key: cord-0777629-r9o20hri
authors: Palit, Partha; Mukhopadhyay, Aparna; Chattopadhyay, Debprasad
title: Phyto‐pharmacological perspective of Silymarin: A potential prophylactic or therapeutic agent for COVID‐19, based on its promising immunomodulatory, anti‐coagulant and anti‐viral property
date: 2021-04-04
journal: Phytother Res
DOI: 10.1002/ptr.7084
sha: 1b71623c26ac2462011b56bfede4f0eee6a06fc0
doc_id: 777629
cord_uid: r9o20hri

Coronavirus disease 2019 (COVID‐19) triggered by a new viral pathogen, named severe acute respiratory syndrome Coronavirus‐2 (SARS‐CoV‐2), is now a global health emergency. This debilitating viral pandemic not only paralyzed the normal daily life of the global community but also spread rapidly via global travel. To date there are no effective vaccines or specific treatments against this highly contagious virus; therefore, there is an urgent need to advocate novel prophylactic or therapeutic interventions for COVID‐19. This brief opinion critically discusses the potential of Silymarin, a flavonolignan with diverse pharmacological activity having antiinflammatory, antioxidant, antiplatelet, and antiviral properties, with versatile immune‐cytokine regulatory functions, that able to bind with transmembrane protease serine 2 (TMPRSS2) and induce endogenous antiviral cytokine interferon‐stimulated gene 15, for the management of COVID‐19. Silymarin inhibits the expression of host cell surface receptor TMPRSS2 with a docking binding energy corresponding to −1,350.61 kcal/mol and a full fitness score of −8.11. The binding affinity of silymarin with an impressive virtual score exhibits significant potential to interfere with SARS‐CoV‐2 replication. We propose in‐depth pre‐clinical and clinical review studies of silymarin for the development of anti‐COVID‐19 lead, based on its clinical manifestations of COVID‐19 and multifaceted bioactivities.

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), a novel coronavirus (nCoV) of zoonotic origin was reported from the Wuhan province of China for the first time in December 2019. Currently, the fatal outcome of this viral infection has taken 23.68 lakhs of human lives and infected 10.80 million people globally (https:// www.worldometers.info/coronavirus update, February 10, 2021). In spite of the global effort to understand the virus and a deluge of publications, the detailed viral biology, life cycle, pathophysiology, and immunopathological response of the host to this highly contagious virus are poor. So far, no specific prophylactic or therapeutic antiviral agent or effective vaccine is available, which has forced the world to go for complete lockdown for several months. Further, the scenario has become grim due to increasing mortality triggered by an unpredictable pathophysiological response like hyperinflammatory disorders, blood clots, pulmonary embolism, thrombosis, and cytokine storm-driven organ damage (Garg, Prabhakar, Malhotra, & Agarwal, 2020; Helms et al., 2020; Penman et al., 2020) . The immunopathological response of CoV-2 is unprecedented and discordant toward the host defense with symptoms-based clinical manifestation and immuno-genomic variation (Toyoshima, Nemoto, Matsumoto, Nakamura, & Kiyotani, 2020; Severe Covid-19 GWAS Group, 2020) .

So far, the clinical management of COVID-19 patients is based on a trial-and-error basis with re-purposed antiviral drugs like ritonavirlopinavir (protease inhibitors), remdesivir (adenosine analog), the antiprotozoal hydroxy-chloroquine (endosomal inhibitor) and so on (Penman et al., 2020) . However, in acute cases, patients sometimes fail to recover due to nonspecific drug binding, adverse drug reaction, and co-morbid conditions including organ malfunctioning (Carter, ThiLanAnh, & Notter, 2020; Renu, Prasanna, & Gopalakrishnan, 2020; Zumla, Chan, Azhar, Hui, & Yuen, 2016) . Many COVID-19 patients with co-morbid or hyperactive and pre-existing immuno-compromised conditions have had a lethal outcome (Li et al., 2020; Renu et al., 2020) . Additionally, patients with pre-existing blood coagulopathy may suffer from pulmonary or vascular stroke, due to an underlying mechanism that could probably mimic sepsis-like syndrome and disseminated intravascular coagulation (Al-Samkari et al., 2020; Coppola et al., 2020; Lemke & Silverman, 2020) .

In this review, we will discuss the potential of commercially available silymarin, and its Food and Drug Administration (FDA) recommended ingredients silybin and silibinin against SARS-CoV-2 infection, particularly to control the pathophysiological response of COVID-19 patients. The present discussion will also highlight the rationality for re-purposing silymarin for COVID-19 patients due to its versatile beneficial role against several pathophysiological disorders.

Silymarin is a standardized extractive fraction derived from the seeds of the traditionally used medicinal plant "milk thistle" or Silybum marianum of the family Asteraceae. The plant is native to the Mediterranean region including Crete, Greece, Iran, and Afghanistan. Chemically silymarin is a polyphenolic flavonolignan complex of seven closely related derivatives (silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin) with one flavonoid taxifolin. The yield of silymarin is 65%-80% to total crude extract (Corchete, 2008; Kroll, Shaw, & Oberlies, 2007) . Silibinin, an active molecule of silymarin, exists as a mixture of two diastereomers, silybin A, and silybin B, in an approximately equimolar ratio. It is used as a supportive treatment in any liver diseases due to its excellent hepatoprotective activities (Gillessen & Schmidt, 2020) . Moreover, it exerts chemoprotective effect from environmental toxins, elicits antiinflammatory, antioxidant, and immunomodulatory activity (Esmaeil, Anaraki, Gharagozloo, & Moayedi, 2017) , and protects from UV-induced photo-carcinogenesis, UVB-induced epidermal hyperplasia, sunburn, and repair UV-induced DNA damage (Balouchi, Gharagozloo, Esmaeil, Mirmoghtadaei, & Moayedi, 2014; Singh & Agarwal, 2009 ). It has a promising antiproliferative effect against human prostate adenocarcinoma, estrogen-dependent and independent breast carcinoma, colon carcinoma, ecto-cervical carcinoma, and small and non-small cell lung carcinoma (Bhatia, Zhao, Wolf, & Agarwal, 1999; Hogan, Krishnegowda, Mikhailova, & Kahlenberg, 2007) . Chemically this bio-active flavonolignan derivative is known as (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one. The structures of the bioactive flavonolignan pharmacophores of silymarin extract have been presented in Figure 1 . All of them pass the Lipinski rule of five descriptors: molecular weight, hydrogen donors and acceptor, and log P suggesting it as the good candidate of the oral drug for future therapy (Liptnski, Lombardo, Dominy, & Feeney, 2001 ; https://pubchem.ncbi.

nlm.nih.gov/compound/31553).

Contemporary literature reveals that silymarin modulates virusspecific and nonspecific T-cell proliferation as a potential immunomodulator (Johnson, He, Osuchowski, & Sharma, 2003) , and elicits antiinflammatory effects via suppression of IFN-γ and IL-10 production (Adeyemo et al., 2013) . Moreover, silymarin had significant antiviral potential (Liu, Jassey, Hsu, & Lin, 2019) , and is a well-known hepatoprotective, antioxidant, and anticoagulant with promising antiinflammatory activity (Delmas, 2020) . Silymarin along with its derivatives, natural and chemical, have shown profound antiinflammatory activity by significant suppression of TNF-α, IL-6, IFN-γ, and IL-4 from bronchoalveolar lavage and lung macrophages in asthma and chronic obstructive pulmonary diseases (Dobiasová et al., 2020; Nasab, Saghazadeh, & Rezaei, 2020) . Currently, a potential antiinflammatory drug Acalabrutinib has been recruited for the treatment of lung injury in severe COVID-19 patients with hypoxia and fibrotic damage, caused by the massive hyper inflammation due to activation of macrophage and endothelial cells from cytokine storm (Roschewski et al., 2020) . It is interesting to note that silymarin has better protection (73.29% reduction) against inflammatory cytokine IL-1β (Toklu et al., 2008) , compared to the standard antiinflammatory agents like Acalabrutinib, which demonstrates a 50% reduction of IL-1β in the CLP mice model. Current literature reveals that the suppressive activity of silymarin and acalabrutinib against pro-inflammatory cytokines TNF-α and IL-6 are interestingly comparable (O'Riordan et al., 2019) . Silymarin not only suppresses the induction of TNF-α but also reduces its serum concentration along with the IL1β, IFN-γ, and other pro-inflammatory cytokines (Nazemian et al., 2010) . Further, it represses the mitogen-activated protein kinase (MAPKs) ERK1/2 and P38 activities and release of Th1-related cytokine IL-2, associated

with T-cell proliferation, which may help in immunosuppression (Gharagozloo et al., 2013) to control the organ damage triggered by cytokine storm during acute COVID-19 (Estrada, 2020; Robba, Battaglini, Pelosi, & Rocco, 2020) .

The antiinflammatory activity of silymarin is quite analogous with the standard FDA-approved drug Baricitinib, used for the treatment of Rheumatoid arthritis (RA) and now recommended as COVID-19

therapy (Tong et al., 2019; Richardson et al., 2020) . It is noteworthy that silymarin and one of its active constituent silibinin have been approved for the non-randomized single-arm clinical trial in RA patients (Shavandi et al., 2017) , due to its inhibitory activity on TNF-α and other pro-inflammatory biomarkers of RA (Dupuis et al., 2018) .

Interestingly, it was reported that a high dose of silymarin can induce the expression of the interferon-stimulated gene (ISG)

15 (Adeyemo et al., 2013) , an antiviral cytokine (Farrell, Broeze, & Lengyel, 1979; Swatek et al., 2018) induced by IFN-γ to promote the innate immune response and thereby stimulate the NK cells during influenza virus infection. Papain-like protease (PLpro), an essential enzyme of Coronaviruses, process viral polyproteins into a replicase complex for maturation, and release of new virion for viral spread (Harcourt et al., 2004; Lim, Ng, & Liu, 2000) , and cleave host proteins to suppress the production of IFN-1 that provide antiviral immune The morbidity and mortality caused by COVID-19 infection have been intensified due to overactivated humoral immune response (Zhao et al., 2020) , the formation of micro-thrombi in the blood vessel leading to blood clotting, viral laden antigen-antibody complexes, and severe allergic shock, along with the probable hypoxemic injury in vital organs like lungs, heart, brain, and kidneys (Garg et al., 2020) . Such clinically uncontrolled manifestations can be managed by promoting cellular immunity with the reduced humoral response, prevention of hypoxemic, and reperfusion of injuries caused by a virus-driven cytokine storm. Here, silymarin could help to control such pathophysiological aberration due to its antiviral, immunomodulatory, antiinflammatory, antioxidant, antiplatelet, and anticoagulant properties (Abenavoli et al., 2018; Neha et al., 2016) in a sensible and phased manner. Further, the SARS-CoV-2 related ARDS, caused by massive elevation of inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-32 in hyper-inflamed host cells (Spinelli, Conti, & Gadina, 2020) , can be managed by silymarin may due to its attenuating activity on JAK overexpression (Agarwal, Tyagi, Kaur, & Agarwal, 2007; Richardson et al., 2020) , as JAK-STAT3 inhibition may mediate the suppression of inflammatory cytokines and respiratory distress (Zegeye et al., 2018) .

Silibinin, another component of silymarin, is known to down-regulate the expression of TMPRSS2 in cell membrane surface in androgen deficient prostate cancer (Farooqi, Mansoor, Ismail, & Bhatti, 2010) .

Further, TMPRSS2 is reported to be an essential enzyme for cleavage of CoV-2 Spike protein(s) necessary for viral attachment with the host cell ACE2 receptor to enter into the host cell (Hoffmann et al., 2020) .

Hence, we hypothesized that silymarin could prevent the spread of SARS-CoV-2 infection by down-regulating the expression of TMPRSS2 receptors. This hypothesis is supported by our in silico docking study, which suggests that silymarin has a strong binding affinity to the homologous catalytic site of TMPRSS2 at its active site ( (Rendina et al., 2014) . Song and Choi (2011) showed that silymarin at 100 μg/ml has potent antiviral activity against influenza virus A/PR/8/34 with 98% protection at an IC 50 of 11.12 μg/ml. These reports collectively suggest that silymarin could be explored further for developing lead against SARS viruses, including novel coronavirus, as it elicited two-fold higher antiviral activity than the standard antiflu drug, oseltamivir (Tamiflu) in the influenza infection model (Song & Choi, 2011) .

Recently it was observed that acute COVID-19 patients often die of blood clots due to induced pulmonary lung coagulopathy followed by internal hemorrhage mediated stroke (Connors & Levy, 2020; Menezes-Rodrigues et al., 2020) . Thus, silymarin might be successfully used to manage and recover SARS-CoV-2 induced thrombotic pulmonary embolism associated strokes, due to its antiplatelet activity that may prevent coagulation. Further, silymarin treatment is found to reverse the blood clot formation in cardiac ischemia (Bijak, 2017; Bijak, Dziedzic, & Saluk-Bijak, 2018; Menezes-Rodrigues et al., 2020) , lung and brain injury (Toklu et al., 2008) , and thus, may help in the management of blood clotinduced severity at the acute inflammatory stage to reduce mortality;

and increased recovery rate of COVID-19 patients with high d-dimer

value. An earlier report suggested that the key flavonolignan derivative silybin of silymarin inhibited the blood coagulation factors thrombin and FXa (Bijak, 2017; Bijak, Ponczek, & Nowak, 2014) .

Furthermore, a recent in silico study suggests that silymarin may block the protein-protein interaction between viral spike glycoprotein and host cell receptor ACE2 by binding with the receptor-binding domain (RBD) of spike protein at the RBD-ACE2 interface to control SARS-CoV infection (Ubani et al., 2020; Unni, Aouti, & Balasundaram, 2020) . Thus, the clinical potency of silymarin could be investigated against mild, moderate, and acute infection caused by SARS-CoV-2, depending on the severity of the disease (Diao et al., 2020) . Levels of circulating cytokines and T cell counts may help to select rational doses of silymarin, due to its well-known immunomodulatory potential, via suppression of CD4 T-cell activation with IL-2 and IFN-γ production at lower doses (Gharagozloo et al., 2010) . Thus, the reviewed scientific literature so far discussed, and our in silico molecular docking study collectively suggests that silymarin could be used for possible therapeutic benefit in the management of COVID-19 patients due to its high safety index with significant antiinflammatory, anticoagulant, immune-modulatory, and antiviral response (Esmaeil et al., 2017) as illustrated in Figure 2 . This may be achieved by varying the clinical doses of silymarin having a high therapeutic index with a broad margin of safety window (Wu, Lin, & Tsai, 2009 ). Therefore, the preclinical and clinical investigation of silymarin against COVID-19 needs to be validated in suitable models to design a potential therapeutic agent against super spreading SARS-CoV-2 mediated pandemic and restoring global normalcy. Summarized Table 2 suggested that in-vitro dose ranging from 50 to 100 μg/ml of silymarin had a promising antiviral response with more than 90% growth inhibition against Chikungunya, Mayaro, and influenza A viruses. Furthermore, 50-100 mg/kg of silymarin reduced the expression of inflammatory bio-markers very significantly and protected the lung injury in rat model at 200 mg/kg. So, its combination therapy with other FDA-approved safe and low doses of antiinflammatory and antiviral drugs need to be clinically investigated for formulating safer therapeutic armaments against COVID-19. The methodology of carried out research has been included in Table 2 for a better understanding of the discussion on the proposed theme.

It is interesting to report that a randomized placebo-controlled trial has been initiated to evaluate the clinical consequence in COVID-19 pneumonia in Phase-3, succeeding administration of silymarin. In-vivo treatment for 20 weeks.

Candida albicans induced in-vivo T cell proliferation assay.

-Candida specific T-cell IFN-γ decreased from a mean 256 to 114 SFU/10 6 PBMC at 700 mg three times a day for 20 weeks in HCV infected mice. Toklu et al., 2008 Toklu et al., 2008 10 days oral treatment with Silymarin Cecal ligation and perforation (CLP)induced sepsis for lung and brain injury & damage in rat model.

Levels of serum pro-inflammatory cytokines (tumor necrosis factoralpha, interleukin-1β, and IL-6), lactate dehydrogenase (LDH) activity and tissue glutathione, as well as malondi-aldehyde and myelo-peroxidase activity, and the survival rate of rat. μM.

-

Currently, there is no promising officious treatment accessible for the highly contagious SARS CoV-2. Thus, identifying novel and fruitful treatments is imperious and would be of great benefit to patients.

However, numerous clinical trials are ongoing globally to discover active drugs for COVID-19 treatment, and no drug has been proclaimed to be fruitful for curing COVID-19 so far. Silymarin is appreciated for its various immune-pharmacological and cytokine regulating effects and appears as a hopeful phytopharmaceutical for the management of COVID-19 ( Figure 2 ). More significantly, derivatives of silymarin like silybin, and silibinin have promising antiviral responses that might also be a good option. However, some vital points such as exact dosing and time course of therapy based on the severity of the disease manifestation need to be addressed for fixing the proper treatment modality to control viral infection. Additionally, the biological function of silymarin is consolidated from in-vitro findings, animal experiments, and clinical data on related diseases may not correspond with clinical efficacy in humans. Therefore, the precise clinical curative or even prophylactic use, the optimal dose and course of treatment must be assessed following suitable preclinical and clinical study.

All authors are thankful to Mr. Amit Kundu for preparing the references.

The authors declare no conflicts of interest.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0002-7544-391X

Debprasad Chattopadhyay https://orcid.org/0000-0002-7999-329X

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