Antiviral activity of Embelia ribes Burm. f. against influenza virus in vitro

  • Md Shahadat Hossan
  • Ayesha Fatima
  • Mohammed Rahmatullah
  • Teng Jin Khoo
  • Veeranoot Nissapatorn
  • Anastasia V. Galochkina
  • Alexander V. Slita
  • Anna A. Shtro
  • Yulia Nikolaeva
  • Vladimir V. Zarubaev
  • Christophe Wiart
Original Article
  • 47 Downloads

Abstract

Viral respiratory infections are raising serious concern globally. Asian medicinal plants could be useful in improving the current treatment strategies for influenza. The present study examines the activity of five plants from Bangladesh against influenza virus. MDCK cells infected with influenza virus A/Puerto Rico/8/34 (H1N1) were treated with increasing concentrations of ethyl acetate extracts, and their cytotoxicity (CC50), virus-inhibiting activity (IC50), and selectivity index (SI) were calculated. The ethyl acetate extract of fruits of Embelia ribes Burm. f. (Myrsinaceae) had the highest antiviral activity, with an IC50 of 0.2 µg/mL and a SI of 32. Its major constituent, embelin, was further isolated and tested against the same virus. Embelin demonstrated antiviral activity, with an IC50 of 0.3 µM and an SI of 10. Time-of-addition experiments revealed that embelin was most effective when added at early stages of the viral life cycle (0-1 h postinfection). Embelin was further evaluated against a panel of influenza viruses including influenza A and B viruses that were susceptible or resistant to rimantadine and oseltamivir. Among the viruses tested, avian influenza virus A/mallard/Pennsylvania/10218/84 (H5N2) was the most susceptible to embelin (SI = 31), while A/Aichi/2/68 (H3N2) virus was the most resistant (SI = 5). In silico molecular docking showed that the binding site for embelin is located in the receptor-binding domain of the viral hemagglutinin. The results of this study provide evidence that E. ribes can be used for development of a novel alternative anti-influenza plant-based agent.

Notes

Acknowledgements

We would like to thank Mr. Rajesh Sreedharan Nair for assisting with HPLC work.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest. This research was supported by a Grant from the Malaysian Ministry of Education (FRGS/1/2014/SG01/UNIM/02/1). We acknowledge the support.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals.

Informed consent

This article does not contain any studies with human participants.

References

  1. 1.
    Dubearnes A, Julius A, Utteridge TMA (2015) A synopsis of the genus Embelia in Peninsular Malaysia and Singapore Studies in Malaysia Myrsinaceae III. Kew Bull 70:2CrossRefGoogle Scholar
  2. 2.
    Murthy S, Samhita S (2012) Chaukhamba Orientala, VaransiGoogle Scholar
  3. 3.
    Perry LM, Metzger J (1980) Medicinal plants of East and Southeast Asia: attributed properties and uses. The MIT Press, CambridgeGoogle Scholar
  4. 4.
    Aslam M (1996) Asian medicine and its practice in Britain. In Trease and Evan’s pharmacognosy, 14th edn. WB Saunders Company Ltd., LondonGoogle Scholar
  5. 5.
    Bhandari U, Ansari MN, Islam F (2008) Cardioprotective effect of aqueous extract of Embelia ribes Burm fruits against isoproterenol-induced myocardial infarction in albino rats. Indian J Exp Biol 46:35–40PubMedGoogle Scholar
  6. 6.
    Chopra RN, Nayar SL, Chopra IC (1996) Glossary of Indian medicinal plants. NISCOM, New DelhiGoogle Scholar
  7. 7.
    Haq K, Ali M, Siddiqui AW (2005) New compounds from the seeds of Embelia ribes. Pharmazie 60:69–71Google Scholar
  8. 8.
    Chitra M, Devi CS, Sukumar E (2003) Antibacterial activity of embelin. Fitoterapia 74:401–403CrossRefPubMedGoogle Scholar
  9. 9.
    Ahn KS, Sethi G, Aggarwal BB (2007) Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products. Mol Pharmacol 71:209–219CrossRefPubMedGoogle Scholar
  10. 10.
    Menon K (1919) Embelia ribes—a medicine for influenza. Indian For 45:210Google Scholar
  11. 11.
    Swartz KA, Luby JP (2007) Pandemic influenza a primer. Tex Med 103:31–34PubMedGoogle Scholar
  12. 12.
    Saxena SK, Mishra N, Saxena R, Saxena S (2009) Swine flu: influenza A/H1N1 2009: the unseen and unsaid. Future Microbiol 4:945–947CrossRefPubMedGoogle Scholar
  13. 13.
    Cox NM (2005) Pandemic influenza: overview of vaccines and antiviral drugs. Yale J Biol Med 78:321–338PubMedPubMedCentralGoogle Scholar
  14. 14.
    Arakawa T, Yamasaki H, Ikeda K, Ejima D, Naito T, Koyama AH (2009) Antiviral and virucidal activities of natural product. Curr Med Chem 16:2485–2497CrossRefPubMedGoogle Scholar
  15. 15.
    Scholtissek C, Quack G, Klenk HD, Webster RG (1998) How to overcome resistance of influenza A viruses against adamantane derivatives. Antivir Res 37:83–95CrossRefPubMedGoogle Scholar
  16. 16.
    Saladino R, Barontini M, Nencioni M, Sgarbanti R, Palamara AT (2010) Current advances in anti-influenza therapy. Curr Med Chem 17:2101–2140CrossRefPubMedGoogle Scholar
  17. 17.
    Dixit R, Khandaker G, Ilgoutz S, Rashid H, Booy R (2013) Emergence of oseltamivir resistance: control and management of Influenza before, during and after the pandemic. Infect Disord Drug Targets 13:34–45CrossRefPubMedGoogle Scholar
  18. 18.
    Kulkarni SV, Damle MC (2015) Development and validation of Stability Indicating HPLC method for estimation of Embelin in Embelia tsjeriam cottam (Vidanga). Int J Ayurvedic Med 6:243–249Google Scholar
  19. 19.
    Mosmann T (1980) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefGoogle Scholar
  20. 20.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J, Yu B, Zhang J, Bryant SH (2016) PubChem substance and compound databases. Nucleic Acids Res 44:D1202–D1213CrossRefPubMedGoogle Scholar
  22. 22.
    Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461PubMedPubMedCentralGoogle Scholar
  23. 23.
    Das K, Aramini JM, Ma LC, Krug RM, Arnold E (2010) Structures of influenza A proteins and insights into antiviral drug targets. Nat Struct Mol Biol 17:530–538CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yang J, Li M, Shen X, Liu S (2013) Influenza A virus entry inhibitors targeting the hemagglutinin. Viruses 5:352–373CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    DeLano WL (2002) Pymol: an open-source molecular graphics tool. CCP4 Newsl Protein Crystallogr 40:82–92Google Scholar
  26. 26.
    Biovia DS (2015) Discovery studio modeling environment, release, 4. Dassault Systemesc, San DiegoGoogle Scholar
  27. 27.
    Hashim NM, Rahmani M, Ee GCL, Sukari MA, Yahayu M, Oktima W, Ali AM, Go R (2012) Antiproliferative activity of xanthones isolated from Artocarpus obtusus. J Biomed Biotechnol 130627:1–9CrossRefGoogle Scholar
  28. 28.
    Ono K, Nakane H, Shimizu S, Koshimura S (1991) Inhibition of HIV-reverse transcriptase activity by asterriquinone and its analogues. Biochem Biophys Res Commun 174:56–62CrossRefPubMedGoogle Scholar
  29. 29.
    Bogdanova NS, Pershin GN, Nikolaeva IS, Grinev AN, Shvedov VI (1970) Antiviral activity of p-benzoquinone and hydroquinone derivatives. Farmakol Toksikol 33:488–496PubMedGoogle Scholar
  30. 30.
    Wagner RR (1951) Studies on the inactivation of influenza virus; comparison of the effects of p-benzoquinone and various inorganic oxidizing agents. Yale J Biol Med 23:288–298PubMedPubMedCentralGoogle Scholar
  31. 31.
    Astani A, Reichling J, Schnitzler P (2011) Screening for antiviral activities of isolated compounds from essential oils. Evid Based Complement Altern Med 2011:253643.  https://doi.org/10.1093/ecam/nep187 CrossRefGoogle Scholar
  32. 32.
    Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP, Wang R, Fang X, Guo R, Zhang M, Lippman ME (2004) Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47:2430–2440CrossRefPubMedGoogle Scholar
  33. 33.
    Heo JY, Kim HJ, Kim SM, Park KR, Park SY, Kim SW, Nam D, Jang HJ, Lee SG, Ahn KS, Kim SH (2011) Embelin suppresses STAT3 signalling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase PTEN. Cancer Lett 308:71–80CrossRefPubMedGoogle Scholar
  34. 34.
    Dai Y, Qiao L, Chan KW, Yang M, Ye J, Ma J, Zou B, Gu Q, Wang J, Pang R, Lan HY (2009) Peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of embelin on colon carcinogenesis. Cancer Res 69:4776–4783CrossRefPubMedGoogle Scholar
  35. 35.
    Chen F, Zhang G, Hong Z, Lin Z, Lei M, Huang M, Hu L (2014) Design, synthesis, and SAR of embelin analogues as the inhibitors of PAI-1 (plasminogen activator inhibitor-1). Bioorg Med Chem Lett 24:2379–2382CrossRefPubMedGoogle Scholar
  36. 36.
    Radhakrishnan N, Gnanamani A (2014) 2, 5-dihydroxy-3-undecyl-1, 4-benzoquinone (Embelin)-A second solid gold of India—a review. Int J Pharm Pharmacol Sci 6:23–30Google Scholar
  37. 37.
    Omura S (ed) (1992) The search for bioactive compounds from microorganisms. Springer, New York. ISBN 978-1-4612-4412-7Google Scholar
  38. 38.
    Naik SR, Niture NT, Ansari AA, Shah PD (2013) Anti-diabetic activity of embelin: involvement of cellular inflammatory mediators, oxidative stress and other biomarkers. Phytomedicine 20:797–804CrossRefPubMedGoogle Scholar
  39. 39.
    Johri RK, Dhar SK, Pahwa GS, Sharma SC, Kaul JL, Zutshi U (1990) Toxicity studies with potassium embelate, a new analgesic compound. Indian J Exp Biol 28:213–217PubMedGoogle Scholar
  40. 40.
    Chiang LC, Ng LT, Cheng PW, Chiang W, Lin CC (2005) Antiviral activities of extracts and selected pure constituents of Ocimum basilicum. Clin Exp Pharmacol Physiol 32:811–816CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Md Shahadat Hossan
    • 1
  • Ayesha Fatima
    • 2
  • Mohammed Rahmatullah
    • 3
  • Teng Jin Khoo
    • 1
  • Veeranoot Nissapatorn
    • 4
  • Anastasia V. Galochkina
    • 5
  • Alexander V. Slita
    • 5
  • Anna A. Shtro
    • 6
  • Yulia Nikolaeva
    • 6
  • Vladimir V. Zarubaev
    • 5
  • Christophe Wiart
    • 1
  1. 1.School of PharmacyUniversity of NottinghamSemenyihMalaysia
  2. 2.Faculty of PharmacyQuest International UniversityIpohMalaysia
  3. 3.Department of Pharmacy, Faculty of Life ScienceUniversity of Development Alternative (UODA)DhakaBangladesh
  4. 4.School of Allied Health SciencesWalailak UniversityNakhon Si ThammaratThailand
  5. 5.Pasteur Institute of Epidemiology and MicrobiologySt. PetersburgRussia
  6. 6.Influenza Research InstituteSt. PetersburgRussia

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