key: cord-0838452-5v64v4a0
authors: Gour, Abhishek; Manhas, Diksha; Bag, Swarnendu; Gorain, Bapi; Nandi, Utpal
title: Flavonoids as potential phytotherapeutics to combat cytokine storm in SARS‐CoV‐2
date: 2021-03-30
journal: Phytother Res
DOI: 10.1002/ptr.7092
sha: d2ecb0802e094a3def02ae6a382815538d32143d
doc_id: 838452
cord_uid: 5v64v4a0

Emergence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection, COVID‐19, has become the global panic since December 2019, which urges the global healthcare professionals to identify novel therapeutics to counteract this pandemic. So far, there is no approved treatment available to control this public health issue; however, a few antiviral agents and repurposed drugs support the patients under medical supervision by compromising their adverse effects, especially in emergency conditions. Only a few vaccines have been approved to date. In this context, several plant natural products‐based research studies are evidenced to play a crucial role in immunomodulation that can prevent the chances of infection as well as combat the cytokine release storm (CRS) generated during COVID‐19 infection. In this present review, we have focused on flavonoids, especially epicatechin, epigallocatechin gallate, hesperidin, naringenin, quercetin, rutin, luteolin, baicalin, diosmin, ge nistein, biochanin A, and silymarin, which can counteract the virus‐mediated elevated levels of inflammatory cytokines leading to multiple organ failure. In addition, a comprehensive discussion on available in silico, in vitro, and in vivo findings with critical analysis has also been evaluated, which might pave the way for further development of phytotherapeutics to identify the potential lead candidatetoward effective and safe management of the SARS‐CoV‐2 disease.

cin) as alone or in combination are at different stages of investigation in multiple clinical trials globally for prophylactic as well as treatment of this disease (Chibber, Haq, Ahmed, Andrabi, & Singh, 2020; Horby et al., 2020; Luo et al., 2020; Million et al., 2020; Rabby, 2020; M. A. Rahman et al., 2020; Scavone et al., 2020) . However, there is no approved therapy available to date to selectively counteract this disease prevalence. Moreover, consumption of the above-mentioned drugs is associated with serious adverse effects, including cardiotoxicity, hepatotoxicity, gastrointestinal toxicity, renal toxicity, reduced red blood cells (RBC) level, etc. (Falcão, de Góes Cavalcanti, Filgueiras Filho, & de Brito, 2020; Funck-Brentano, Nguyen, & Salem, 2020; Million et al., 2020; Sacks et al., 2018; Sardana, Sinha, & Sachdeva, 2020) . Under these circumstances, natural products have immense potential to heighten the immunity status of the people. Moreover, pathophysiological investigation of the COVID-19 patients showed a crucial role of cytokine storm in the severity and complexity of the disease (Nile et al., 2020; Q. Ye, Wang, & Mao, 2020; Ming Zhao, 2020) . Currently, supplementation therapy with zinc, vitamin C, vitamin D, deferoxamine, lactoferrin, omega-3-fatty acids, glycine, and probiotics has also been prescribed to minimize the likelihood of infection (http://ctri.nic.in; https://www.clinicaltrials.gov). In this direction, biological activities like immunomodulatory, antiviral, antiinflammatory, and so on are crucial to prevent the chances of infection as well as combat the cytokine release storm (CRS) generated during this viral infection (Boozari & Hosseinzadeh, 2020; Islam et al., 2020; Yang, Zhang, et al., 2020) . Natural products are well known for these above-mentioned pharmacological actions because a large proportion of marketed drugs are indirectly or directly obtained from natural origin. Currently, several research works are also ongoing under this purview as there are quite a few reported evidences in the literature. Plants species like Allium, Piper, Boswellia, Curcuma, Echinacea, Glycyrrhiza, etc., are known to have immunomodulatory and antiinflammatory effects for treating COVID-19 patients (Brendler et al., 2020; Yang, Zhang, et al., 2020) . Similarly, cannabidiol-rich extract of Cannabis sativa had shown to modulate the expression of ACE2 and serine protease, TMPRSS2 (Wang, Kovalchuk, et al., 2020) .

The extract also reported possessing an anti-inflammatory activity to regulate the cytokine storm during COVID-19 infection (Onaivi & Sharma, 2020) . Additionally, plant-based natural products like homoharringtonine, silvestrol, tylophorine, 7-methoxycryptopleurine, and so on are reported for their potent antiviral activity . Based on the ADMET profile of different natural bioactive compounds, Abd El-Mageed et al. (2021) reported that caulerpin could be considered as a potential candidate to target SARS-CoV-2 spike protein, SARS-CoV-2,3-chymotrypsin-like protease, and a host target human angiotensin-converting-enzyme 2 (ACE2) receptor.

Methyl tanshinonate, sugiol, α-cadinol, 8-β-hydroxyabieta-9,13-dien-12-one, dehydroabieta-7-one, and tanshinone-I are plant-based terpenes or their derivatives exhibited activity against SARS-CoV-2 protease (Alrasheid, Babiker, & Awad, 2021; Diniz, Perez-Castillo, Elshabrawy, & de Sousa, 2021) . Rhein, an active metabolite of diacerein (anthraquinone derivative), is known to inhibit cytokine storm and viral replication as well as inhibits SARS-CoV-2 spike protein and ACE2 activity (de Oliveira et al., 2020) . Concurrently, studies on ayurvedic preparations or traditional plant-based medicines are ongoing in different parts of the world to prevent chances of infection as well as for improving the immunity of a person to combat this disease (Iqubal, Iqubal, Ahmed, & Haque, 2021) 

Tinospora cordifolia, Glycyrrhiza glabra, Cocculus hirsutus, Withania somnifera, Ocimum sanctum, Bryonia alba, Curcuma longa, Brazilian green propolis, resistant starch, ayurvedic kadha, shanshamani vati plus, etc.

(http://ctri.nic.in; https://www.clinicaltrials.gov). Despite the unprecedented advancement of the modern system of medicine, a high percentage of marketed drugs are evidenced from natural origin, especially plant-based products (Gurnani, Mehta, Gupta, & Mehta, 2014) . Among these herbal components, flavonoids are known to be useful to combat against overproduction of cytokines and/or boosting the immune system based on their several key pharmacological properties (A. Agrawal, 2011; García-Lafuente, Guillamón, Villares, Rostagno, & Martínez, 2009; Havsteen, 1983; Serafini, Peluso, & Raguzzini, 2010; Tripoli, La Guardia, Giammanco, Di Majo, & Giammanco, 2007) . Additionally, flavonoids are also found to be beneficial to protect drug-induced toxicity in major organs as evidenced in COVID-19 patients (Dillard & German, 2000; Sadzuka, Sugiyama, Shimoi, Kinae, & Hirota, 1997; Shahbazi, Dashti-Khavidaki, Khalili, & Lessan-Pezeshki, 2012 ). Therefore, we had explored the available literature on flavonoids for their inhibitory effect on important cytokines, particularly interleukins (ILs) like IL-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), including the pathways of action based on in vitro as well as an in vivo platforms. Most of the reported preclinical efficacy by the flavonoids was evaluated under the lung injury model, which could be closely in line with the SARS-CoV-2 infection.

Available reports on flavonoids based antiviral effects as well as in silico molecular docking studies to predict the binding of SARS-CoV-2 with flavonoids are also described. Being the first of a kind, to the best of our knowledge, this comprehensive information of flavonoids can be handy for the researchers toward the development of phytotherapeutics for the prevention as well as symptomatic management of COVID-19.

The pathophysiological mechanism of SARS-CoV-2 infection involves invasion of the virus within the cell through ACE2 receptor, primarily via the toll-like receptor-4 (TLR-4) (Ekaidem, Moses, & Tatfeng, 2020; Liu, Xiao, et al., 2020) . Thereafter, this virus-mediated infection stimulates the immune response by recruiting the macrophages as well as monocytes, cytokines, and adaptive B and T cell immune responses in the microenvironment of the lung cells. Viral infection and replication of SARS-CoV-2 in the airway epithelial cells induce elevated virusmediated pyroptosis (programmed cell death due to viral infection) with vascular leakage, which triggers the subsequent inflammatory responses (I.-Y. Chen, Moriyama, Chang, & Ichinohe, 2019; Fink & Cookson, 2005; Zhang, Zhou, et al., 2020) . IL-1β, the major inflammatory cytokine, is released during pyroptosis and additionally increased during SARS-CoV-2 infection ( Figure 1 ) .

The pathogen-associated molecular patterns (e.g., viral RNA) and damage-associated molecular patterns (e.g., ATP, nucleic acid and, ASC oligomers) by a variety of pattern-recognition receptors, alveolar macrophages, and alveolar epithelial cells were reported. After confirmation of COVID-19, proinflammatory cytokines and chemokines such as IL-6, interferon-gamma (IFN-γ), monocyte chemoattractant protein-1(MCP1), and inducible protein (IP-10) were reported to be F I G U R E 1 A schematic overview of SARS-CoV-2 invasion into the lung cells via ACE 2 receptor and generation of cytokine storm to adversely affect the lungs alveoli to ARDS [Colour figure can be viewed at wileyonlinelibrary.com] elevated into the blood of infected patients Zhang, Dong, et al., 2020) . These cytokines attract immune cells, particularly monocytes and T lymphocytes, from the blood to the site of infection (S. Tian et al., 2019; Xu, Shi, et al., 2020) .

The recruitment of immune cells and permeation of lymphocytes into the airways can elucidate the lymphopenia and elevated neutrophillymphocyte ratio in 80% of SARS-CoV-2 infected patients S. Liu et al., 2016) . Significant complications of lung occur mainly due to inflammation, which is again induced by interleukin and cytokine storm (Figure 1 ). Data on COVID-19 patients demonstrated that the elevated levels of serum cytokines, including IL-6, IL-10, IL-1β, TNF-α, IFN-γ, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), MCP-1, and macrophage inflammatory protein 1-α (MIP 1-α) might increase hospitalization of the patients, particularly in the intensive care units (ICUs) Mehta et al., 2020; Zhou, Fu, Zheng, Wang, & Zhao, 2020) . Actually, stimulation of interleukins (e.g., IL-6, IL-1β, and TNF-α) facilitates the production of specific cytotoxic CD8+ T cells followed by the stimulation of antigen-specific B cells and antibody via CD4+ helper T cells (Ahmadpoor & Rostaing, 2020) . COVID-19 patients possessed average or reduced lymphopenia, and white cell counts, as well as patients with severe disease had demonstrated considerably augmented levels of neutrophils and urea in their blood Tan et al., 2020) . IL-6 level in COVID-19 patients had shown to increase constantly, which is positively connected with severity of the disease (critically ill patients > severely ill patients > ordinary patients). In addition, the level of IL-6 was reported to be relatively higher in non-survivors as compared to the survivors of COVID-19 (L. Chen et al., 2020a; Sinha, Matthay, & Calfee, 2020; Zhou, Yu, et al., 2020) . Patients with severe diseased conditions exhibited a highly inflammatory monocyte-derived FCN1 + macrophage population within the bronchoalveolar lavage fluid (BALF) (Liao et al., 2020) . These patients demonstrated a considerably higher percentage of CD14 + and CD16 + inflammatory monocytes in peripheral blood (Y. Zhou, Fu, et al., 2020) . These cells are known to produce inflammatory cytokines that could further contribute to the cytokine storm. Hyperproduction of cytokines possibly promotes edema, viral sepsis, and lung injury, which result in acute respiratory distress syndrome (ARDS) followed by hepatic, renal, and cardiovascular complications ( Figure 1 ) (Costela-Ruiz, Illescas-Montes, Puerta-Puerta, Ruiz, & Melguizo-Rodríguez, 2020; Huang, Wang, et al., 2020; Luo et al., 2020; Moon, 2020; Prompetchara, Ketloy, & Palaga, 2020; Wang, He, & Wu, 2020) .

During SARS-CoV-2 infection, the response elicited by the cytokines has been regarded as a decisive part of immunity and immunepathophysiology (Channappanavar & Perlman, 2017) . The augmented level of serum cytokines, including TNF-α, IL-6, IL-10, and IFN-γ, were linked with the severity of the disease and adverse clinical outcomes Liu, Zhang, et al., 2020) . Among these, several cytokines exhibit different intracellular signaling pathway mediated by Janus kinase (JAK)-signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and nuclear factor-kappa B (NF-κB) (S. M. U. Ahmed, Luo, Namani, Wang, & Tang, 2017; Catanzaro et al., 2020; Dzobo, Chiririwa, Dandara, & Dzobo, 2021; J. S. Kim et al., 2021; Schwartz et al., 2017) . It could be stated that the involvement of cytokines acts as a significant part in the CRS, triggers the JAK-STAT, MAPK, and NF-κB followed by stimulation of transcription signaling pathway to confer various biological functions, including lymphocyte growth and differentiation, immune regulation, oxidative stress, and so on (S. M. U. Ahmed et al., 2017; Catanzaro et al., 2020; Kang, Tanaka, Narazaki, & Kishimoto, 2019; Schwartz et al., 2017) . Stimulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is known to inhibit the activation of proinflammatory cytokines, viz., IL-6, IL-1β, TNF-α, and promote the upregulation of anti-inflammatory gene responses (S. M. U. Ahmed et al., 2017) . In this context, it is noteworthy to mention that inflammatory storm, which engenders during SARS-CoV-2 infection, can be effectively managed by the flavonoids through targeting JAK-STAT, MAPK, NF-κB, and Nrf2 inflammatory signaling pathways (J. S. Kim et al., 2021; Serafini et al., 2010; Tisoncik et al., 2012; Zeinali, Rezaee, & Hosseinzadeh, 2017) . On the other hand, NF-κB, a transcription factor, is activated by inflammatory stimuli and stimulates IκB kinase in the cytosol (Brasier, 2010) . Consequently, signaling pathways lead to migration of NF-κB toward the nucleus via canonical or noncanonical, which initiate the target-specific gene. Upon stimulation, NF-κB pathway acts very quickly and subsequently elevated the proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α), ultimately results in apoptosis. Again, signaling of TNF-α receptor plays a significant role in the canonical pathway of NF-κB in cellular apoptosis. Following the discussion in the previous section, IL-6 is one of the main activators of JAK/STAT signaling pathway and associated with acute inflammation and cytokine storm (Luo et al., 2020; Mehta et al., 2020; Qin et al., 2020; Tisoncik et al., 2012) . It had been demonstrated that activation of membrane-bound IL-6 receptor stimulates the downstream activation of JAK/STAT signaling, which further triggers the production of IL-6 (Zhang, Wu, Li, Zhao, & Wang, 2020) . These pathways had been reported to be activated aberrantly in COVID-19 patients, thereby aggravating the inflammatory response within host (Catanzaro et al., 2020) . Several repurposed drugs have been identified based on the target, including viral protease, regulating immunity, reducing the inflammatory CRS, declining viral loads, and improving pulmonary function. Currently, the treatment of COVID-19 disease is primarily focused on symptomatic treatment of inflammation, CRS, and compromised respiratory function targeting the inflammatory signaling pathways (Nile et al., 2020) . A specific anti-cytokine approach had been proven to be more effective in treating cytokine storm syndromes targeting IL-1 and IL-6 (Nasonov & Samsonov, 2020; . However, rapid research on the pathophysiology of SARS-CoV-2 helps to reveal some novel targets for potential treatment. Several drugs that have been experimented based on different immuno targets to manage SARS-CoV-2 infection are represented in Table 1 , and their clinical trials are ongoing at an exceptional pace to validate their efficacy and safety to combat the severity of the disease. In recent times, synthetic drugs like hydroxychloroquine, azithromycin, adalimumab, tocilizumab, and baricitinib have been explored under purview of management inflammatory conditions in SARS-CoV-2 infection, however, these agents are associated with several adverse effects including QT prolongation, hepatotoxicity, dyspepsia, abdominal cramps, erythema, eosinophilia, and so on (Bakadia et al., 2020; Falcão et al., 2020; Funck-Brentano et al., 2020; Million et al., 2020; Sernicola et al., 2020; Srinivasa, Tosounidou, & Gordon, 2017; Tsilimbaris et al., 2009; .

Alternatively, the convalescent serum has become one of the best options in the treatment of SARS-CoV-2 infection; however, transfusion of plasma has several side effects, including allergic and anaphylactic reactions, hemolysis, and transfusion-related acute lung injury (MacLennan & Barbara, 2006) . A higher level of inflammation induced by viral load aggravates these adverse effects, especially the hyperactivity of bronchial lining followed by apnea, hypoxia, and multiorgan failure, even leading to death (Fajgenbaum & June, 2020; Gibson, Qin, & Puah, 2020; Huang, Wang, et al., 2020; Wang, Hu, et al., 2020) . Therefore, there is a high demand for suitable alternatives from natural sources where plant-based natural products can safely fulfill the purpose. . Under these circumstances, T A B L E 1 Potential drugs/therapeutic agents with its target on immune system for the treatment of SARS-CoV-2 infection

Chloroquine Suppression of IL-6 and TNF-α (Gao, Tian, & Yang, 2020) Hydroxychloroquine Reduce viral load by inhibiting the IL-6 and TNF-α Azithromycin Blockage of IL-6 and TNF-α Gautret et al., 2020) Anakinra Inhibits the secretion of IL-6 (Monteagudo, Boothby, & Gertner, 2020)

Reduce the level of inflammatory cytokines, chemokines, and adhesion molecules (Horby et al., 2020) Tocilizumab IL-6 receptor antagonists and block IL-6 signaling to revert the cytokine storm production (Zhang, Wu, et al., 2020) Adalimumab Specific blockade of TNF-α (Rizk et al., 2020) Certolizumab Anti-TNF-α antibody Eculizumab Inhibitor of the terminal complement system (Scavone et al., 2020) Baricitinib Targets JAK-STAT and inhibits viral entry and inflammation (Cantini et al., 2020; Zhang, Zhang, Qiao, Zhang, & Qi, 2020) Ruxolitinib JAK-STAT inhibitor (Luo et al., 2020) Fedratinib JAK-STAT inhibitor (Stebbing et al., 2020) Tofacitinib JAK-STAT and TYK2 inhibitor (Luo et al., 2020) Sarilumab Inhibits anti-human IL-6R (Benucci et al., 2020) Myo-inositol Reduction in IL-6 levels, and prevent the cascade inflammation response (Bizzarri, Laganà, Aragona, & Unfer, 2020) Chymotrypsin and papain-like protease Inhibits the host innate immune responses (L. Chen et al., 2005) Mesenchymal stem cell Down-regulation of IL-1, IL-12, TNF-α, and IFN-γ (Leng et al., 2020) Convalescent plasma therapy Inhibits viremia and regulate overactive immune system (cytokine storm) (Chen, Xiong, Bao, & Shi, 2020b) The mechanism of actions to obtain the physiological role depends on several pathways that can be targeted to combat the production of a cytokine storm in COVID-19. The targets with different pathways for action are depicted in Figure 2 . Alternatively, the effect of flavonoids on major cytokines and pathways of action using cell-based in vitro assay models are summarized in Table 2 . The anti-inflammatory action of flavonoids on inhibition of serum cytokines, including IL-6, IL-1β, and TNF-α, along with their pathways of action in the preclinical model of in vivo inflammation like lung injury model is presented in Table 3 , whereas the clinical data of flavonoids toward the cytokine inhibition are summarized in Table 4 . Their antiviral effects can be an added advantage in developing as phytotherapeutics. Their potential can have great importance to reduce the mortality in severe and critically ill COVID-19 patients. We have summarized a few of the important flavonoids in the connecting sections, which are possessing prominent roles toward combating COVID-19.

Epicatechin is a flavonoid that belongs to the class of flavan-3-ol. It is widely present in tea (Chan et al., 1999) . Epicatechin exhibited significant inhibition of IL-6 andIL-8 in human whole blood culture stimulated with phytohemagglutinin (PHA) and lipopolysaccharide (LPS) (Al-Hanbali et al., 2009) . It also has ability to impede significantly the IL-1β action (Mitjans et al., 2004) . Epicatechin at a dose of 15 mg/kg in a preclinical mice model of acute lung injury had depicted noticeable inhibition of IL-6 and TNF-ɑ secretion by interfering with p38 MAPK signaling pathways (Xing et al., 2019) . Epicatechin exhibited the role of a potent reverse transcriptase inhibitor activity in HIV (Chang, Hsu, & Lin, 1994; Chu, Hsieh, & Lin, 1992) . Tea catechins, which contain both epicatechin and epigallocatechin gallate (EGCG), are permitted for use in adults at 500-1000 mg/day (or Camellia sinensis extract at 1000-2000 mg/day) as nutraceuticals (FSSAI, 2016) . A recent in silico report by Ghosh and team revealed that three polyphenols of green tea extract, specifically EGCG, and gallocatechin-3-gallate, possess drug likeliness with less conformational fluctuations. Furthermore, the authors suggested its efficacy against the main protease of SARS-CoV-2 to prevent the key component of a viral replication (Ghosh, Chakraborty, Biswas, & Chowdhuri, 2020) . Similarly, Storozhuk also reported that catechin constituents in green tea are favorable to decrease the associated risks of COVID-19 disease (Storozhuk, 2020 ).

EGCG is another compound from the class of flavan-3-ol and is also widely present in tea (Chan et al., 1999) . It had been reported that EGCG inhibits IL-6, TNF-ɑ, and IL-8 levels in phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated human mast cells (HMC-1) (Shin et al., 2007) . On the other hand, EGCG suppresses the secretion of IL-6, IL-1β, and TNF-ɑ in fluoride (Shanmugam et al., 2016) and sea aspiration (Liu, Dong, et al., 2014 Overall, it could be summarized that EGCG could be a potential candidate to combat SARS-Cov-2.

Hesperidin is the most common citrus flavonoid from the class of flavanones and is widely found in lemons, sweet oranges, and in a few (Continues) Its aglycone part, namely hesperitin, is reported to inhibit TNF-α, IL-1β, and IL-6 significantly by hindering multiple pathways like JNK, NF-κB, and MAPK based on the in vitro (Choi & Lee, 2010; Ren et al., 2016) and in vivo investigations (Kaya, 2020; J. Ye et al., 2019) . In a clinical study involving human adults, hesperidin exhibited a significant reduction of IL-6 level at an oral dose of 160 mg/day (Buscemi et al., 2012; Pla-Pagà et al., 2019) . Computational studies demonstrated that hesperidin could perform a significant antiviral activity against SARS-CoV-2 due to its binding affinity to spike protein, ACE-2, and main protease (Bellavite & Donzelli, 2020; Meneguzzo, Ciriminna, Zabini, & Pagliaro, 2020) . Furthermore, virtual screening purposed that it can interfere with the interaction of ACE-2 receptors, thus preventing the entry of the virus into lung cells (Haggag, El-Ashmawy, & Okasha, 2020) . It exhibited a greater binding affinity toward 3CL-pro, S2-RBD, TMPRSS, and PD-ACE2 to inhibit the SARS-CoV-2 infection (Utomo, Putri, Salsabila, & Meiyanto, 2020) . Hesperidin is considered safe to be administered as nutraceuticals (FSSAI, 2016) . Recently, this is under clinical investigation for the management of COVID-19 (NCT04452799).

Naringenin is an extensively used flavonoid from the class of flavanones and predominantly present in grapefruits (Pandey, Gurung, & Sohng, 2015) . It had shown inhibitory effect of IL-6, IL-1β, and TNF-ɑ levels in LPS-stimulated U937 cells and RAW 264.7 cells (Soromou et al., 2012) . It had also reported inhibiting the secretion of IL-6, IL-1β, and TNF-ɑ in LPS-stimulated acute lung injury in C57/BL6 mice by targeting the inhibition of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway (Minghong Zhao et al., 2017) . It had also shown to reduce the levels of IL-6 and TNF-ɑ in LPS-stimulated acute lung injury in rats via inhibition of the NF-κB pathway (Fouad et al., 2016) . In both cases, the required effective dose was found to be 100 mg/kg through the oral route. Naringin, a glycoside of naringenin, has reported to effectively control the levels of IL-6, IL-1β, TNF-ɑ, IL-4, and IL-17 even at a dose 

Quercetin belongs to the category of flavonols and is widely present in berries, grapes, apples, shallots, onions, and tomatoes ( Note: ‡ Dose mentioned if significant inhibition showed by flavonoid at a particular dose instead of all the experimental dose level(s); ⊥, Significant inhibition; #, In-significant inhibition;

", Activation.

Kolesárová, 2020). In PMACI-stimulated HMC-1, quercetin notably reduced the secretion of IL-6, IL-1β, IL-8, and TNF-α . The production of IL-6, IL-1β, and TNF-α was notably inhibited at 5 μM in A549 cells (T.-C. Wu et al., 2018) . A similar result on IL-1β was also reported in RAW 264.7 cell lines (Blonska et al., 2003) . The levels of IL-6, IL-1β, and TNF-α were reduced significantly in LPS-induced acute lung injury in C57/BL6 mice through reduced expression of cyclooxygenase-2 (COX-2), high mobility group box 1 (HMGB1), inducible nitric oxide synthase (iNOS), and NF-κB p65 phosphorylation (L. Wang et al., 2014) . In clinical subjects with coronary artery disease, quercetin treatment at only 120 mg/kg through oral route significantly inhibited the secretion of IL-1β, and TNF-α (Chekalina et al., 2018) . Minute reduction in IL-6 and TNF-α was observed in community-dwelling adults at 500-1000 mg/day in combination with vitamin C and niacin (Knab et al., 2011) . It has been reported that administration of quercetin could lead to reduced level Clercq, & Neyts, 2008; Pagani, 1990) . In Vero cells, it showed to inhibit the dengue virus type-2 replication that can cause a 67% reduction of viral load at a concentration of 36 μg/ml (Zandi et al., 2011) . Pretreatment of quercetin blocked virulence, entry, and replication of rhinovirus in BEAS-2B cells (Ganesan et al., 2012) . It notably inhibited the reverse transcriptase activity in a dosedependent manner in cultured cells infected with Maloney murine leukemia virus, Rous-associated virus-2, and Avian myeloblastosis reverse transcriptase (Spedding, Ratty, & Middleton Jr, 1989) . It also demonstrated a potent inhibition activity against HIV and hepatitis C virus protease as well as ability to interfere with virus assembly by modulating the heat shock protein expression (Bachmetov et al., 2012; Gonzalez et al., 2009; H.-X. Xu, Wan, Dong, BuT, & Foo, 2000) . Quercetin and its galactoside are known to interfere with the proteolytic activity by binding to SARS-CoV 3CL protease (Alrasheid et al., 2021; Colunga Biancatelli et al., 2020) . In silico studies illustrated that quercetin could interfere with M pro and ACE2 as well as showed potential inhibition when compared to the synthetic repurposed drug, hydroxychloroquine (Omar, Bouziane, Bouslama, & Djemel, 2020) . Quercetin impedes the entry of the SARS virus by targeting ACE2 and exhibits antiviral activity (P. K. Agrawal, Agrawal, & Blunden, 2020; Chaabi, 2020; Pawar & Pal, 2020) . Derosa and its team demonstrated the role of quercetin in SARS-CoV-2 due to its ability to inhibit main protease as well as its anti-inflammatory and thrombin-inhibitory activities (Bastaminejad & Bakhtiyari, 2020 (Boots, Drent, de Boer, Bast, & Haenen, 2011) 120 mg/day Oral 8 weeks Inhibited IL-1β and TNF-α in coronary artery disease (Chekalina et al., 2018) 500 and 1000 mg/day in combination with vitamin C and Niacin

Oral 12 weeks A minute reduction in IL-6 level in community-dwelling adult (Knab et al., 2011) Luteolin 100 mg/day Oral 26 weeks Reduced IL-6 and TNF-α levels in children with autism spectrum disorders (Tsilioni, Taliou, Francis, & Theoharides, 2015) Diosmin 1200 mg/day Oral 12 weeks Decreased IL-6 and TNF-α levels in patients with chronic venous disorders (Feldo et al., 2019) Silymarin 420 mg/day Oral 12 weeks Decreased serum TNF-ɑ level and enhanced IL-4 and IFN-γ levels in β-thalassemia patients (Gharagozloo, Karimi, & Amirghofran, 2013) Silibinin 240 mg/day Oral 16 weeks Reduced IL-6, IL-8 and TNF-α levels and increased production of IL-2 and IL-10 in active rheumatoid patients (Hussain, Mortada, Jasim, & Gorial, 2016) Mahmoudian-Sani, 2021). A tripartite combination consisting of quercetin/vitamin D/estradiol had depicted the expression of 73% of human genes encoding SARS-CoV-2 targets (Glinsky, 2020) . Aucoin and co-workers demonstrated the effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans (Aucoin et al., 2020) . It might act as a therapeutic drug to treat SARS-CoV-2 induced nephrotoxicity (Diniz, Souza, Duarte, & Sousa, 2020) . Supplementation of quercetin along with multivitamin and trace elements (vitamins A, B complex, C, D and E, zinc) can be useful in prophylaxis and treatment of mild symptomatic COVID-19

patients (Petric, 2020) . (Veckenstedt, Béládi, & Mucsi, 1978) . Quercetin obtained from the extracts of citrus fruits and other vegetables is recommended as a nutraceutical, where the maximum recommended intake of quercetin is 100 mg/day (FSSAI, 2016) . Quercetin in phytosomal formulation, which was developed using food grade lecithin to boost its oral absorption, was found to be effective in allergies through stabilization of the mast cell membranes to decrease the release of histamine (Colunga Biancatelli et al., 2020) . Recently, this is under clinical investigation for the management of SARS-CoV-2 (NCT04377789, NCT04578158).

Rutin is one of the common flavonols widely distributed in citrus fruits and buckwheat (Lachman, Orsak, Pivec, & Faustusova, 2000) . It is basically a glycoside form of quercetin. Treatment of rutin significantly inhibited the secretion of IL-6, IL-1β, IL-8, and TNF-α in PMACI-stimulated HMC-1 cells . Al-Zahrani, 2020; Xu, Yang, et al., 2020) . A Molecular docking study showed significant binding of rutin with RdRp, M pro , PL pro , and S-proteins of SARS-CoV-2 (F. Rahman et al., 2021) . Rutin from fruit peels is considered as safe to use as nutraceuticals (FSSAI, 2016).

Luteolin is one of the most common flavones, which are widely distributed in fruits and vegetables such as cabbages, carrots, broccoli, celery, parsley, and apple skins (López-Lázaro, 2009 ). In an in vitro nickel-stimulated A549 cell lines assay, luteolin considerably reduced the production of IL-6, IL-1β, IL-10, and TNF-α. It inhibited the secretion of IL-6 and TNF-α in LPS-stimulated RAW 264.7 cells (Xagorari et al., 2001) . Similar downregulation activities of the important cytokines are also reported in the in vitro assay at a very low micro-molar level using PBMCs and RAW 264.7 cells (Hougee et al., 2005) . 

Baicalein is a flavone extracted mainly from the roots of Scutellaria baicalensis and Scutellaria lateriflora (Varsha et al., 2017) . It had shown the inhibitory effect of IL-6 and TNF-ɑ secretion significantly in LPSstimulated HUVECs as well as H5N1 virus-induced stimulation of cytokines in A549 cells (Sithisarn et al., 2013) . The ability to inhibit IL-8 and IL-1β was also reported using HUVECs and RAW 264.7 cells, respectively (Blonska et al., 2003) . Baicalein treatment significantly decreased the level of IL-6, IL-1β, and TNF-ɑ in LPS-induced acute lung injury in Sprague-Dawley rats through inhibition of NF-κB mediated inflammatory response and upregulation of Nrf2/Heme oxygenase-1 (HO-1) pathway (Tsai et al., 2014) . Similar activity of hindering IL-6, TNF-ɑ, and IL-8 was also reported for baicalin, the aglycone of baicalein in Type II pneumocytes as well as in vivo acute lung injury model (Lixuan et al., 2010; Meng et al., 2019) . Moreover, this aglycone baicalin had been shown to inhibit TGF-β and IL-18 in LPSinduced CX3CL1 knockout mice model of lung injury (Ding et al., 2016) . Baicalein, at a concentration of 2 μg/ml, exhibited a 70%

inhibition of HIV reverse transcriptase activity (Ono, Nakane, Fukushima, Chermann, & Barré-Sinoussi, 1990 Baicalin had been reported to inhibit ACE activity (Yang, Islam, Wang, Li, & Chen, 2020) . Baicalein and its aglycone unit possessed a significant inhibition against 3CL pro of SARS-CoV-2 (Su et al., 2020) . A recent report revealed that the application of baicalein would inhibit the replication of the SARS-CoV-2 through the interference of mitochondrial oxidative phosphorylation. The inhibitory effect of baicalein is mPTP dependent and reversible, where co-application of mPTP inhibitors with baicalein could act synergistically in the control of SARS-CoV-2 ).

Diosmin is one of the most prevalent flavones that is consumed through diverse dietary sources like fruits, viz., grapes, citrus fruits, berries, pomegranates, and apples; vegetables, viz., onions, broccoli, and leafy greens; legumes, soy products, as well as beverages, viz., red wine and tea (Roy, Azamthulla, & Mukkerjee, 2020) . Diosmin had significantly reduced the production of IL-6 and TNF-α in LPS-induced acute lung injury in Balb/c mice via targeting the TLR4-MyD88-NF-κB signaling pathway (Imam et al., 2015) . Diosmin is a glycoside of diosmetin, which had also shown a significant inhibitory effect on IL-6, IL-1β, and TNF-α via activation of Nrf2 and inhibition of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in LPS-induced animal model of lung injury (Q. Liu et al., 2018) . Diosmin decreased the production of IL-1β and TNF-α in patients with chronic venous disorders (Feldo et al., 2019) . In silico studies have demonstrated that diosmin possess the ability to interfere with 3CLpro of SARS-CoV-2 by blocking its substrate-binding site, with an IC 50 of 8.3 μM (Chen, Yiu, & Wong, 2020) . Molecular docking studies revealed that diosmin is a potent candidate to inhibit the M pro (Adem, Eyupoglu, Sarfraz, Rasul, & Ali, 2020) . It exhibited a greater binding affinity toward 3CL-pro, S2-RBD, TMPRSS, and ACE2 to inhibit the SARS-CoV-2 infection (Utomo et al., 2020) . Citrus flavonoids are safe to use at 150-600 mg/kg as mentioned in nutraceuticals guidelines (FSSAI, 2016) . Recently, this agent is under clinical investigation for the management of SARS-CoV-2 (NCT04452799).

Genistein is an isoflavone, which is primarily found in edible legumes, red clover, and soy-based foods (Liggins et al., 2000) . The level of IL-6 and TNF-α was notably inhibited by genistein in both LPS-stimulated RAW 264.7 cells and Jurkat E6.1 T cells (Karieb & Fox, 2013 The above compound inhibited the production of virus and prevented plaque generation with an IC 50 of 46 μM and 33μM for macaque and human fibroblasts, respectively. Genistein reduced the viral load by 99% and 93% in combination with ganciclovir and acyclovir, respectively, using the same concentration of IC 50 (LeCher, Diep, Krug, & Hilliard, 2019) . It inhibited in vitro viral replication and its associated proteins in Vero cells infected with the swine flu virus (Arabyan et al., 2018) .

Molecular docking studies reported that genistein interferes with M pro and RdRp to inhibit the activity of SARS-CoV-2 .

Genistein or its sources like soya protein isolate/edible legume seed protein isolate are safe to use as a nutraceutical (FSSAI, 2016).

Biochanin A is an isoflavone that is widely present in zigzag clover, red clover, crimson clover, and also in other plants such as soy, peanuts, alfalfa, and chickpea (Sundaresan, Radhiga, & Deivasigamani, 2018) . It had been reported to inhibit IL-6, IL-1β, and TNF-α production in LPSstimulated RAW 264.7 cells via regulating the NF-κB pathway (Kole et al., 2011) . Moreover, treatment of Biochanin A significantly reduced the secretion of IL-6 in H5N1 virus-induced stimulation of cytokines in A549 cells via reducing the activation of multiple pathways like Akt, extracellular signal-regulated kinases (ERK), and NF-κB (Sithisarn et al., 2013) . In an in vivo model of LPS-induced acute lung injury in C57/BL6 mice, biochanin A notably reduced the level of IL-6, IL-1β, and TNF-ɑ through downregulation of TLR4/NF-κB signaling pathway and upregulation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) . The replication of the avian influenza H5N1 virus strain was reduced to 55-fold by biochanin A at a concentration of 40 μM in A549 cells (Sithisarn et al., 2013) . Molecular docking analysis revealed that biochanin A significantly binds to the active sites of RBD-Sand ACE2 to inhibit the viral infection (Gorla, Rao, Kulandaivelu, Alavala, & Panda, 2020 ).

Silymarin is one of the common flavonolignans and is widely present in milk thistle (Vaknin, Hadas, Schafferman, Murkhovsky, & Bashan, 2008) . Treatment of silymarin had decreased the level of IL-6

and TNF-ɑ significantly in LPS-induced acute lung injury in Wistar rats via downregulation of the NF-κB signaling pathway (Z. Zhu & Sun, 2018) . In β-thalassemia patients, oral treatment of silymarin at a dose of 420 mg/day demonstrated a reduced level of TNF-ɑ but enhanced the production of IL-4 and IFN-γ (Gharagozloo et al., 2013) .

The compound exhibited threefold inhibition at a concentration of 25 μg/ml against the chikungunya virus in cultured cells (Lani et al., 2015) . Tables 2 and 3 .

In spite of rapid advances in the modern system of medicines, there is no effective and safe therapy available to date for the management of COVID-19. Therefore, exploration of dietary supplementation was evaluated for their beneficial role in the management of the critical situation, where these were found to be an effective option to boost up the immunity for the prevention and recovery from SARS-CoV-2 infection. Based on the inhibitory effect of important cytokines, e.g., IL-6, IL- Clinical exploration is warranted to establish suitable phytotherapeutics and their regimens for the effective and safe management of the cytokine storm in COVID-19 condition to manage ARDS.

AG and DM are thankful to DST and CSIR (New Delhi, India), respectively, for providing fellowship to carry out research work.

The authors declare that they have no conflict of interest to disclose.

Data sharing not applicable -no new data generated (Review article).

Utpal Nandi https://orcid.org/0000-0002-7868-0240

Combination and tricombination therapy to destabilize the structural integrity of COVID-19 by some bioactive compounds with antiviral drugs: Insights from molecular docking study

Identification of potent COVID-19 main protease (Mpro) inhibitors from natural polyphenols: An in silico strategy unveils a hope against CORONA

Potential roles of medicinal plants for the treatment of viral diseases focusing on COVID-19: A review

Pharmacological activities of flavonoids: A review

Quercetin: Antiviral significance and possible COVID-19 integrative considerations

Therapeutic potential of flavonoids and their mechanism of action against microbial and viral infections-A review

Naringin attenuates the development of carrageenan-induced acute lung inflammation through inhibition of NF-κb, STAT3 and pro-inflammatory mediators and enhancement of IκBα and anti-inflammatory cytokines

Inhibition of chikungunya virus replication by hesperetin and naringenin

Why the immune system fails to mount an adaptive immune response to a Covid-19 infection

Effects of quadruple therapy: Zinc, quercetin, bromelain and vitamin C on the clinical outcomes of patients infected with COVID-19

Nrf2 signaling pathway: Pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease

Epicatechin suppresses IL-6, IL-8 and enhances IL-10 production with NF-κB nuclear translocation in whole blood stimulated system

Evaluation of certain medicinal plants compounds as new potential inhibitors of novel corona virus (COVID-19) using molecular docking analysis

Immunomodulatory effects of quercetin in patient with active rheumatoid arthritis

Rutin as a promising inhibitor of main protease and other protein targets of Covid-19: In silico study. Natural Product Communications

Luteolin: A dietary molecule as potential anti-COVID-19 agent

Genistein inhibits African swine fever virus replication in vitro by disrupting viral DNA synthesis

The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review

Suppression of hepatitis C virus by the flavonoid quercetin is mediated by inhibition of NS3 protease activity

Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine

Bioflavonoid quercetin-food sources, bioavailability, absorbtion and effect on animal cells

Quercetin and its relative therapeutic Potential against COVID-19: A retrospective review and prospective overview

Hesperidin and SARS-CoV-2: New light on the healthy function of citrus fruits

COVID-19 pneumonia treated with Sarilumab: A clinical series of eight patients

Inositol and pulmonary function. Could myo-inositol treatment downregulate inflammation and cytokine release syndrome in SARS-CoV-2?

Effect of flavone derivatives on interleukin-1β (IL-1β) mRNA expression and IL-1β protein synthesis in stimulated RAW 264.7 macrophages

Naringenin has antiinflammatory properties in macrophage and ex vivo human wholeblood models

Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis

Natural products for COVID-19 prevention and treatment regarding to previous coronavirus infections and novel studies

The nuclear factor-κB-interleukin-6 signalling pathway mediating vascular inflammation

Botanical drugs and supplements affecting the immune response in the time of COVID-19: Implications for research and clinical practice

Natural flavonoids: Classification, potential role, and application of flavonoid analogues

Effects of red orange juice intake on endothelial function and inflammatory markers in adult subjects with increased cardiovascular risk

Genistein can mitigate the effect of radiation on rat lung tissue

Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

The green tea molecule EGCG inhibits Zika virus entry

Immune response in COVID-19: Addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2

Antiviral effects of quercetin and related compounds

Jasmine green tea epicatechins are hypolipidemic in hamsters (Mesocricetus auratus) fed a high fat diet

Inhibitory effects of polyphenolic catechins from Chinese green tea on HIV reverse transcriptase activity

Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Paper presented at the Seminars in Immunopathology

Quercetin reduces the transcriptional activity of NF-kB in stable coronary artery disease

Luteolin ameliorates experimental lung fibrosis both in vivo and in vitro: Implications for therapy of lung fibrosis

Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome

Synergistic activity of baicalein with ribavirin against influenza A (H1N1) virus infections in cell culture and in mice

Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro

Convalescent plasma as a potential therapy for COVID-19

Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice

Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro ) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

Efficacy of hydroxychloroquine in patients with COVID-19: Results of a randomized clinical trial

Advances in the possible treatment of COVID-19: A review

Effects of hesperetin on the production of inflammatory mediators in IL-1β treated human synovial cells

Phytochemicals containing biologically active polyphenols as an effective agent against Covid-19-inducing coronavirus

Inhibitory effects of flavonoids on Moloney murine leukemia virus reverse transcriptase activity

Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro

Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19)

WHO declares COVID-19 a pandemic

Antiviral effect of silymarin against Zika virus in vitro

Diacerein: A potential multi-target therapeutic drug for COVID-19

Selective inhibitors of picornavirus replication

Citrus limon: A source of flavonoids of pharmaceutical interest

A role for quercetin in coronavirus disease 2019 (COVID-19)

Phytochemicals: Nutraceuticals and human health

Baicalin exerts protective effects against lipopolysaccharide-induced acute lung injury by regulating the crosstalk between the CX3CL1-CX3CR1 axis and NF-κB pathway in CX3CL1-knockout mice

Bioactive terpenes and their derivatives as potential SARS-CoV-2 proteases inhibitors from molecular modeling studies

Mechanistic aspects and therapeutic potential of quercetin against COVID-19-associated acute kidney injury

Coronavirus disease-2019 treatment strategies targeting interleukin-6 signaling and herbal medicine

Immunoinformatics design of novel multi-epitope subunit vaccine for SARS-CoV-2 by exploring virus conserved sequences of the spike glycoproteins

Natural products may interfere with SARS-CoV-2 attachment to the host cell

Cytokine storm

Case Report: Hepatotoxicity associated with the use of hydroxychloroquine in a patient with COVID-19

Antiviral activity of luteolin against Japanese encephalitis virus

Effect of diosmin administration in patients with chronic venous disorders on selected factors affecting angiogenesis

Fisetin alleviates lipopolysaccharide-induced acute lung injury via TLR4-mediated NF-κB signaling pathway in rats

Daidzein attenuates lipopolysaccharide-induced acute lung injury via toll-like receptor

Identifying new pathways and targets for wound healing and therapeutics from natural sources

Apoptosis, pyroptosis, and necrosis: Mechanistic description of dead and dying eukaryotic cells

Protective effect of naringenin against lipopolysaccharide-induced acute lung injury in rats

Antibacterial, antiviral, and antifungal properties of wines and winery byproducts in relation to their flavonoid content

Food safety and standards authority of India, ministry of health and family welfare

Retraction and republication: Cardiac toxicity of hydroxychloroquine in COVID-19

Quercetin inhibits rhinovirus replication in vitro and in vivo

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease

Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids

Immunomodulatory effects of silymarin in patients with β-thalassemia major

Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (M pro ) inhibitors-An in silico docking and molecular dynamics simulation study

COVID-19 acute respiratory distress syndrome (ARDS): Clinical features and differences from typical pre-COVID-19 ARDS

Tripartite combination of candidate pandemic mitigation agents: Vitamin D, quercetin, and estradiol manifest properties of medicinal agents for targeted mitigation of the COVID-19 pandemic defined by genomics-guided tracing of SARS-CoV-2 targets in human cells

Lead finding from selected flavonoids with antiviral (SARS-CoV-2) potentials against COVID-19: An in-silico evaluation

Clinical characteristics of coronavirus disease 2019 in China

Protective effect of silibinin on lipopolysaccharide-induced inflammatory responses in equine peripheral blood mononuclear cells, an in vitro study

(+)-Catechin inhibits tumour angiogenesis and regulates the production of nitric oxide and TNF-α in LPS-stimulated macrophages

Is hesperidin essential for prophylaxis and treatment of COVID-19 infection? Medical Hypotheses

Anti-inflammatory effects of flavonoids: Genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-κB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-κB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages

Noval coronavirus disease (COVID-19): A pandemic (epidemiology, pathogenesis and potential therapeutics)

Flavonoid content of US fruits, vegetables, and nuts

Flavonoids, a class of natural products of high pharmacological potency

Effect of dexamethasone in hospitalized patients with COVID-19: Preliminary report

Myricetin attenuates LPS-induced inflammation in RAW 264.7 macrophages and mouse models

Decreased pro-inflammatory cytokine production by LPS-stimulated PBMC upon in vitro incubation with the flavonoids apigenin, luteolin or chrysin, due to selective elimination of monocytes/macrophages

Biochanin A protect against lipopolysaccharide-induced acute lung injury in mice by regulating TLR4/NF-κB and PPAR-γ pathway

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Luteolin inhibits cell cycle progression and induces apoptosis of breast cancer cells through downregulation of human telomerase reverse transcriptase

Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner

Silibinin improves the effects of methotrexate in patients with active rheumatoid arthritis: Pilot clinical study

Diosmin downregulates the expression of T cell receptors, pro-inflammatory cytokines and NF-κB activation against LPS-induced acute lung injury in mice

Diet supplementation, probiotics, and nutraceuticals in SARS-CoV-2 infection: A scoping review

Natural products, a potential therapeutic modality in management and treatment of nCoV-19 infection: Preclinical and clinical based evidence

Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data

Tea polyphenols EGCG and theaflavin inhibit the activity of SARS-CoV-2 3CL-protease in vitro

Plant-derived immunomodulators: An insight on their preclinical evaluation and clinical trials

Enhancing immunity in viral infections, with special emphasis on COVID-19: A review

Inhibition of SARS-CoV 3CL protease by flavonoids

Flavonoids and cardiovascular diseases

Anti-inflammatory effects of galangin on lipopolysaccharide-activated macrophages via ERK and NF-κB pathway regulation

Targeting interleukin-6 signaling in clinic

Suppression of T cell-induced osteoclast formation

Antiviral effect of flavonoids on human viruses

Protective effects of hesperetin on lipopolysaccharideinduced acute lung injury in a rat model

In vitro antiviral activity of fisetin, rutin and naringenin against dengue virus type-2

Identification of dietary molecules as therapeutic agents to combat COVID-19 using molecular docking studies

Genistein inhibits pro-inflammatory cytokines in human mast cell activation through the inhibition of the ERK pathway

Antiinflammatory plant flavonoids and cellular action mechanisms

Naringin protects acrolein-induced pulmonary injuries through modulating apoptotic signaling and inflammation signaling pathways in mice

Immunopathogenesis and treatment of cytokine storm in COVID-19

Theaflavin inhibits LPS-induced IL-6, MCP-1, and ICAM-1 expression in bone marrow-derived macrophages through the blockade of NF-κB and MAPK signaling pathways

Antiinflammatory effects of liquiritigenin as a consequence of the inhibition of NF-κB-dependent iNOS and proinflammatory cytokines production

Influence of quercetin supplementation on disease risk factors in community-dwelling adults

Theaflavin-3, 3 0 -digallate, a black tea polyphenol, attenuates adipocyte-activated inflammatory response of macrophage associated with the switch of M1/M2-like phenotype

Isoflavone aglycones attenuate cigarette smokeinduced emphysema via suppression of neutrophilic inflammation in a COPD murine model

Biochanin-A, an isoflavon, showed anti-proliferative and anti-inflammatory activities through the inhibition of iNOS expression, p38-MAPK and ATF-2 phosphorylation and blocking NFκB nuclear translocation

Chemistry and biological activities of flavonoids: An overview

Content of rutin in selected plant sources

Structure-activity association of flavonoids in lung diseases

Flavonoids in food and natural antioxidants in wine

Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia

Antiviral activity of silymarin against chikungunya virus

Genistein has antiviral activity against herpes b virus and acts synergistically with antiviral treatments to reduce effective dose

Anti-inflammatory effects of eriodictyol in lipopolysaccharide stimulated raw 264.7 murine macrophages

Barrier protective effects of rutin in LPS-induced inflammation in vitro and in vivo

Anti-inflammatory effects of Baicalin, Baicalein, and Wogonin in vitro and in vivo

Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia

Flavonoids as cytokine modulators: A possible therapy for inflammation-related diseases

Apigenin C-glycosides of Microcos paniculata protects lipopolysaccharide induced apoptosis and inflammation in acute lung injury through TLR4 signaling pathway

Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia

Luteolin suppresses inflammatory mediator expression by blocking the Akt/NFκB pathway in acute lung injury induced by lipopolysaccharide in mice

The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing

Daidzein and genistein contents of vegetables

Casticin inhibits interleukin-1β-induced ICAM-1 and MUC5AC expression by blocking NF-κB, PI3K-Akt, and MAPK signaling in human lung epithelial cells

Casticin inhibits COX-2 and iNOS expression via suppression of NF-κB and MAPK signaling in lipopolysaccharide-stimulated mouse macrophages

Genistein alleviates radiation-induced pneumonitis by depressing Ape1/Ref-1 expression to down-regulate inflammatory cytokines

Diosmetin alleviates lipopolysaccharide-induced acute lung injury through activating the Nrf2 pathway and inhibiting the NLRP3 inflammasome

Pinocembrin protects human brain microvascular endothelial cells against fibrillar amyloid-β1− 40 injury by suppressing the MAPK/NF-κ B inflammatory pathways

Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury

Fisetin inhibits lipopolysaccharide-induced macrophage activation and dendritic cell maturation

Epigallocatechin-3-gallate ameliorates seawater aspiration-induced acute lung injury via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats

Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19

Elevated plasma level of selective cytokines in COVID-19 patients reflect viral load and lung injury

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2

Baicalin attenuates inflammation by inhibiting NF-κB activation in cigarette smoke induced inflammatory models

Distribution and biological activities of the flavonoid luteolin

Targeting JAK-STAT signaling to control cytokine release syndrome in COVID-19

Isovitexin exerts anti-inflammatory and anti-oxidant activities on lipopolysaccharide-induced acute lung injury by inhibiting MAPK and NF-κB and activating HO-1/Nrf2 pathways

Formononetin inhibited the inflammation of LPS-induced acute lung injury in mice associated with induction of PPAR gamma expression

Risks and side effects of therapy with plasma and plasma fractions

Epigallocatechin gallate and theaflavin gallate interaction in SARS-CoV-2 spike-protein central channel with reference to the hydroxychloroquine interaction: Bioinformatics and molecular docking study

Myricetin attenuates lung inflammation and provides protection against lipopolysaccharide-induced acute lung injury by inhibition of NF-κB pathway in rats

COVID-19: Consider cytokine storm syndromes and immunosuppression

Accelerated production of hesperidin-rich citrus pectin from waste citrus peel for prevention and therapy of COVID-19

Baicalin ameliorates lipopolysaccharide-induced acute lung injury in mice by suppressing oxidative stress and inflammation via the activation of the Nrf2-mediated HO-1 signaling pathway

Full-length title: Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille

Novel epicatechin derivatives with antioxidant activity modulate interleukin-1β release in lipopolysaccharide-stimulated human blood

Continuous intravenous Anakinra infusion to calm the cytokine storm in macrophage activation syndrome

Fighting COVID-19 exhausts T cells

The role of Interleukin 6 inhibitors in therapy of severe COVID-19

Flavonoids in human urine as biomarkers for intake of fruits and vegetables

COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons

The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua liu xing bing xue za zhi= Zhonghua liuxingbingxue zazhi

In-silico identification of potent inhibitors of COVID-19 main protease (M pro ) and angiotensin converting enzyme 2 (ACE2) from natural products

Quercetin, hispidulin, and cirsimaritin exhibited better potential inhibition than hydroxy-chloroquine against COVID-19 main protease active site and ACE2

Cannabis for COVID-19: Can cannabinoids quell the cytokine storm?

Differential inhibitory effects of various flavonoids on the activities of reverse transcriptase and cellular DNA and RNA polymerases

Effects of propolis flavonoids on virus infectivity and replication

Dietary sources, bioavailability and biological activities of naringenin and its derivatives

Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells

Molecular and functional resemblance of dexamethasone and quercetin: A paradigm worth exploring in dexamethasone-nonresponsive COVID-19 patients

Fisetin inhibits the generation of inflammatory mediators in interleukin-1β-induced human lung epithelial cells by suppressing the Nf-κb and Erk1/2 pathways

Quercetin and COVID-19

Effects of hesperidin consumption on cardiovascular risk biomarkers: A systematic review of animal studies and human randomized clinical trials

Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic

Current drugs with potential for treatment of COVID-19: A literature review

Molecular docking analysis of rutin reveals possible inhibition of SARS-CoV-2 vital proteins

Comparison of viral clearance between ivermectin with doxycycline and hydroxychloroquine with azithromycin in COVID-19 patients

Hesperetin suppresses inflammatory responses in lipopolysaccharideinduced RAW 264.7 cells via the inhibition of NF-κB and activation of Nrf2/HO-1 pathways

Taxifolin inhibited the nitric oxide production and expression of pro-inflammatory cytokine mRNA in lipopolysaccharide-stimulated RAW264. 7 cells

Pharmaco-immunomodulatory therapy in COVID-19

Hesperidin and diosmin-a novel drugs

Luteolin attenuates acute lung injury in experimental mouse model of sepsis

Antioxidant polyphenols in cancer treatment: Friend, foe or foil? Paper presented at the Seminars in Cancer Biology

Roles of flavonoids against coronavirus infection

Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke

Protective effect of flavonoids on doxorubicin-induced cardiotoxicity

Antiinflammatory potential of Quercetin in COVID-19 treatment

Hydroxychloroquine in dermatology and beyond: Recent update

Current pharmacological treatments for COVID-19: What's next?

JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

Flavonoids as antiinflammatory agents

Toxic erythema" and eosinophilia associated to tocilizumab therapy in a COVID-19 patient

Potential renoprotective effects of silymarin against nephrotoxic drugs: A review of literature

Epigallocatechin gallate potentially abrogates fluoride induced lung oxidative stress, inflammation via Nrf2/Keap1 signaling pathway in rats: An in-vivo and in-silico study

Luteolin and abyssinone II as potential inhibitors of SARS-CoV-2: An in silico molecular modeling approach in battling the COVID-19 outbreak

COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Epigallocatechin-3-gallate inhibits secretion of TNF-α, IL-6 and IL-8 through the attenuation of ERK and NF-κB in HMC-1 cells

Galangin dampens mice lipopolysaccharide-induced acute lung injury

Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases

Is a "cytokine storm" relevant to COVID-19?

Differential antiviral and anti-inflammatory mechanisms of the flavonoids biochanin A and baicalein in H5N1 influenza A virus-infected cells

World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19)

Silymarin efficacy against influenza A virus replication

Antiviral effect of catechins in green tea on influenza virus

In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses

Anti-inflammatory effects of flavonoids in neurodegenerative disorders

Inhibition of reverse transcriptases by flavonoids

Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: A brand-related issue?

COVID-19: Combining antiviral and antiinflammatory treatments

COVID-19: Could green tea catechins reduce the risks? MedRxiv

Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro

Biological activity of biochanin A: A review

(+)-Catechin attenuates NF-κB activation through regulation of Akt, MAPK, and AMPK signaling pathways in LPS-induced BV-2 microglial cells

Lymphopenia predicts disease severity of COVID-19: A descriptive and predictive study

Flavonoids and asthma

Natural products for drug discovery in the 21st century: Innovations for novel drug discovery

Therapeutic effects of silibinin on LPSinduced acute lung injury by inhibiting NLRP3 and NF-κB signaling pathways

Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer

The effects of morin on lipopolysaccharide-induced acute lung injury by suppressing the lung NLRP3 inflammasome

Into the eye of the cytokine storm

Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review

Baicalein, an active component of Scutellaria baicalensis, protects against lipopolysaccharide-induced acute lung injury in rats

Evaluation of potential retinal toxicity of adalimumab (Humira)

Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6

Naringenin, a flavanone with antiviral and anti-inflammatory effects: A promising treatment strategy against COVID-19

Evaluation of medicinal herbs as a potential therapeutic option against SARS-CoV-2 targeting its main protease

The chemopreventive potential of diosmin and hesperidin for COVID-19 and its comorbid diseases

The potential of milk thistle (Silybum marianum L.), an Israeli native, as a source of edible sprouts rich in antioxidants

Natural plant-derived anticancer drugs nanotherapeutics: A review on preclinical to clinical success

Effect of treatment with certain flavonoids on Mengo virus-induced encephalitis in mice

In search of preventative strategies: Novel anti-inflammatory high-CBD Cannabis sativa extracts modulate ACE2 expression in COVID-19 gateway tissues

Casticin inhibits lipopolysaccharide-induced acute lung injury in mice

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan

Casticin alleviates lipopolysaccharide-induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF-κB pathways

Protective effect of quercetin on lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammatory cell influx

The definition and risks of cytokine release syndrome-like in 11 COVID-19-infected pneumonia critically ill patients: Disease characteristics and retrospective analysis

Updated understanding of the outbreak of

Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells

In vitro and in vivo anti-inflammatory effects of theaflavin-3, 3 0 -digallate on lipopolysaccharide-induced inflammation

Luteolin inhibits an endotoxinstimulated phosphorylation cascade and proinflammatory cytokine production in macrophages

The açaí flavonoid velutin is a potent anti-inflammatory agent: Blockade of LPS-mediated TNF-α and IL-6 production through inhibiting NF-κB activation and MAPK pathway

Epicatechin alleviates inflammation in lipopolysaccharide-induced acute lung injury in mice by inhibiting the p38 MAPK signaling pathway

Inhibitory activity of flavonoids and tannins against HIV-1 protease

Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Discovery of potential flavonoid inhibitors against COVID-19 3CL proteinase based on virtual screening strategy

Food as medicine: A possible preventive measure against coronavirus disease (COVID-19)

Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): A review and perspective

Chrysin attenuates carrageenaninduced pleurisy and lung injury via activation of SIRT1/NRF2 pathway in rats

Wogonin prevents lipopolysaccharide-induced acute lung injury and inflammation in mice via peroxisome proliferator-activated receptor gamma-mediated attenuation of the nuclear factor-kappaB pathway

Protective effects of hesperetin on lipopolysaccharide-induced acute lung injury by targeting MD2

The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19

The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro

Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK-NF-κB pathway

Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells

Anti-Inflammatory activities of licorice extract and its active compounds, glycyrrhizic acid, liquiritin and liquiritigenin, in BV2 cells and mice liver

COVID-19 pathophysiology: A review

Flavonoids: Promising natural compounds against viral infections

Antiviral activity of four types of bioflavonoid against dengue virus type-2

Novel antiviral activity of baicalein against dengue virus

Cardiovascular effects of hesperidin: A flavanone glycoside

An overview on immunoregulatory and anti-inflammatory properties of chrysin and flavonoids substances

Silybin attenuates LPS-induced lung injury in mice by inhibiting NF-κB signaling and NLRP3 activation

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Kaempferol ameliorates H9N2 swine influenza virus-induced acute lung injury by inactivation of TLR4/MyD88-mediated NF-κB and MAPK signaling pathways

COVID-19: Melatonin as a potential adjuvant treatment

Antioxidant, anti-inflammatory, antibacterial, and analgesic activities and mechanisms of quinolines, indoles and related derivatives

Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies

Naringenin ameliorates LPS-induced acute lung injury through its anti-oxidative and anti-inflammatory activity and by inhibition of the PI3K/AKT pathway

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study

Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients

Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity

Silymarin mitigates lung impairments in a rat model of acute respiratory distress syndrome

Flavonoids as potential phytotherapeutics to combat cytokine storm in SARS-CoV-2