key: cord-0927399-8sy3knn9
authors: Tutunchi, Helda; Naeini, Fatemeh; Ostadrahimi, Alireza; Hosseinzadeh‐Attar, Mohammad Javad
title: Naringenin, a flavanone with antiviral and anti‐inflammatory effects: A promising treatment strategy against COVID‐19
date: 2020-07-02
journal: Phytother Res
DOI: 10.1002/ptr.6781
sha: 1092f0bce8fca9c4e911d710558eecc99f77c124
doc_id: 927399
cord_uid: 8sy3knn9

At the end of 2019, a novel flu‐like coronavirus named COVID‐19 (coronavirus disease 2019) was recognized by World Health Organization. No specific treatments exist for COVID‐19 at this time. New evidence suggests that therapeutic options focusing on antiviral agents may alleviate COVID‐19 symptoms as well as those that lead to the decrease in the inflammatory responses. Flavonoids, as phenolic compounds, have attracted considerable attention due to their various biological properties. In this review, the promising effects and possible mechanisms of action of naringenin, a citrus‐derived flavonoid, against COVID‐19 were discussed. We searched PubMed/Medline, Science direct, Scopus, and Google Scholar databases up to March 2020 using the definitive keywords. The evidence reviewed here indicates that naringenin might exert therapeutic effects against COVID‐19 through the inhibition of COVID‐19 main protease, 3‐chymotrypsin‐like protease (3CLpro), and reduction of angiotensin converting enzyme receptors activity. One of the other mechanisms by which naringenin might exert therapeutic effects against COVID‐19 is, at least partly, by attenuating inflammatory responses. The antiviral activity of the flavanone naringenin against some viruses has also been reported. On the whole, the favorable effects of naringenin lead to a conclusion that naringenin may be a promising treatment strategy against COVID‐19.

reached pandemic proportions, which resulted in a great concern of public health worldwide (Sehn, 2020) . Currently, no specific treatments exist for COVID-19 (Guo et al., 2020) , and up to April 7, 2020, more than 1,279,000 cases of COVID-19 have been reported by WHO. Severe acute respiratory syndrome (SARS-CoV-2) has affected 211 countries worldwide (WHO, 2020) . The acute respiratory distress syndrome (ARDS) is the most prevalent cause of death among the patients with COVID-19 that finally leads to multiple organ failure and sepsis (Wang, Zhao, Xu, & Gu, 2020) . The groups who are at the highest risk of COVID-19 are older adults and subjects with major chronic diseases such as cancers, diabetes, and hypertension . The (Schoeman & Fielding, 2019; Zhong et al., 2003) .

The most important reason for the high transmission rate of COVID-19 is genetic recombination event at S protein in the receptor binding domain (RBD) region of this virus (Ghaffari, Roshanravan, Tutunchi, Ostadrahimi, & Kafil, 2020; Zhu et al., 2020) . SARS-CoV-2 RNA sequence has almost 30,000 bases in length (Xiao et al., 2020) , and the analysis of whole-genome sequencing data has exhibited a strong similarity between SARS-CoV-2 and SARS-CoV in the RBD (Zhang & Holmes, 2020) . SARS-CoV-2 RBD has a great binding affinity to the human angiotensin-converting enzyme 2 (ACE2) receptors, which are widely expressed in various cells belonged to kidney, lung, brain, and digestive tract. ACE2 can negatively modulate the reninangiotensin system (RAS) through the degradation of angiotensin II, and can play a protective role against the progression of acute lung failure (Madjid, Safavi-Naeini, Solomon, & Vardeny, 2020) . SARS-CoV-2 seems to infect host cells through ACE2 (Diaz, 2020) . It is supposed that, the decreased ACE2 activity in host-cell membranes may reduce the ability of SARS-CoV-2 to enter cells (Letko, Marzi, & Munster, 2020) . According to the current theory, the entrance of the virus into cells increases the inflammatory activity, which leads to serious damages, especially in the respiratory tract. Collectively, COVID-19 seems to be the fifth endemic CoV worldwide. Since an established vaccine or medication is yet to be discovered against this viral infection, preventive policies are very crucial at this time. New evidence suggests that therapeutic options focusing on antiviral agents may alleviate COVID-19 symptoms as well as those that lead to the decrease in the inflammatory responses (Monteleone & Ardizzone, 2020; Stebbing et al., 2020) . Various important biological activities of flavonoids, as phenolic compounds, have been reported that include antiviral, anti-inflammatory, therapeutic, antibacterial, and other properties in nature (Tapas, Sakarkar, & Kakde, 2008) . Among the naturally occurring flavonoids, naringenin, due to its potent biological roles, is one of the most important flavonoids (Den Hartogh & Tsiani, 2019) . Therefore, in the present study, we aimed to discuss the promising effects and possible mechanisms of action of naringenin, which is a flavonoid with antiviral and anti-inflammatory activities, against COVID-19.

We investigated four most popular search engines PubMed/Medline, Science direct, Scopus, and Google Scholar using the following keywords: "naringenin" or "naringenin7-sulfate" or "4 0 5 7-trihydro xyflavanone" in the title and "viral diseases" or "virus-related diseases" or "infectious disease" or "inflammatory lung diseases" or "lung injury" or "inflammation" or "COVID-19 00 or "coronaviruses" in the title or abstract. Relevant studies published in the English language up to March 2020 were eligible. All articles evaluating the effects of naringenin on viral diseases, infectious disease, and inflammatory lung diseases were included. Studies with insufficient information were excluded from the review. To minimize the loss of studies, the reference lists of articles that were included were also reviewed to identify additional studies. The articles identified in the search were saved in an EndNote software file and sorted to remove duplicate reports. The remaining studies were examined for choosing eligible articles. Then, the full texts of the screened articles were critically analyzed for extraction of data.

In total, 103 potentially title/abstract were retrieved by the search strategy, of which 71 were considered after removal of duplicate articles. Of these, 58 articles were excluded because of not providing the inclusion criteria. Finally, 13 articles were included in the present study based on the research topic. Figure 1 presents the diagram for the search and selection process of the present review. Details of the selected studies are presented in Table 1 .

Based on the available information, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro), as CoV-encoded proteins, play crucial roles in CoV replication, and also exert essential roles in the inhibition of host innate immune responses (Baez-Santos, St John, & Mesecar, 2015) . Therefore, targeting these proteases appears to be pivotal for the treatment of COVID-19 (Tahir Ul Qamar, Alqahtani, Alamri, & Chen, 2020). Recent data suggests that some metabolites from a group called flavonoids can inhibit the activity of these proteins. In fact, flavonoid compounds attach to the active site of proteins, and then inactivate them (Sawikowska, 2020) . Moreover, flavonoids are a large class of plant pigments by having many subgroups including chalcones, flavones, flavonols, and isoflavones (Panche, Diwan, & Chandra, 2016) . Flavonoids have been shown to have multiple functions including antioxidant activity, free radical scavenging capacity, hepatoprotective, anti-inflammatory, anticancer, and antibacterial effects, as well as the potential antiviral activities (Pietta, 2000) . In this regard, Shimizu et al. (2017) demonstrated that flavonoids could act against hepatitis C virus (HCV) infection by blocking the entry stage of HCV cycle. As a citrus flavonoid, naringenin could alleviate HCV infection by causing a reduction in apolipoprotein B100 (apoB100) secretion, which is required for HCV infection (Hernandez-Aquino & Muriel, 2018) . Mechanistically, it is documented that the antiviral activity of some flavonoids against SARS-CoV-2 can be mediated through their ability in blocking 3CLpro (Jo, Kim, Shin, & Kim, 2020) .

Among flavonoids, naringenin with the chemical name of 4 0 5 7-trihydroxyflavanone, is considered as one of the most important flavonoids, mainly a flavanone, due to its potential biological activities such as antioxidant, anti-inflammatory, and antiviral properties (Den Hartogh & Tsiani, 2019). Naringenin is the aglycone of naringin, known as the bitter component of citrus fruits (Ameer, Weintraub, Johnson, Yost, & Rouseff, 1996) . This flavanone is widely distributed in a variety of fruits and vegetables such as grapefruit, lemon, oranges, bergamot, and tomatoes; and thus, its consumption from the diet can be relatively high (Manchope, Casagrande, & Verri Jr., 2017) . To date, oral bioavailability rate of naringenin is almost 5.81% and its absorption occurs through both passive diffusion and active transport in gastrointestinal tract (Kanaze, Bounartzi, Georgarakis, & Niopas, 2007) . Moreover , Xu et al. (2009) demonstrated that the absorption rate of naringenin was 47, 42, and 39% in deudenum, terminal illeum, and jejunum, respectively. After absorption, naringenin binds to albumin and is then distributed in the highly perfused organs such as the liver, cerebrum, kidney, spleen, and heart (Erlund, Meririnne, Alfthan, & Aro, 2001) . Finally, metabolites of naringenin can be excreted through biliary and urinary pathways (Barreca et al., 2017 (Zobeiri et al., 2018) . In 1996, the first study was conducted on the toxicity of naringenin. In a model system of the isolated rat liver nuclei, naringenin induced a concentration-dependent peroxidation of nuclear membrane lipids along with DNA strand breaks (Sahu & Gray, 1997) . In addition, naringenin can be oxidized to generate naringenin phenoxyl radicals (Galati, Moridani, Chan, & O'Brien, 2001) and it also exhibited a medium lethal dose LD(50) > 5,000 mg/kg (Ortiz-Andrade et al., 2008) . However, due to the relatively low bioavailability and the rapid metabolism and elimination of most of the flavonoids like naringenin, no side effects have been reported by consuming them (Clark, Zahradka, & Taylor, 2015) . In this regard, a pharmacokinetic study exhibited no undesirable or adverse effects after the oral administration of naringenin in the human subjects (Kanaze et al., 2007) . Similarly, no side effects were observed in a clinical study that assessed the efficacy and safety of polyphenolic citrus dry extract including naringenin among the healthy overweight subjects (Dallas et al., 2014) . However, due to the lack of adequate studies performed on the safety and toxicity of naringenin, this flavanone should be cautiously used in clinical settings (Hernandez-Aquino & Muriel, 2018). and HCV (Nahmias et al., 2008) . In another study, naringenin administration inhibited HCV secretion with no effect on intracellular viral RNA or on protein levels. The assembly of infectious virus particles was also blocked by naringenin. Moreover, by activating peroxisome proliferator-activated receptor α (PPARα), naringenin led to a reduction in VLDL production, which is necessary for secretion of HCV particles (Goldwasser et al., 2011) . 15 (BHK-21), administration of 25 μg/ml naringenin blocked sindbis neurovirulent strain (NSV) replication up to 80% (Paredes et al., 2003) .

As an antiviral biomarker in Guiera senegalensis, a traditional medicinal plant, naringenin administration (0.14 μg/mg) could inhibit hepatitis B virus (HBV) life cycle either by targeting viral envelopes or by reversetranscriptases (Alam et al., 2017) . The summary of the studies demonstrating antiviral effects of naringenin is presented in Table 1 .

The antioxidant activity of naringenin is attributed to hydroxyl substituents (OH) in its structure. These hydroxyl groups have high reactivity against reactive oxygen species (ROS) and reactive nitrogen species 

Curcumin has been shown to regulate many transcription factors, cytokines, adhesion molecules, and enzymes associated with inflammation. In this regard, numerous studies have revealed the potential role of curcumin in the prevention and treatment of various proinflammatory diseases (Moballegh Nasery et al., 2020). Zerumbone, which is isolated from the tropical plant Zingiber zerumbet Smith, has been reported to have anti-inflammatory effects by inhibiting iNOS, COX-2 expressions, and prostaglandin E 2 (PGE 2 ) production (Prasannan et al., 2012) . Thymoquinone is considered as the main active component in Nigella sativa that has been found to exert antiinflammatory activities by reducing the expression of iNOS protein Siveen, Mustafa et al., 2014) . The NF-κB inhibition activity of honokiol, as a phenolic compound (Rajendran et al., 2012) ; escin, as the main active ingredient of Aesculus hippocastanum seed extract (Tan et al., 2010) ; pinitol, which is isolated from Abies pindrow leaves (Sethi, Ahn, Sung, & Aggarwal, 2008) ; and tocotrienols, which are the members of vitamin E family Siveen, Mustafa et al., 2014) , have also been reported.

Due to the dose-related side effects of curcumin and thymoquinone at the dosages of 12 g/day (Hewlings & Kalman, 2017 ) and 2-3 g/day (Goyal et al., 2017) , respectively, the use of some novel agents like naringenin with no undesirable side effects, can be considered. In comparison to naringenin, zerumbone has shown antimicrobial effects against fungi and bacteria as well as some anti-inflammatory activities (Nagaraj, Shridhar, Nirguna Babu, & Gowrishankar, 2012) . However, antiviral effects of zerumbone have not been reported yet. Although escin, pinitol, and tocotrienols exhibit anti-inflammatory and antiviral activities, the beneficial biological effects of naringenin on human health appear to be more extensive (Michelini, Alche, & Bueno, 2018; Mileva & Galabov, 2018; Sethi et al., 2008) . In fact, flavonoid compounds have received much attention due to having many types of pharmacological activities including antioxidative, anti-inflammatory, anti-mutagenic, antimicrobial, hepatoprotective, and anti-carcinogenic effects (Panche et al., 2016) . To the best of our knowledge, all the natural agents with the above-mentioned anti-inflammatory activities, except curcumin and thymoquinone, showed no inhibitory effect on COVID-19 main protease. However, naringenin is capable of inhibiting the enzymatic activity of CoV 3CLpro (Khaerunnisa et al., 2020) .

A recent study suggests that some flavonoids such as naringenin, kaempferol, quercetin, and apigenin are the most recommended compounds that may act as the potential inhibitors of SARS-CoV-2 main protease (Khaerunnisa et al., 2020) . These agents share a pharmacophore similar to nelfinavir (Dabeek & Marra, 2019; Salehi et al., 2019) . Nelfinavir is a protease inhibitor used in patients infected by the human immunodeficiency virus (HIV) (Yamamoto et al., 2004) .

Because proteases play essential roles in viral replication of different types of viruses, they may be considered as potential pharmacological targets for preventing CoV replication (Chang, Kim, Lovell, Rathnayake, & Groutas, 2019; Xin Liu & Wang, 2020) . main protease, Protein Data Bank (PDB) ID 6 LU7, is pivotal for the proteolytic maturation of CoV (Xin Liu & Wang, 2020) . SARS-CoV-2 main protease or 3CLpro contains two chains, which make a homodimer (Berman et al., 2002) . The molecular docking analysis study demonstrated that naringenin binds to 3CLpro chains as a ligand and blocks its activity. The binding energy obtained from docking 6 LU7 with naringenin was −7.99 kcal/mol, which was associated with the number of H-bonds formed with 6 LU7. Naringenin H-bonds interact with amino acids histidine (His164), glutamic acid (Glu166), aspartic acid (Asp187), threonine (Thr190) in the CoV main protease active site. Altogether, due to the lower binding energy of naringenin and the presence of H-bonds, the affinity of naringenin bonds is high and this flavanone is capable of inhibiting the enzymatic activity of CoV 3CLpro (Khaerunnisa et al., 2020) .

As it was mentioned earlier, it has also been indicated that CoVs use the ACE2 receptors to enter the host cells; thus, compounds that can reduce the ACE2 activity may be useful in the treatment of the patients with COVID-19 (Letko et al., 2020; Lu et al., 2020) . A recent study has investigated the immunoregulatory effects of citrus flavonoids as well as their impacts on ACE2 activity. The binding affinity of these compounds to ACE2 was assessed by molecular docking. The interaction between naringenin and ACE2 was also examined by binding energy. The docking findings demonstrate that naringenin is able to bind to ACE2 with docking energy of −6.05 kcal/mol, with binding site proline (PRO-146), leucine (LEU-143), and lysine (LYS-131). On the whole, the findings of the recent study showed that the energy required for the binding between naringenin and ACE2 was low, so it could easily bind to ACE2. The authors concluded that naringenin might be a promising treatment strategy for COVID-19 ).

An emerging evidence demonstrates that the patients infected with SARS-CoV-2 have high levels of cytokines including TNF-α, IL-1β, IL-10, interferon γ (IFNγ), and monocyte chemoattractant protein-1 (MCP-1). These findings indicate that the cytokine storm contributes to disease severity (Huang, Wang et al., 2020) . To date, corticosteroids may be beneficial if utilized at the early acute stages of infection (Russell, Moss, Rigg, & Van Hemelrijck, 2020) . Therefore, the use of anti-inflammatory agents may be considered as a promising treatment approach to relieve COVID-19 symptoms (Stebbing et al., 2020) . As it was mentioned earlier, naringenin exhibits a potent anti-inflammatory activity and can be recognized as an option to decrease cytokine levels of inflammatory markers including TNF-α, IL-1β, IL-10, and IFNγ in the patients with COVID-19 . Also, a protective effect of naringenin against lipopolysaccharide-induced acute lung injury was reported in rats. Naringenin at two doses (50 and 100 mg/kg/day), significantly attenuated the production of inflammatory cytokines, pulmonary edema, neutrophil recruitment, myeloperoxidase activity, and F I G U R E 2 Possible mechanisms for the actions of naringenin against COVID-19. ACE2, angiotensin-converting enzyme 2; NRG, naringenin; NF-κB, nuclear factor kappa B; 3CLpro, 3-Chymotrypsin-like protease; SARS, Severe acute respiratory syndrome [Colour figure can be viewed at wileyonlinelibrary.com] decreased the markers of oxidative/nitrosative stress in lungs of LPSchallenged rats (Fouad et al., 2016) . Moreover, administration of 100 mg/kg naringenin to rats with lung damage led to the down regulation of the expressions of NF-κB and COX2 (Ali et al., 2017) . Fan, Pan, Zhu, and Zhang (2017) also found that administration of 5-20 mg/kg naringenin to Wistar rats with arthritic inflammation resulted in a decrease in TNF-α and NF-κB mRNA levels. Furthermore, an in vivo study demonstrated a reduction in NF-κB, TNF-α, IL-6, and IL-1β after naringenin administration (Hua et al., 2016) . Besides, in the mice treated with 10 mg/kg naringenin, inflammatory markers including TNF-α, IL-6, TLR4, iNOS, COX2, NADPH oxidase-2 (NOX2), NF-κB, and mitogen-activated protein kinase (MAPK) were suppressed (X. Liu et al., 2016) . A post-translational inhibition of TNF-α and IL-6 was also observed in an in vitro study that assessed the effects of naringenin on murine macrophage cell line RAW264.7 (Jin, Zeng, Zhang, Zhang, & Liang, 2017) . In addition, mRNA and protein expression levels of TNFα, IL-6, and IL-1β were attenuated by naringenin administration in female mice with hypertrophic scars (Shan et al., 2017) . Collectively, a large amount of evidence supports the notion that naringenin represents a potential therapeutic agent to control the inflammation-related diseases. Therefore, one of the other mechanisms by which naringenin might exert therapeutic effects against COVID-19 is, at least partly, by attenuating inflammatory responses. The summary of the possible mechanisms for the protective effects of naringenin against COVID-19 is presented in Figure 2 .

In conclusion, the evidence reviewed here indicates that naringenin might exert therapeutic effects against COVID-19 through the inhibition of COVID-19 main protease, 3CLpro, and reduction of ACE2 receptors activity. One of the other mechanisms by which naringenin might exert therapeutic effects against COVID-19 is, at least partly, by attenuating inflammatory responses. The antiviral activity of the flavanone naringenin has also been reported against some viruses. On the whole, the favorable effects of naringenin lead to a conclusion that naringenin may be considered as a promising treatment strategy against COVID-19. However, the beneficial effects of naringenin still need to be confirmed in clinical trials.

The authors declare no potential conflict of interest.

https://orcid.org/0000-0002-4795-1757

Alireza Ostadrahimi https://orcid.org/0000-0002-1058-1481

Mohammad Javad Hosseinzadeh-Attar https://orcid.org/0000-0002-5787-4089

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