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Table of Contents
MINI REVIEW
Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 47-50

Licorice plant extract: Does it hold a promise for coronavirus disease-2019


1 Navin Upchar Kendra; Pratibha Complex Buxipur, Gorakhpur, Uttar Pradesh, India
2 Sundaram Arulrhaj Hospitals, Tutiporin, Tamil Nadu, India

Date of Submission11-Oct-2020
Date of Acceptance07-Nov-2020
Date of Web Publication13-Apr-2021

Correspondence Address:
Dr. Vivek Chandra
Navin Upchar Kendra 2, Pratibha Complex Buxipur, Gorakhpur - 273 001, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrnm.jrnm_26_20

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  Abstract 


Coronavirus (CoV) disease 2019 (COVID-19) is defined as illness caused by a novel CoV first identified amid an outbreak of respiratory illness cases in Wuhan, China. Data provided by the World Health Organization Health Emergency Dashboard (September 16, 2020) reports 29,444,198 confirmed cases worldwide since the beginning of the epidemic of which 931,321 cases have been fatal. No drugs or biologics have proven to be 100% effective for the prevention or treatment of COVID-19 so far. Glycyrrhizin (GL) is one of the major compounds isolated from the roots of licorice. Many studies have confirmed the antiviral activity of GL. GL is an effective antiviral compound against hepatitis C virus, HIV, CVB3, DHV, EV71, CVA16, HSV, and H5N1 by weakening virus activity, such as inhibiting virus gene expression and replication, reducing adhesion force and stress, and reducing HMGB1 binding to DNA. The primary areas of concern are the regulation of dosage, hypokalemia, toxicity, drug interactions, routes of administration, and blood pressure management. Does licorice needs more studies on COVID-19 patients to demonstrate its merit and does licorice have some promise as an adjuvant if not cure for COVID-19 pandemic.

Keywords: Coronavirus disease-2019, flavonoids, interleukin 6, licorice, pneumonia


How to cite this article:
Chandra V, Sundaram A. Licorice plant extract: Does it hold a promise for coronavirus disease-2019. J Renal Nutr Metab 2020;6:47-50

How to cite this URL:
Chandra V, Sundaram A. Licorice plant extract: Does it hold a promise for coronavirus disease-2019. J Renal Nutr Metab [serial online] 2020 [cited 2021 Jun 13];6:47-50. Available from: http://www.jrnm.in/text.asp?2020/6/3/47/313631



Coronavirus (CoV) disease 2019 (COVID-19) is defined as illness caused by a novel CoV first identified amid an outbreak of respiratory illness cases in Wuhan City, Hubei Province, China. It was initially reported to the World Health Organization (WHO) on December 31, 2019. On January 30, 2020, the WHO declared the COVID-19 outbreak a global health emergency. On March 11, 2020, the WHO declared COVID-19 a global pandemic, its first such designation since declaring H1N1 influenza a pandemic in 2009.

No drugs or biologics have been proven to be fully effective for the prevention or treatment of COVID-19 so far. Numerous antiviral agents, immunotherapies, and vaccines are being investigated and developed as potential therapies.[1]

CoVs are positive-stranded RNA viruses with a crown-like appearance under an electron microscope (coronam is the Latin term for crown) due to the presence of spike glycoproteins on the envelope. The structure of coronavirus is composed of RNA-based proteins that contain amino (-NH2) and carboxyl (-COOH) groups. It includes nucleocapsid protein (N-protein), spike protein (S-protein), envelope, and hemagglutinin-esterase dimer. These proteins affect adversely on the human gastrointestinal system, heart, kidney, liver, and central nervous system leading to several organ damages. Genomic characterization has shown that probably bats and rodents are the gene sources of alphaCoVs and betaCoVs, whereas avian species seem to represent the gene sources of deltaCoVs and gammaCoVs.

Members of this large family of viruses can cause respiratory, enteric, hepatic, and neurological diseases in different animal species. In general, estimates suggest that 2% of the population are healthy carriers of a CoV and that these viruses are responsible for about 5% to 10% of acute respiratory infections, although the numbers may be set for a change.[2]

  • Common human CoVs: HCoV-OC43, and HCoV-HKU1 (betaCoVs of the A lineage); HCoV-229E, and HCoV-NL63 (alphaCoVs). They can cause common colds and self-limiting upper respiratory infections in immunocompetent individuals. In immunocompromised individuals and the elderly, lower respiratory tract infections can occur
  • Other human CoVs: SARS-CoV, SARS-CoV-2, and MERS-CoV (betaCoVs of the B and C lineage, respectively). These cause epidemics with variable clinical severity featuring respiratory and extra-respiratory manifestations. Concerning SARS-CoV, MERS-CoV, the mortality rates are up to 10% and 35%, respectively.


As SARS-CoV-2 belongs to the betaCoVs category and has round or elliptic and often pleomorphic form, and a diameter of approximately 60–140 nm, it is sensitive to ultraviolet rays and heat. Furthermore, these viruses can be effectively inactivated by lipid solvents including ether (75%), ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform except for chlorhexidine.[2]

Since the first cases of the COVID-19 disease were linked to direct exposure to the Huanan seafood wholesale market of Wuhan, the animal-to-human transmission was presumed as the main mechanism, but subsequent cases were not associated with this exposure mechanism. Thus, it was concluded that the virus could also be transmitted from human-to-human, and symptomatic people are the most frequent source of COVID-19 spread.

The possibility of transmission before symptoms develop is valid. Data till now suggest that the use of isolation and social distancing is the best way to contain this epidemic.

As with other respiratory pathogens, including flu and rhinovirus, the transmission is believed to occur through respiratory droplets from coughing and sneezing. Aerosol transmission is also possible in case of protracted exposure to elevated aerosol concentrations in closed spaces.

Data provided by the WHO Health Emergency Dashboard (September 16, 2020) report 29,444,198 confirmed cases worldwide since the beginning of the epidemic of which 931,321 cases have been fatal.

CoVs are enveloped, positive-stranded RNA viruses with nucleocapsid. For addressing pathogenetic mechanisms of SARS-CoV-2, its viral structure, and genome must be considerations. In CoVs, the genomic structure is organized in a +ssRNA of approximately 30 kb in length — the largest known RNA viruses — and with a 5′-cap structure and 3′poly-A tail. Starting from the viral RNA, the synthesis of polyprotein 1a/1ab (pp1a/pp1ab) in the host is realized. The transcription works through the replication-transcription complex (RTC) organized in double-membrane vesicles and through the synthesis of subgenomic RNAs sequences. Of note, transcription termination occurs at transcription regulatory sequences, located between the so-called open reading frames (ORFs) that work as templates for the production of subgenomic mRNAs. In the atypical CoV genome, at least six ORFs can be present. Among these, a frameshift between ORF1a and ORF1b guides the production of both pp1a and pp1ab polypeptides that are processed by virally encoded chymotrypsin-like protease (3CLpro) or main protease, as well as one or two papain-like proteases for producing 16 nonstructural proteins. Apart from ORF1a and ORF1b, other ORFs encode for structural proteins, including spike, membrane, envelope, and nucleocapsid proteins.[2]

The pathogenic mechanism that produces pneumonia seems to be particularly complex. Clinical and preclinical research will have to explain many aspects that underlie the particular clinical presentations of the disease. The data so far available seem to indicate that the viral infection is capable of producing an excessive immune reaction in the host. In some cases, a reaction takes place which as a whole is labeled a “cytokine storm.” The effect is extensive tissue damage. The protagonist of this storm is interleukin (IL)-6. IL-6 is produced by activated leukocytes and acts on a large number of cells and tissues.[3]

The clinical spectrum of COVID-19 varies from asymptomatic or paucisymptomatic forms to clinical conditions characterized by respiratory failure that necessitates mechanical ventilation and support in an intensive care unit, to multiorgan and systemic manifestations in terms of sepsis, septic shock, and multiple organ dysfunction syndromes.

The finding of increased d-dimer levels in patients with COVID-19 has prompted questions regarding co-existence of venous thromboembolism exacerbating ventilation-perfusion mismatch and some studies have shown that pulmonary emboli are prevalent.

A compound from herbal remedies proposed to be looked at to control COVID-19 is diammonium glycyrrhizinate, an extract of liquorice roots. Liquorice, glycyrrhiza glabra, has long been employed against coughs and colds as well as to settle disturbed digestion, while diammonium glycyrrhizinate has anti-inflammatory activity. Some studies are already looking at a combination of diammonium glycyrrhizinate and Vitamin C as a COVID-19 therapy.

Compared to chemical drugs, herbal medicines and plant natural products are less understood mechanistically, but several clinical investigations have been started to more precisely evaluate their effects.

In routine drug development, researchers first discover a drug molecule with potential therapeutic activity against a certain target, then optimize its structure and validate its function using in vitro experiments followed by animal and clinical trials. By contrast, many herbal drugs have been used in clinics for hundreds or thousands of years, and thus their safety and effects have been repeatedly tested. During emergencies, once a herbal decoction or component is found to be effective, it can be immediately used for treating patients, given its safety is already established.

Antiviral herbal medicines have been used in many historic epidemics, for example, the previous two CoV outbreaks (SARS-CoV in 2013 and MERS-CoV in 2012).

These herbal medicines are generally not highly potent and thus cannot be regarded as a cure but as a complementary treatment, they can elevate recovery rates when combined with other treatments, moreover in an emergency such as the current COVID-19 pandemic.

Plants are important not only for food but also for medicine. Understanding the taxonomy, ecology, and conservation of herbs, as well as the pathways of secondary metabolite synthesis, is important for drug development. Investing in research into ethnobotany, phytochemistry, plant physiology, and ecology will be vital in protecting the global population from current and future pandemics.[4]


  Licorice Top


Licorice contains >20 triterpenoids and nearly 300 flavonoids. Among them, only two triterpenes, Glycyrrhizin (GL) and 18 β-glycyrrhetinic acid (GA) have been chiefly reported to have antiviral effects. They can weaken virus activities by virus gene expression and replication inhibition.[5]

GL is one of the major compounds isolated from the roots of licorice. In recent years, many studies have confirmed the antiviral activity of GL. Matsumoto et al. reported that GL targeted the release step in which infectious anti-hepatitis C virus (HCV) particles were infecting cells. These findings indicated possible novel roles for GL to treat patients suffering from chronic hepatitis C. In another study, researchers also found that GL treatment inhibited HCV titer and caused 50% reduction of HCV at the concentration of 14 ± 2 μg/mL by inhibiting HCV full-length viral particles and their core gene expression.

Data suggest that GL may present as a new therapeutic approach for the treatment of viral myocarditis, by significantly reduced expression of proinflammatory cytokines such as IL6. Several studies have demonstrated that GL showed a significant inhibiting effect to influenza virus. At a concentration of 100 μg/mL (a therapeutically achievable concentration), GL weakened H5N1-induced production of chemokine (C-X-C motif) ligand 10 (CXCL10), IL-6 and chemokine (C-C motif) ligand 5 (CCL5), and suppressed H5N1-induced apoptosis.

Above all, GL is an effective antiviral compound against HCV, HIV, CVB3, DHV, EV71, CVA16, HSV, and H5N1 by weakening virus activity, such as inhibiting virus gene expression and replication, reducing adhesion force and stress, and reducing HMGB1 binding to DNA. The compound also enhances host cell activity, for example, by blocking the degradation of IκB, activating T-lymphocyte proliferation, and/or suppressing host cell apoptosis.

GA: Compared with GL, studies of the antiviral activity of GA are limited. GA treatment inhibited rotavirus replication, which likely occurred at steps subsequent to virus entry. GA reduced rotavirus yields by 99% when it was added to infected cultures postviral adsorption. The levels of viral proteins VP2, VP6, and NSP2 were substantially reduced. GA also showed potent anti-human respiratory syncytial virus (HRSV) activity. It inhibited HRSV mainly by internalization, stimulating interferon secretion, and preventing viral attachment.

There is a difference between the antiviral profiles of GA and GL. GA has activity against rotavirus and HRSV. However, the antiviral mechanisms of these compounds are similar. GA exerts its antiviral activity also by inhibiting virus replication, preventing viral attachment, or enhancing host cell activity.

The Newcastle disease represents as one of the most infectious viral disease, which afflicts almost every species of birds. The causative agent of the disease is a single-stranded RNA virus with rapid replication capability. Studies have shown that 60 mg/100 ml glycyrrhiza extract inhibits the replication of Newcastle disease virus and is nontoxic in the embryonated eggs. Hence, glycyrrhiza glabra extract may be further evaluated in future to determine the potentially active compounds for their antiviral activity.[6]

GL is known to exert antiviral and anti-inflammatory effects. Studies have looked at the effects of an approved parenteral GL preparation (Stronger Neo-Minophafen C) on highly pathogenic influenza A H5N1 virus replication, H5N1-induced apoptosis, and H5N1-induced pro-inflammatory responses in lung epithelial (A549) cells. Therapeutic GL concentrations substantially inhibited H5N1-induced expression of the pro-inflammatory molecules CXCL10, IL 6, CCL2, and CCL5 (effective GL concentrations 25–50 μg/ml) but interfered with H5N1 replication and H5N1-induced apoptosis to a lesser extent (effective GL concentrations 100 μg/ml or higher). GL also diminished monocyte migration toward supernatants of H5N1-infected A549 cells. The mechanism by which GL interferes with H5N1 replication and H5N1-induced pro-inflammatory gene expression includes inhibition of H5N1-induced formation of reactive oxygen species and (in turn) reduced activation of NFκB, JNK, and p38, redox-sensitive signaling events known to be relevant for influenza A virus replication. Therefore, GL showed promise to complement the arsenal of potential drugs for the treatment of H5N1 disease.[7]

The outbreak of COVID-19 has emerged as a severe threat for public health and economy throughout the world. Some investigations reveal that the extracted components of natural plants, especially hydroxyl (-OH) groups react chemically to deactivate the active components of the virus by the esterification process. As a case study, using one of the natural resources, licorice (Glycyrrhiza glabra) which has the components of GL, glycyrrhetic acid, liquiritin, and isoliquiritin showed that it can be used to neutralize the activeness of COVID-19 and it can be used as an antiviral drug.[8]

The outbreak of SARS warrants the search for antiviral compounds to treat the disease. At present, no specific treatment has been identified for SARS-associated CoV infection. The clinical center of Frankfurt University, Germany, finds GL as the most active in inhibiting replication of the SARS-associated virus. Such findings suggest that GL should be assessed for the treatment of SARS.[9] These studies show a way in which we may proceed on SARS-2 as well.

The primary areas of concern are the regulation of dosage, hypokalemia, toxicity, drug interactions, routes of administration, and blood pressure management.

Submission: As research studies have already shown the antiviral and anti-oxidative effects of glycyrrhizin (licorice) on viruses such as the H5N1 Influenza virus, it may hereby be proposed to consider licorice (and its duly processed components) as a potential adjuvant to immunity-boosting therapies already in use by the authorities after the required procedure protocol, look up studies on routes of administration (nasal, inhalers, and nebulization) and also it calls for more studies and trials on the possibility of benefits of using licorice on COVID-19 patients to come out successful in the fight against the COVID-19 pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Bergman SJ, Cennimo DJ, Miller MM, Olsen KM. Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies. Medscape Drugs and Diseases. First posted online March 2020 and updated regularly during the pandemic.  Back to cited text no. 1
    
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Omer MO, AlMalki WH, Shahid I, Khuram S, Altaf I, Imran S. Comparative study to evaluate the anti-viral efficacy of Glycyrrhiza glabra extract and ribavirin against the Newcastle disease virus Pharmacognosy Res 2014;6:6-11.  Back to cited text no. 6
    
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Michaelis M, Geiler J, Naczk P, Sithisarn P, Leutz A, Doerr HW, et al. Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PLoS One 2011;6:e19705.  Back to cited text no. 7
    
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Shahid AA, Chowdhury MA, Kashem MA. Biopolymers: Scope of natural plant extract to deactivate COVID-19. Preprint from Research Square, 2020. DOI: 10.21203/rs.3.rs-19240/v1 PPR: PPR129365.  Back to cited text no. 8
    
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Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003;361:2045-6.  Back to cited text no. 9
    




 

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