Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Inhibition of Herpes Simplex Viruses, Types 1 and 2, by Ginsenoside 20(S)-Rg3

  • Wright, Stephen M. (Department of Biology and the Tennessee Center for Botanical Medicine Research, Middle Tennessee State University) ;
  • Altman, Elliot (Department of Biology and the Tennessee Center for Botanical Medicine Research, Middle Tennessee State University)
  • Received : 2019.08.26
  • Accepted : 2019.11.02
  • Published : 2020.01.28
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Abstract

Infections by herpes simplex viruses have an immense impact on humans, ranging from self-limiting, benign illness to serious, life-threatening diseases. While nucleoside analog drugs are available, resistance has been increasing and currently no vaccine exists. Ginsenosides derived from Panax ginseng have been documented to inhibit several viruses and bolster immune defenses. This study evaluated 12 of the most relevant ginsenosides from P. ginseng for toxicities and inhibition of herpes simplex viruses types 1 and 2 in Vero cells. The effects of test compounds and virus infection were determined using a PrestoBlue cell viability assay. Time course studies were also conducted to better understand at what points the virus life cycle was affected. Non-toxic concentrations of the ginsenosides were determined and ranged from 12.5 μM to greater than 100 μM. Ginsenoside 20(S)-Rg3 demonstrated the greatest inhibitory effect and was active against both HSV-1 and HSV-2 with an IC50 of approximately 35 μM. The most dramatic inhibition-over 100% compared to controls-occurred when the virus was exposed to 20(S)-Rg3 for 4 h prior to being added to cells. 20(S)-Rg3 holds promise as a potential chemotherapeutic agent against herpes simplex viruses and, when used together with valacyclovir, may prevent increased resistance to drugs.

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References

  1. Faral-Tello P, Mirazo S, Dutra C, Perez A, Geis-Asteggiante L, Frabasile S, et al. 2012. Cytotoxic, virucidal, and antiviral activity of South American plant and algae extracts. Sci. World J. 2012: 174837.
  2. Bookstaver PB, Mohorn PL, Shah A, Tesh LD, Quidley AM, Kothari R, et al. 2017. Management of viral central nervous system infections: a primer for clinicians. J. Cent. Nerv. Syst. Dis. 9: 1-12.
  3. Hogestyn JM, Mock DJ, Mayer-Proschel M. 2018. Contributions of neurotropic human herpesviruses herpes simplex 1 and human herpesvirus 6 to neurodegenerative disease pathology. Neural. Regen. Res. 13: 211-221. https://doi.org/10.4103/1673-5374.226380
  4. Koelle DM. 2006. Vaccines for herpes simplex virus infections. Curr. Opin. Investig. Drugs 7: 136-141.
  5. Akhtar J, Shukla D. 2009. Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry. FEBS J. 276: 7228-7236. https://doi.org/10.1111/j.1742-4658.2009.07402.x
  6. Sedy JR, Spear PG, Ware CF. 2008. Cross-regulation between herpesviruses and the TNF superfamily members. Nat. Rev. Immunol. 8: 861-873. https://doi.org/10.1038/nri2434
  7. Sandri-Goldin RM, Goldin AL, Holland LE, Glorioso JC, Levine M. 1983. Expression of herpes simplex virus beta and gamma genes integrated in mammalian cells and their induction by an alpha gene product. Mol. Cell Biol. 3: 2028-2044. https://doi.org/10.1128/MCB.3.11.2028
  8. Kuo YC, Lin LC, Tsai WJ, Chou CJ, Kung SH, Ho YH. 2002. Samarangenin B from Limonium sinense suppresses herpes simplex virus type 1 replication in Vero cells by regulation of viral macromolecular synthesis. Antimicrob. Agents Chemother. 46: 2854-2864. https://doi.org/10.1128/AAC.46.9.2854-2864.2002
  9. Piret J, Boivin G. 2011. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrob. Agents Chemother. 55: 459-472. https://doi.org/10.1128/AAC.00615-10
  10. Chattopadhya D, Chawla-Sarkar M, Chatterjee T, Dey RS, Bag P, Chakraborti S, et al. 2009. Recent advancements for the evaluation of anti-viral activities of natural products. New Biotechnol. 25: 347-368. https://doi.org/10.1016/j.nbt.2009.03.007
  11. Coleman CI, Hebert JH, Reddy P. 2003. The effects of Panax ginseng on quality of life. J. Clin. Pharm. Ther. 28: 5-15. https://doi.org/10.1046/j.1365-2710.2003.00467.x
  12. Dragos D, Gilca M, Gaman L, Vlad A, Iosif L, Stoian I, et al. 2017. Phytomedicine in joint disorders. Nutrients 9: 1-18. https://doi.org/10.3390/nu9010001
  13. Chen G, Li H, Zhao Y, Cai E, Gao Y, Liu S, et al. 2017. Saponins from stems and leaves of Panex ginseng prevent obesity via regulating thermogenesis, lipogenesis and lipolysis in high-fat diet-induced obese C57BL/6 mice. Food Chem. Toxicol. 106: 393-403. https://doi.org/10.1016/j.fct.2017.06.012
  14. Kim SJ, Jang JY, Kim EJ, Cho EK, Ahn DG, Kim C, et al. 2017. Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrian dynamics and inhibits virus propagation. Hepatology 66: 758-771. https://doi.org/10.1002/hep.29177
  15. Im K, Kim J, Min H. 2016. Ginseng, the natural effectual antiviral: protective effects of Korean red ginseng against viral infection. J. Ginseng Res. 40: 309-314. https://doi.org/10.1016/j.jgr.2015.09.002
  16. Xin-Mei C, Chang-Zheng Z, Xiao-Ping Z. New progress on the pharmacological and pharmacokinetical study of ginsenoside Rg3. J. Drug Metabol. Toxicol. 3: 114.
  17. Shin B-Y, Kwon SW, Park JH. 2015. Chemical diversity of ginseng saponins from Panax ginseng. J. Ginseng Res. 39: 287-298. https://doi.org/10.1016/j.jgr.2014.12.005
  18. Peng M, Yi YX, Zhang T, Ding Y, Le J. 2018. Stereoisomers of saponins in Panax notoginseng (Sanqi): a review. Front. Pharmacol. 9: 188. https://doi.org/10.3389/fphar.2018.00188
  19. Sun S, Qi L-W, Du G-J, Mehendale SR, Wang C-Z, Yuan CS. 2011. Red notoginsneng: higher ginsenoside content and stronger anticancer potential than Asian and American ginseng. Food Chem. 125: 1299-1305. https://doi.org/10.1016/j.foodchem.2010.10.049
  20. Ha J, Shim Y-S, Seo D, Kim K, Ito M, Nakagawa H. 2013. Determination of 22 ginsenosides in ginseng products using ultra-high-performance liquid chromatography. J. Chromatogr. Sci. 51: 355-360. https://doi.org/10.1093/chromsci/bms148
  21. Han S, Lim TG, Kim JE, Yang H, Oh DK, Yoon Park JH, et al. 2017. The ginsenoside derivative 20(S)-protopanaxadiol inhibits solar ultraviolet light-induced matrix metalloproteinase-1 expression. J. Cell Biochem. 118: 3756-3764. https://doi.org/10.1002/jcb.26023
  22. Bak DH, Kim HD, Kim YO, Park CG, Han SY, Kim JJ. 2016. Neuroprotective effects of 20(S)-protopanaxadiol against glutamate-induced mitochondrial dysfunction in PC12 cells. Int. J. Mol. Med. 37: 378-386. https://doi.org/10.3892/ijmm.2015.2440
  23. Liang YY, Wang B, Qian DM, Li L, Wang ZH, Hu M, et al. 2012. Inhibitory effects of ginsenoside Rb1 on apoptosis caused by HSV-1 in human glioma cells. Virol. Sin. 27: 19 -25. https://doi.org/10.1007/s12250-012-3220-6
  24. Chen W, Qiu Y. 2015. Ginsenoside Rh2 targets EGFR by upregulation of miR-491 to enhance anti-tumor activity in hepatitis B virus-related hepatocellular carcinoma. Cell. Biochem. Biophys. 72: 325-331. https://doi.org/10.1007/s12013-014-0456-9
  25. Song JH, Choi HJ, Song HH, Hong EH, Lee BR, Oh SR, et al. 2014. Antiviral activity of ginsenosides against coxsackievirus B3, enterovirus 71, and human rhinovirus 3. J. Ginseng Res. 38: 173-179. https://doi.org/10.1016/j.jgr.2014.04.003
  26. Song X, Chen J, Sakwiwatkul K, Li R, Hu S. 2010. Enhancement of immune responses to influenza vaccine (H3N2) by ginsenoside Re. Int. Immunopharmacol. 10: 351-356. https://doi.org/10.1016/j.intimp.2009.12.009
  27. Kwon HY, Kim EH, Kim SW, Kim SN, Park JD, Rhee DK. 2008. Selective toxicity of ginsenoside Rg3 on multidrug resistant cells by membrane fluidity modulation. Arch. Pharm. Res. 31: 171-177. https://doi.org/10.1007/s12272-001-1137-y
  28. Hien TT, Kim ND, Kim HS, Kang KW. 2010. Ginsenoside Rg3 inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules in human endothelial cells. Pharmazie 65: 699-701.
  29. Yang H, Oh KH, Kim HJ, Cho YH, Yoo YC. 2018. Ginsenoside-Rb2 and 20(S)-ginsenoside-Rg3 from Korean red ginseng prevent rotavirus infection in newborn mice. J. Microbiol. Biotechnol. 28: 391-396. https://doi.org/10.4014/jmb.1801.01006
  30. Joo EJ, Chun J, Ha YW, Ko HJ, Xu MY, Kim YS. 2015. Novel roles of ginsenoside Rg3 in apoptosis through downregulation of epidermal growth factor receptor. Chem. Biol. Interact. 233: 25-34. https://doi.org/10.1016/j.cbi.2015.03.016
  31. Kang LJ, Choi YJ, Lee SG. 2013. Stimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signaling by ginsenoside Rg3 attenuates hepatitis B virus replication. Int. J. Biochem. Cell Biol. 45: 2612-2621. https://doi.org/10.1016/j.biocel.2013.08.016
  32. Kang S, Song MJ, Min H. 2018. Antiviral activity of ginsenoside Rg3 isomers against gammaherpesvirus through inhibition of p38- and JNK-associated pathways. J. Functional Foods 40: 219-228. https://doi.org/10.1016/j.jff.2017.11.011
  33. Cho A, Roh YS, Uyangaa E, Park S, Kim JW, Lim KH, et al. 2013. Protective effects of red ginseng extract against vaginal herpes simplex virus infection. J. Ginseng Res. 37: 210-218. https://doi.org/10.5142/jgr.2013.37.210
  34. O'Donnell CD, Shukla D. 2008. The importance of heparin sulfate in herpesvirus infection. Virol. Sin. 23: 383-393. https://doi.org/10.1007/s12250-008-2992-1
  35. Uchida H, Chan J, Goins WF, Grandi P, Kumagai I, Cohen JB, et al. 2010. A double mutation in glycoprotein gB compensates for ineffective gD-dependent initiation of herpes simplex virus type 1 infection. J. Virol. 84: 12200-12209. https://doi.org/10.1128/JVI.01633-10

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