, Tang X, Tian J, Li C, Zhang G, Jiang W, et al. Cardioprotective effect of sulphonated formononetin on acute myocardial infarction in rats. Basic Clin Pharmacol Toxicol. 2011;108(6):390–5.CrossRefPubMed Zhang S, Tang X, Tian J, Li C, Zhang G, Jiang W, et al. Cardioprotective effect of sulphonated formononetin on acute myocardial infarction in rats. Basic Clin Pharmacol Toxicol. 2011;108(6):390–5.CrossRefPubMed
30.
go back to reference Sun M, Zhou T, Zhou L, Q C, Yu Y, Yang H, et al. Formononetin protects neurons against hypoxia-induced cytotoxicity through upregulation of ADAM10 and sAβPPα. J Alzheimers Dis. 2012;28(4):795–808.PubMed Sun M, Zhou T, Zhou L, Q C, Yu Y, Yang H, et al. Formononetin protects neurons against hypoxia-induced cytotoxicity through upregulation of ADAM10 and sAβPPα. J Alzheimers Dis. 2012;28(4):795–808.PubMed
31.
go back to reference Kapoor GS, O’Rourke DM. Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. Cancer Biol Ther. 2003;2(4):330–42.CrossRefPubMed Kapoor GS, O’Rourke DM. Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. Cancer Biol Ther. 2003;2(4):330–42.CrossRefPubMed
32.
go back to reference Ohtsu H, Dempsey PJ, Eguchi S. ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol. 2006;291(1):C1–10.CrossRefPubMed Ohtsu H, Dempsey PJ, Eguchi S. ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol. 2006;291(1):C1–10.CrossRefPubMed
33.
go back to reference Fischer B, Marinov M, Arcaro A. Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far? Cancer Treat Rev. 2007;33(4):391–406.CrossRefPubMed Fischer B, Marinov M, Arcaro A. Targeting receptor tyrosine kinase signalling in small cell lung cancer (SCLC): what have we learned so far? Cancer Treat Rev. 2007;33(4):391–406.CrossRefPubMed
34.
go back to reference Rodemann HP, Dittmann K, Toulany M. Radiation-induced EGFR-signaling and control of DNA-damage repair. Int J Radiat Biol. 2007;83(11–12):781–91.CrossRefPubMed Rodemann HP, Dittmann K, Toulany M. Radiation-induced EGFR-signaling and control of DNA-damage repair. Int J Radiat Biol. 2007;83(11–12):781–91.CrossRefPubMed
35.
go back to reference Wei YH, Fang W, Wan ZY, Wang KM, Yang QY, Cai XF, et al. Antiviral effects against EV71 of pimprinine and its derivatives isolated from Streptomyces sp. Virol J. 2014;11:195.CrossRefPubMedCentralPubMed Wei YH, Fang W, Wan ZY, Wang KM, Yang QY, Cai XF, et al. Antiviral effects against EV71 of pimprinine and its derivatives isolated from Streptomyces sp. Virol J. 2014;11:195.CrossRefPubMedCentralPubMed
36.
go back to reference Chen X, Wang C, Xu L, Wang W, Yang G, Tan RX, et al. A laboratory evaluation of medicinal herbs used in china for the treatment of hand, foot, and mouth disease. Evid Based Complement Alternat Med. 2013;2013:504563.PubMedCentralPubMed Chen X, Wang C, Xu L, Wang W, Yang G, Tan RX, et al. A laboratory evaluation of medicinal herbs used in china for the treatment of hand, foot, and mouth disease. Evid Based Complement Alternat Med. 2013;2013:504563.PubMedCentralPubMed
37.
go back to reference Clercq ED. Highlights in Antiviral Drug Research: Antivirals at the Horizon, Med. Res. Rev., 00, No. 0, 1–34, 2012 Clercq ED. Highlights in Antiviral Drug Research: Antivirals at the Horizon, Med. Res. Rev., 00, No. 0, 1–34, 2012
38.
go back to reference Thibaut HJ, De Palma AM, Neyts J. Combating enterovirus replication: state-of-the-art on antiviral research. Biochem Pharmacol. 2012;83(2):185–92.CrossRefPubMed Thibaut HJ, De Palma AM, Neyts J. Combating enterovirus replication: state-of-the-art on antiviral research. Biochem Pharmacol. 2012;83(2):185–92.CrossRefPubMed
39.
go back to reference Lin JY, Li ML, Huang PN, Chien KY, Horng JT, Shih SR. Heterogeneous nuclear ribonuclear protein K interacts with the enterovirus 71 5’ untranslated region and participates in virus replication. J Gen Virol. 2008;89(Pt 10):2540–9.CrossRefPubMed Lin JY, Li ML, Huang PN, Chien KY, Horng JT, Shih SR. Heterogeneous nuclear ribonuclear protein K interacts with the enterovirus 71 5’ untranslated region and participates in virus replication. J Gen Virol. 2008;89(Pt 10):2540–9.CrossRefPubMed
40.
go back to reference Yi L, He Y, Chen Y, Kung HF, He ML. Potent inhibition of human enterovirus 71 replication by type I interferon subtypes. Antivir Ther. 2011;16(1):51–8.CrossRefPubMed Yi L, He Y, Chen Y, Kung HF, He ML. Potent inhibition of human enterovirus 71 replication by type I interferon subtypes. Antivir Ther. 2011;16(1):51–8.CrossRefPubMed
Metadata
Title
Formononetin inhibits enterovirus 71 replication by regulating COX- 2/PGE2 expression
Authors
Huiqiang Wang
Dajun Zhang
Miao Ge
Zhuorong Li
Jiandong Jiang
Yuhuan Li
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2015
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-015-0264-x

Other articles of this Issue 1/2015

Virology Journal 1/2015 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.