Salvatore Chirumbolo- Department of Medicine-Unit of Geriatry, University Laboratories for Medical Research, University of Verona, Verona, Italy
A commentary on
The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb
by Wang, L., Yang, R., Yuan, B., Liu, Y., and Liu, C. (2015). Acta Pharm. Sin. B. 5, 310–315. doi: 10.1016/j.apsb.2015.05.005
A recent paper by Wang et al. about the anti-microbial and anti-viral properties of natural products should raise the concern how much organic acids, polyphenols, and terpenoids contained in herbal raw extracts, are powerful against microbial or viral pathogens-mediate infections (Wang et al., 2015). Usually, in the Traditional Chinese Medicine, licorice is known as Gan-Cao, coming from extracts of dried roots of Glycyrrhiza uralensis, Glycyrrhiza glabra, and Glycyrrhiza inflata, of which chemical analyses were performed (Zhang and Ye, 2009; Qiao et al., 2015). This paper gives me the opportunity to address some hot issue.
According to these authors, 18-β-glycyrrhetinic acid and glycyrrhizin possess an anti-viral potential, assessing previous evidence about the antiviral properties of Glycyrrhiza species (Fiore et al., 2008; Sabouri Ghannad et al., 2014). However, likewise any plant raw extract, the biological activity of a complex mixture of organic molecules is a non-predictable result of both bimodal and pleiotropic potential possessed by the many phenolic or terpenoid derivatives present in the extract (Wink, 2015). Although the authors focused on only six compounds among 20 triterpenoids and nearly 300 flavonoids to show evidence about their anti-viral and anti-microbial activity, questions remain if licorice is really effective either as food or herbal medicine or in the form of isolated purified molecules as active principles. This is the current concern about most of existing natural products.
Molecular interactions between 18-β-glycyrrhetinic acid and glycyrrhizin modulates the inhibition of several drug-metabolizing enzymes and efflux transporters (Feng et al., 2015), adsorption of licorice active triterpenes depends on sugars and bioavailability is better for licorice than purified glycyrrhizin (Hou et al., 2005a,b). Flavonoids in licorice act as most of flavonoids present in other plant-derived extracts, i.e., inhibiting or promoting apoptosis, switching off or modulating survival signaling pathways, increasing cytotoxicity in cancer cells. Liquiritin, isoliquiritin, and isoliquirigenin significantly increase cytotoxicity in non-small lung cancer cell line A459, up-regulate p53 and p21, decrease the expression of PCNA, PARP, Bcl-2, p-Akt, p-GSK-3β, pro-caspases (8 and 9), and downregulate the apoptotic pathways, hence encompassing a wide space of target activity (Zhou and Ho, 2014). Furthermore, the “Janus-like” behavior of many compounds contained in Glycyrrhiza extracts contributes in hampering a full comprehension of their beneficial effects. Licocalchone A downregulates the inflammation-induced P450 1B1 while isoliquiritigenin exerts an opposite effect, then differentially influencing the role of estrogens in chronic inflammation and in carcinogenesis (Dunlap et al., 2015). The same glycyrrhizic acid has been associated to a panoply of different beneficial effects (Ming and Yin, 2013). Wang and coworkers showed in theit thorough paper, how many anti-inflammatory properties against microbes and viruses have been attributed to licorice, though clinical trials are quite scanty.
The authors did not address either clinical trial about licorice activity against microbes.
Glycyrrhiza-derived purified substances, such as glabridin, are recently addressed as promising tools to prevent bacterial infections and against parasites (Cheema et al., 2014; Singh et al., 2015). Glabridin is an isoflavane, such as equol (4,7-isoflavandiol), which is a metabolite from daidzein, a well-known soy-derived isoflavonoid likewise genistein. These components are potent phytoestrogens, e.g., liquiritigenin and are able to behave as like as estradiol with estrogen receptors ERα and ERβ (Gong et al., 2014). Wang et al. described the role exerted by some triterpenes and flavonoids, such as chalcones, in inducing an anti-microbial or anti-viral, more generally an anti-inflammatory condition to prevent the onset of infections. Yet, these molecules may promote the immune response just acting as natural phytoestrogens (Kovats, 2015). A suggestion about the possible anti-microbial role of licorice phytoestrogens may come from the role exerted by estrogens and estrogen receptors on dendritic cells (Kovats, 2012). The hormone 17β-estradiol, to which plant phytoestrogens are functionally similar, regulates GM-CSF- or Flt3 ligand-driven dendritic cell (DC) development via the signaling of ERα in myeloid progenitors (Seillet et al., 2013), and moreover it regulates DCs function in immune reactions (Douin-Echinard et al., 2008). Actually, both 18-β-glycyrrhetinic acid and its alpha isomer, appears to promote DCs maturation and activity (Bordbar et al., 2014), so playing a fundamental role in immune response to microbes (Wang et al., 2015) but controversial results would suggest that the role of these compounds as phytoestrogens is not finely regulated as endogenous hormones and deserves further investigation (Kim et al., 2013). For example, despite its phytoestrogen-like property, glabridin seems to inhibit rather than promote DCs maturation and the expression of CD40, CD80, CD86, MHC-I, and MHC-II (Kim et al., 2010), though it is considered a phyto-SERM (Simmler et al., 2013).
Moreover, the role exerted by licorice in blood pressure may influence immunity and DCs functionality, as the equilibrium between the inflammatory response induced by T cell and T cell suppressor responses is critical for the regulation of blood pressure levels (Rodríguez-Iturbe et al., 2014; Ottenbacher and Blehm, 2015), although this speculative hypothesis merits to be further highlighted. Yet, despite the great deal of evidence reported by Wang et al. the presumptive anti-microbial potential of licorice overshadows even bewildering and unsuspected adverse effects (Yasue et al., 2007; van Beers et al., 2011; Yoshino et al., 2014).
This evidence supports the idea that the introduction of a whatsoever can be considered as a beneficial phytochemical from raw plants in the highly complex network of signaling interactions between cells and organs, even considering the different individual ability coming from genetics and phenotypic polymorphism or from epigenetics and lifestyle, cannot allow physicians, as well as researchers, to foresee the “real” effect of that substance in the whole organism. An interesting hypothesis is that phytochemicals, as toxic substances, produced by plants to protect themselves are beneficial only in a restricted range of doses. In this perspective, there is interesting evidence about the role of low doses of phytochemicals, particularly flavonoids, on stress response and immune reactions in vitro, yet surely clinical evidence is needed.
Author Contributions
The author confirms being the sole contributor of this work and approved it for publication.
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Bordbar, N., Karimi, M. H., and Amirghofran, Z. (2014). Phenotypic and functional maturation of murine dendritic cells induced by 18 alpha- and beta-glycyrrhetinic acid. Immunopharmacol. Immunotoxicol. 36, 52–60. doi: 10.3109/08923973.2013.864670
Cheema, H. S., Prakash, O., Pal, A., Khan, F., Bawankule, D. U., and Darokar, M. P. (2014). Glabridin induces oxidative stress mediated apoptosis like cell death of malaria parasite Plasmodium falciparum. Parasitol Int. 63, 349–358. doi: 10.1016/j.parint.2013.12.005
Douin-Echinard, V., Laffont, S., Seillet, C., Delpy, L., Krust, A., Chambon, P., et al. (2008). Estrogen receptor α, but not β, is required for optimal dendritic cell differentiation and CD40-induced cytokine production. J. Immunol. 180, 3661–3669. doi: 10.4049/jimmunol.180.6.3661
Dunlap, T. L., Wang, S., Simmler, C., Chen, S. N., Pauli, G. F., Dietz, B. M., et al. (2015). Differential effects of glycyrrhiza species on genotoxic estrogen metabolism:licochalcone a downregulates P450 1B1, whereas isoliquiritigenin stimulates it. Chem. Res Toxicol. 28, 1584–1594. doi: 10.1021/acs.chemrestox.5b00157
Feng, X., Ding, L., and Qiu, F. (2015). Potential drug interactions associated with glycyrrhizin and glycyrrhetinic acid. Drug Metab. Rev. 47, 229–238. doi: 10.3109/03602532.2015.1029634
Fiore, C., Eisenhut, M., Krausse, R., Ragazzi, E., Pellati, D., Armanini, D., et al. (2008). Antiviral effects of Glycyrrhiza species. Phytother. Res. 22, 141–148. doi: 10.1002/ptr.2295
Gong, P., Madak-Erdogan, Z., Li, J., Cheng, J., Greenlief, C. M., Helferich, W., et al. (2014). Transcriptomic analysis identifies gene networks regulated by estrogen receptor α (ERα) and ERβ that control distinct effects of different botanical estrogens. Nucleic Recept. Signal. 12:e001. doi: 10.1621/nrs.12001
Hou, Y. C., Ching, H., Chao, P. D., Tsai, S. Y., Wen, K. C., Hsieh, P. H., et al. (2005b). Effects of glucose, fructose and 5-hydroxymethyl-2-furaldehyde on the presystemic metabolism and absorption of glycyrrhizin in rabbits. J. Pharm. Pharmacol. 57, 247–251. doi: 10.1211/0022357055281
Hou, Y. C., Hsiu, S. L., Ching, H., Lin, Y. T., Tsai, S. Y., Wen, K. C., et al. (2005a). Profound difference of metabolic pharmacokinetics between pure glycyrrhizin and glycyrrhizin in licorice decoction. Life Sci. 76, 1167–1176. doi: 10.1016/j.lfs.2004.10.020
Kim, J. Y., Kang, J. S., Kim, H. M., Ryu, H. S., Kim, H. S., Lee, H. K., et al. (2010). Inhibition of bone marrow-derived dendritic cell maturation by glabridin. Int. Immunopharmacol. 10, 1185–1193. doi: 10.1016/j.intimp.2010.06.025
Kim, M. E., Kim, H. K., Kim, D. H., Yoon, J. H., and Lee, J. S. (2013). 18β-Glycyrrhetinic acid from licorice root impairs dendritic cells maturation and Th1 immune responses. Immunopharmacol. Immunotoxicol. 35, 329–335. doi: 10.3109/08923973.2013.768636
Kovats, S. (2012). Estrogen receptors regulate an inflammatory pathway of dendritic cell differentiation: mechanisms and implications for immunity. Horm. Behav. 62, 254–262. doi: 10.1016/j.yhbeh.2012.04.011
Kovats, S. (2015). Estrogen receptors regulate innate immune cells and signaling pathways. Cell. Immunol. 294, 63–69. doi: 10.1016/j.cellimm.2015.01.018
Ming, L. J., and Yin, A. C. (2013). Therapeutic effects of glycyrrhizic acid. Nat. Prod. Commun. 8, 415–418.
Ottenbacher, R., and Blehm, J. (2015). An unusual case of licorice-induced hypertensive crisis. S. D. Med. 68, 346–347.
Qiao, X., Song, W., Ji, S., Wang, Q., Guo, D. A., and Ye, M. (2015). Separation and characterization of phenolic compounds and triterpenoid saponins in licorice (Glycyrrhiza uralensis) using mobile phase-dependent reversed-phase × reversed-phase comprehensive two-dimensional liquid chromatography coupled with mass spectrometry. J. Chromatogr. A 1402, 36–45. doi: 10.1016/j.chroma.2015.05.006
Rodríguez-Iturbe, B., Pons, H., Quiroz, Y., and Johnson, R. J. (2014). The immunological basis of hypertension. Am. J. Hypertens. 27, 1327–1337. doi: 10.1093/ajh/hpu142
Sabouri Ghannad, M., Mohammadi, A., Safiallahy, S., Faradmal, J., Azizi, M., and Ahmadvand, Z. (2014). The effect of aqueous extract of Glycyrrhiza glabra on Herpes simplex virus 1. Jundishapur J. Microbiol. 7:e11616. doi: 10.5812/jjm.11616
Seillet, C., Rouquié, N., Foulon, E., Douin-Echinard, V., Krust, A., Chambon, P., et al. (2013). Estradiol promotes functional responses in inflammatory and steady-state dendritic cells through differential requirement for activation function-1 of estrogen receptor α. J. Immunol. 190, 5459–5470. doi: 10.4049/jimmunol.1203312
Simmler, C., Pauli, G. F., and Chen, S. N. (2013). Phytochemistry and biological properties of glabridin. Fitoterapia 90, 160–184. doi: 10.1016/j.fitote.2013.07.003
Singh, V., Pal, A., and Darokar, M. P. (2015). A polyphenolic flavonoid glabridin: oxidative stress response in multidrug-resistant Staphylococcus aureus. Free Radic. Biol. Med. 87, 48–57. doi: 10.1016/j.freeradbiomed.2015.06.016
van Beers, E. J., Stam, J., and van den Bergh, W. M. (2011). Licorice consumption as a cause of posterior reversible encephalopathy syndrome: a case report. Crit. Care 15:R64. doi: 10.1186/cc10040
Wang, L., Yang, R., Yuan, B., Liu, Y., and Liu, C. (2015). The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Acta Pharm. Sin. B 5, 310–315. doi: 10.1016/j.apsb.2015.05.005
Wink (2015). Modes of action of herbal medicines and plant secondary metabolites. Medicines 2, 251–286. doi: 10.3390/medicines2030251
Yasue, H., Itoh, T., Mizuno, Y., and Harada, E. (2007). Severe hypokalemia, rhabdomyolysis, muscle paralysis, and respiratory impairment in a hypertensive patient taking herbal medicines containing licorice. Intern. Med. 46, 575–578. doi: 10.2169/internalmedicine.46.6316
Yoshino, T., Yanagawa, T., and Watanabe, K. (2014). Risk factors for pseudoaldosteronism with rhabdomyolysis caused by consumption of drugs containing licorice and differences between incidence of these conditions in Japan and other countries: case report and literature review. J. Altern. Complement. Med. 20, 516–520. doi: 10.1089/acm.2013.0454
Zhang, Q., and Ye, M. (2009). Chemical analysis of the Chinese herbal medicine Gan-Cao (licorice). J. Chromatogr. A 1216, 1954–1969. doi: 10.1016/j.chroma.2008.07.072
Keywords: licorice, immune system, dendritic cells, flavonoids, terpenoids
Citation: Chirumbolo S (2016) Commentary: The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. Front. Microbiol. 7:531. doi: 10.3389/fmicb.2016.00531
Received: 20 November 2015; Accepted: 31 March 2016;
Published: 18 April 2016.
Edited by:
Luis Cláudio Nascimento Da Silva, CEUMA University (University Centre of Maranhão), BrazilReviewed by:
Michael Wink, Heidelberg University, GermanyFilomena Nazzaro, National Research Council, Italy
Copyright © 2016 Chirumbolo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Salvatore Chirumbolo, salvatore.chirumbolo@univr.it