key: cord-0689514-r0vdc02v authors: Gomaa, Adel A.; Abdel-Wadood, Yasmin A. title: The potential of glycyrrhizin and licorice extract in combating COVID-19 and associated conditions date: 2021-02-17 journal: Phytomedicine Plus : International journal of phytotherapy and phytopharmacology DOI: 10.1016/j.phyplu.2021.100043 sha: 2d35de79ef1b028bbe7930ef6d1f3f15efb11094 doc_id: 689514 cord_uid: r0vdc02v Background Several recent studies have stated that glycyrrhizin and licorice extract are present in most traditional Chinese medicine formulas used against SARS-CoV-2 in China. Significant data are showing that glycyrrhizin and licorice extract have multiple beneficial activities in combating most features of SARS-CoV-2 Purpose The aim of current review was to highlight recent progresses in research that showed the evidence of the potential use of glycyrrhizin and licorice extract against COVID-19. Methodology We have reviewed the information published from 1979 to October 2020. These studies demonstrated the effects , use and safety of glycyrrhizin and icorice extract against viral infections,bacterial infections, inflammatory disorders of lung ( in vitro and in vivo). These studies were collated through online electronic databases research (Academic libraries as PubMed, Scopus, Web of Science and Egyptian Knowledge Bank). Results Pooled effect size of articles provides information about the rationale for using glycyrrhizin and licorice extract to treat COVID-19. Fifty studies demonstrate antiviral activity of glycyrrhizin and licorice extract. The most frequent mechanism of the antiviral activity is due to disrupting viral uptake into the host cells and disrupting the interaction between receptor- binding domain (RBD) of SARS-COV2 and ACE2 in recent articles. Fifty studies indicate that glycyrrhizin and licorice extract have significant antioxidant, anti-inflammatory and immunomodulatory effects. Twenty five studies provide evidence for the protective effect of glycyrrhizin and licorice extract against inflammation-induced acute lung injury and cardiovascular disorders. Conclusion The current study showed several evidence regarding the beneficial effects of glycyrrhizin and licorice extract in combating COVID-19. More randomized clinical trials are needed to obtain a precise conclusion. Introduction prepare licorice roots extracts (Tian et al., 2008) . Licorice extract or its constituents 150 suppress many RNA and DNA viruses (Fiore et al., 2008; Batiha et al., 2020 ) . 151 Moreover, it has been shown that a small dose of licorice extract has anti-aging 152 activity (Reigada et al., 2020) ,therefore , it can eliminate the accumulation of acute lung injury prevention, cardioprotective and hepatoprotective activities (Wang 188 et al., 2020; Editorial: Nat Plants., 2020) . We will discuss and evaluate the different 189 effects of glycyrrhizin and licorice extract that can be used to combat and neutralize any tissue destructive effects of the virus. Antiviral effect of glycyrrhizin and licorice extract 192 Several review articles concluded that the antiviral activity of licorice extract and 193 glycyrrhizin has been reported against various viruses including SARS-CoV and 194 SARS-CoV2 Pastorino et al 2018; Sun et al.,2019; Bailly et 195 al.,2020) . Licorice extract has been documented to inhibit the growth of viruses and 196 exhibit potent inhibitory activity against virus entry. In past years, Pompei et al. 197 (1979) published the first study demonstrating the efficacy of licorice extract against than other ingredients of licorice (Srivastava et al., 2020) . 215 The active ingredients of licorice extract that have antiviral activity include certain 216 triterpenoids, flavonoids, and oleanane-type triterpene saponins (Wei et al., 2014) . Glycyrrhizin, glycyrrhetinic acid, and its derivatives are the main triterpenoid active 218 components of licorice extract. These compounds have broad-spectrum antiviral 219 activity against many RNA and DNA viruses such as SARS coronavirus, herpes 220 virus, HIV, hepatitis virus, influenza viruses, cytomegaloviruses, and respiratory 221 syncytial virus (Pu et al., 2013; Pastorino et al., 2018; Batiha et al., 222 2020) (Table 1&2 ). Different studies have suggested that two triterpenoids of licorice 223 are mainly responsible for the antiviral activity reported: glycyrrhizin and 18β-224 glycyrrhetinic acid Pastorino et al., 2018) . Glycyrrhizin 225 suppresses many RNA and DNA viruses (Baltina et al., 2009 (activating protein I and nuclear factor-kB) (Baltina et al., 2009) . Glycyrrhizin was found to be effective against viral hepatitis. It prevents the early 231 stage of HCV-infection through affecting viral attachment and penetration. Glycyrrhizin is used clinically in the therapy of chronic viral hepatitis B in Japan and China for about 40 years (Sato et al., 1996; Sun et al., 2019 ). An anti-HBV 234 mechanism of glycyrrhizin is through affecting the hepatitis B surface antigen 235 (HBsAg). It reduced transport to the membrane and sialylation of the hepatitis B 236 virus surface antigen (Sun et al., 2019) . Glycyrrhizin has been used also, by I .V. has broad spectrum anti-coronavirus . Certain derivatives of the glycyrrhizic acid (glycyrrhizin) have been shown to have a 275 tenfold increase in the antiviral activity (Xiao et al., 2018) . The anti-SARS-CoV 276 activity of glycyrrhizic acid (glycyrrhizin) was shown to be increased up to 70-fold by 277 conjugation of glycyrrhizin with an amide or two amino acid residues, however, the 278 cytotoxicity also increased resulting in a decrease in the selectivity index (Hoever et 279 al., 2005) . Recently, it has been observed that glycyrrhizic acid derivatives were 280 observed as Dengue virus inhibitors (Baltina et al., 2019) . More recently, Tong et 281 al., (2020) observed that glycyrrhizic-Acid-Based Carbon Dots (Gly-CDs), , K.H., Ahn, S., Won, R., et.al., 2020. Michaelis, M., Geiler, J., Naczk, P., Sithisarn, P., Leutz, A., Doerr, H.W., et al., 2011. 963 Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and Glycyrrhizic Acid and its derivatives Table 3 . Protective effect of glycyrrhizin and licorice extract against acute lung injury 1196 that may occur due to COVID-19 or others in articles published from 2011 to 2020. 1197 Active substance used Liquorice 999 (Glycyrrhiza glabra): A phytochemical and pharmacological review Glycyrrhizic acid 1002 inhibits virus growth and inactivates virus particles Antiviral activity 1004 of glycyrrhizic acid Glycyrrhizic acid ameliorates LPS-induced 1008 Antioxidant and Antiaging Effects of Licorice on the Caenorhabditis elegans 1012 Liquorice Extract in Patients with Bronchial Asthma: A Randomized Controlled Trial Therapeutic basis of glycyrrhizin in 1018 chronic hepatitis B Antibacterial activity of Glycyrrhiza glabra against oral pathogens: an in 1021 vitro study Glycyrrhiza glabra and Its Major Constituent Glycyrrhizin on Inflammation-1024 Glycyrrhetinic acid alleviates hepatic 1030 inflammation injury in viral hepatitis disease via a HMGB1-TLR4 signaling pathway Licorice Root Associated With Intracranial 1033 Enhancement of interferon-gamma 1036 production in glycyrrhizin-treated human peripheral lymphocytes in response to 1037 concanavalin A and to surface antigen of hepatitis B virus An Evaluation of 1040 Triterpenoids manipulate 1043 a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral 1044 envelopes antiviral triterpenoid saponins from 1047 the roots of Glycyrrhiza uralensis Antiviral and immune stimulant 1049 activities of glycyrrhizin against duck hepatitis virus Molecular Docking and ADMET Study of 1052 Bioactive Compounds of Glycyrrhiza glabra Against Main Protease of SARS Epub ahead of print Antibacterial compounds of 1059 licorice against upper airway respiratory tract pathogens AKI by suppression of inflammation involving NF-κB pathway isoliquiritigenin, an aldose reductase inhibitor in licorice Extraction of glycyrrhizic acid and glabridin 1068 from licorice Based Carbon Dots with High Antiviral Activity by Multisite Inhibition Mechanisms Glycyrrhiza glabra (Licorice) root 1073 extract attenuates doxorubicin-induced cardiotoxicity via alleviating oxidative stress 1074 and stabilising the cardiac health in H9c2 cardiomyocytes In-vitro Anti-inflammatory activity of Liquorice (Glycyrrhiza glabra) using 1078 Estimation of total flavonoid, phenolic content and free radical scavenging potential of Glycyrrhiza glabra root extract Evaluation of antioxidant and anti-1084 atherogenic properties of Glycyrrhiza glabra root using in vitro models Khopade, A. Glycyrrhiza glabra Linn-Klitaka: A review Wuhan: An analysis based on decade-long structural studies 1090 of SARS Chinese Materia Medica: Licorice. Evid Based Complement Alternat Med Observing Anti-inflammatory and Anti-1095 nociceptive Activities of Glycyrrhizin Through Regulating COX-2 and Pro-1096 The antiviral and antimicrobial 1099 activities of licorice, a widely-used Chinese herb of oleanane-type triterpene saponins from the roots of Glycyrrhiza glabra Herbal Tea for the Management of 1104 Pharyngitis: Inhibition of Streptococcus pyogenes Growth and Biofilm Formation by 1105 Glycyrrhizin 1107 inhibits influenza A virus uptake into the cell Antibacterial Effect and Mode of Action of 1109 Flavonoids From Licorice Against Methicillin-Resistant Staphylococcus aureus antiviral activity and mechanism study of pentacyclic triterpenoids and their 1113 derivatives Isoliquiritigenin alleviated the Ang II-1115 induced hypertensive renal injury through suppressing inflammation cytokines and 1116 oxidative stress-induced apoptosis via Nrf2 and NF-κB pathways Glycyrrhizic acid ameliorates 1119 myocardial ischemic injury by the regulation of inflammation and oxidative state High 1122 expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa Glycyrrhizin Attenuates Salmonella enterica 1125 Serovar Typhimurium Infection: New Insights Into Its Protective Mechanism The anti-inflammatory 1128 activity of licorice, a widely used Chinese herb Study on in Vitro Anti-1131 Inflammatory Activity of Total Flavonoids From Glycyrrhizae Radix Et Rhizoma and 1132 the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): A 1135 Chemical Profile and Anti-inflammatory 1138 Activity of Total Flavonoids from Glycyrrhiza Uralensis Fisch pentacyclic triterpenoids as potential entry inhibitors of influenza viruses Glycyrrhizic acid exerts inhibitory activity against 1144 the spike protein of SARS-CoV-2 Multi-pathway integrated adjustment 1147 mechanism of licorice flavonoids presenting anti-inflammatory activity Flavonoids: promising natural 1150 compounds against viral infections Purification, partial 1153 characterization and antioxidant activity of polysaccharides from Glycyrrhiza 1154 Potential interventions for novel coronavirus in China: A 1156 systematic review Isoliquiritigenin Protects Against 1158 Pancreatic Injury and Intestinal Dysfunction After Severe Acute Pancreatitis via Nrf2 1159 Protective Effects of Isoliquiritigenin Induced Acute Lung Injury by Activating PPAR-γ A strategy for qualitative and quantitative 1165 profiling of glycyrrhiza extract and discovery of potential markers by fingerprint-1166 Cardioprotective Effect of Monoammonium 1169 Glycyrrhizinate Injection Against Myocardial Ischemic Injury in vivo and in vitro Involvement of Inhibiting Oxidative Stress and Regulating Ca2+ Homeostasis by L-1171 Type Calcium Channels Paeonia lactiflora A pneumonia outbreak associated 1178 with a new coronavirus of probable bat origin Major finding Mechanism of actions Unknown Pompei et al., 1979 Pompei et al., 1980 Sato et al., 1996 Ribavirin Modified glycyrrhizin has 70-fold increased activity against SARS-CoV but also increased cytotoxicity.It has antiviral effect and this inhibitory effect was abolished by treatment 1h after virus infection.It inhibited H5N1-induced expression of the proinflammatory molecules CXCL10, interleukin 6, CCL2, and CCL5 and interfered with H5N1 replication.Strong inhibitory effects on influenza viral strains, H1N1, H9N2, novel H1N1 (WT), and oseltamivir-resistant novel H1N1and synergistic effect with oseltamivir.GL inhibit HCV full length and function in a dose dependent manner and had synergistic effect with interferon.GRA, but not GA, has significant antiviral activity against rotavirus replication in vitro,The mechanism of glycyrrhizin's activity against SARS-CV may be through Glycyrrhizin affects cellular signalling pathways such as protein kinase C; casein kinase II; and transcription factors such as activator protein 1 and nuclear factor κB.The antiviral activity is mediated by an interaction with the cell membrane which most likely results in reduced endocytotic activity and hence reduced virus uptake.Inhibition of H5N1-induced formation of reactive oxygen species and (in turn) reduced activation of NFκB, JNK, and p38, redox-sensitive signalling events known to be relevant for influenza A. GL dose dependently inhibit the expression of HCV 3a core gene both at mRNA and protein levels.Inhibitory effects on various neuraminidases. GRA demonstrated a strong antiherpes simplex virus type 1, (HSV1) activity, resistance typewhereas rapamycin had no activity.Glycyrrhizin significantly reduced PRRSV proliferation and PRRSVencoded protein expression in a dosedependent manner.GL derivatives are potent as anti-influenza A/H1N1 agents.Entecavir and glycyrrhizic acid combination but not Glycyrrhizin produce synergistic anti-HBV activity.Due to its inhibitory effect on PLA2G1B( phospholipase A2 of group 1B PLA2Triterpenoids bind tightly to the viral envelope hemagglutinin (HA), disrupting the interaction of HA with the sialic acid receptor and thus the attachment of viruses to host cells.GRA induced a Beclin 1 production that was more than twofold higher than that produced by rapamycin, GRA is a strong inducer of the autophagy activator Beclin 1, which establishes a resistance state to HSV1 replication.Gycyrrhizin mainly inhibits the penetration stage, and has little effect on the steps of adsorption or release of PRRSV in its life cycle.With multisite inhibition mechanisms. SKBHT suppresses GL inhibited proinflammatory cytokines playing a key role in the initial phase of inflammatory response, through inhibition of the TLR-4/NF-κB signal pathway GA inhibited the production of inflammatory factors and regulates the PI3K/AKT/mTOR pathway related autophagy.Antiinflammatory and antioxidative stress.Not only by suppressing HMGB1 release and blocking HMGB1 cytokine activity, but also via block an underlying viralinduced HMGB1-TLR4 immunological regulation axis that occurs during the cytokine storm.Gl act by block Smad2/3 signaling pathway through inhibiting highmobility group box1 (HMGB1).By regulating the expression of inflammatory Qu et al., 2019 Shen et al., 2020 Shi et al., 2020 Gui et al., 2020 . Kim SH et al., 2020 Kim KH et al., 2020