key: cord-0685252-5epe0jgu
authors: Shah, Muhammad Ajmal; Rasul, Azhar; Yousaf, Rimsha; Haris, Muhammad; Faheem, Hafiza Ishmal; Hamid, Ayesha; Khan, Haroon; Khan, Abdul Haleem; Aschnar, Michael; Batiha, Gaber El‐Saber
title: Combination of natural antivirals and potent immune invigorators: A natural remedy to combat COVID‐19
date: 2021-08-15
journal: Phytother Res
DOI: 10.1002/ptr.7228
sha: 822b6ade23ed624045aebeb60f2b779d8150cbce
doc_id: 685252
cord_uid: 5epe0jgu

The flare‐up in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that emerged in December 2019 in Wuhan, China, and spread expeditiously worldwide has become a health challenge globally. The rapid transmission, absence of anti‐SARS‐CoV‐2 drugs, and inexistence of vaccine are further exacerbating the situation. Several drugs, including chloroquine, remdesivir, and favipiravir, are presently undergoing clinical investigation to further scrutinize their effectiveness and validity in the management of COVID‐19. Natural products (NPs) in general, and plants constituents specifically, are unique sources for various effective and novel drugs. Immunostimulants, including vitamins, iron, zinc, chrysin, caffeic acid, and gallic acid, act as potent weapons against COVID‐19 by reinvigorating the defensive mechanisms of the immune system. Immunity boosters prevent COVID‐19 by stimulating the proliferation of T‐cells, B‐cells, and neutrophils, neutralizing the free radicals, inhibiting the immunosuppressive agents, and promoting cytokine production. Presently, antiviral therapy includes several lead compounds, such as baicalin, glycyrrhizin, theaflavin, and herbacetin, all of which seem to act against SARS‐CoV‐2 via particular targets, such as blocking virus entry, attachment to host cell receptor, inhibiting viral replication, and assembly and release.

Even with the invested enormous scientific efforts, the emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a paramount concern for human health . The continuing flare-up of the novel pandemic COVID-19 caused by SARS-CoV-2 has become the leading health issue worldwide . Several research institutes are making efforts to develop vaccines to quell and manage the but there is no vaccine available so far. Now, the vaccine is under trial in different countries, and there is not any particular efficacious antiviral therapy for COVID-19 (Kwok et al., 2021; Nusbaum, 2020; Zhou et al., 2020) .

Natural components may also afford protection against COVID-19. They are generally readily available and safer than synthetic agents (Islam et al., 2020) . To date, 30 such compounds have been identified (Dong, Hu, et al., 2020) .

The therapeutic effects of plants have been long recognized Thomford et al., 2018) . Many diseases have been treated with medicinal plants due to their phytochemical diversity (Thomford et al., 2018) , and natural products (NPs) are commonly used to promote health care and prevent diseases (Chen et al., 2018) .

Since the discovery of the first antibiotic, more than 23,000 NPs have been identified (Nawaz et al., 2020) . According to WHO, 80% of the human population rely on medicinal plants for maintaining a healthy lifestyle . NPs serve as an incomparable source of unparalleled and distinctive compounds that can prevent inflammation and fight against cancer (Chahyadi et al., 2014; Wei, Rasul, et al., 2019) . In addition to these activities, NPs have the ability to boost the immune system, protecting against infectious diseases (Amor et al., 2007; Sarfraz et al., 2020) .

The most important strategy to prevent and control SARS-CoV-2 is to boost the immune system. During the incubation stage, it is necessary to eradicate the virus and prevent its replication, by mounting an efficient immune response.

Nutraceuticals have the ability to boost and restore both innate and adaptive immune responses (Ibrahim & El-Sayed, 2016) . The competence of the immune system depends upon the nutritional status, and the deficiency of micronutrients can lead to the impairment of the immune system (Alpert, 2017) . It has been shown that the immune system functions optimally when micronutrients such as vitamins and minerals for their synergistic roles in supporting the immune system are at adequate levels (Gombart et al., 2020) . Micronutrients strengthen the immune system as they enhance the skin epithelium barrier, boost antibody synthesis, stimulate cell-mediated immune response, regulate inflammation, and maintain antioxidant/oxidant balance in the body (Alpert, 2017; Farhan Aslam et al., 2017; Gombart et al., 2020) .

In spite of the progression in the field of immunomodulation and vaccination, there is still a lack of preventive measures and antiviral medicaments for several infections (Lin et al., 2014) . Thus, antiviral agents obtained from natural origin may play an essential role in preventing infection or killing the virus (Lateef Mousa, 2015; Wang et al., 2012 ). An ideal antiviral should inhibit the replication of the virus (Lalani & Poh, 2020) and targeting membranes by which virus enters into the host cell (Lalani & Poh, 2020; Vázquez-Calvo et al., 2017) . It is obviously known that the western drugs have lofty importance than natural antivirals that possess both immune-boosting and antiviral properties having a significant role in the cure and elimination of disease (Moghbelli et al., 2020) . NPs acquiring antiviral properties remain a leading source that could provide dominant and safest therapies for the future progress in the treatment of fatal diseases (El Sayed, 2000) .

The aim of this review is to discuss NPs as antivirals and potent invigorators of the immune system because of their phenomenal biological and pharmacological activities. The outcomes of different NPs discussed herein should pave the way for further research on them regarding the prevention and treatment of COVID-19.

Vitamins, minerals, and trace elements are required for the optimal functioning of the immune system (Alpert, 2017) . Nutraceuticals boost immunity and promote the proliferation of T-cells and B-cells.

T-cells protect the body from pathogens, and B-cells produce antibody-producing plasma cells. Nutraceuticals stimulate macrophages and neutrophils, which are involved in the phagocytosis of microbes (Gombart et al., 2020) . One of the major steps against any viral disease is to prevent the immunosuppressive activities within the body. One of the immunosuppressive agents is PGE 2 , which is blocked by vitamin E (Lee & Han, 2018) . Reactive oxygen species (ROS) and reactive nitrogen species (RNS) at high concentrations can inactivate cellular molecules (Farhan Aslam et al., 2017) . Along with nutraceuticals, phytochemicals are also used for their immunostimulant activity (Boothapandi & Ramanibai, 2019) . Different phytochemicals also regulate the assembly and release of various cytokines, including IL-12p70, TNF, INF-γ, MCP-1, and IL-6, which are very requisite for the activation of different immune cells (Reyes et al., 2018) .

The cytokines not only boost immunity but also act as potent weapons against viruses, such as interferon (INF), and various phytochemicals utilize this strategy to combat COVID-19 (Laguno et al., 2008) .

The first and the most important strategy against viral infections is to block the host receptor, inhibiting the fusion mechanism of viruses with host cell membranes (Du et al., 2009; Sieczkarski & Whittaker, 2002) . The main strategy of antivirals is the inhibition of viral enzymes such as PLpro, 3CLpro, and RdRp, leading to the inhibition of viral replication (Wu, Liu, et al., 2020) . Another strategy is the inhibition of viral gene expression, which includes translation and transcription of viral RNA (Chen, Liu, & et al., 2020) . Strategies targeting host factors, such as the inhibition of virus-host interactions, and altering the pH of endosomes also play a central role in combating COVID-19 (Abramo et al., 2012) .

The immune system is a complex web of cells, tissues, and organs that provides resistance to infection and toxins. It has been recognized that vitamins, minerals, and other phytonutrients are key players in stimulating the immune system (Alpert, 2017; Ibrahim & El-Sayed, 2016) . COVID-19 has a higher degree of occurrence in older men who are immunocompromised (Author & Society, n.d.) .

NPs having immunostimulatory activity are exclusively used for a wide range of afflictions (Mohamed et al., 2017) . Compounds derived from plants, such as glycosides, alkaloids, β-glucan, vitamins, sterols, essential oils, and flavonoids, and part of our diets such as fruit, vegetables, and grains are NPs (Chakraborty & Hancz, 2011) . Figure 2 summarizes natural immunostimulators that may help to combat COVID-19. immunostimulant nutraceuticals.

The fat-soluble vitamin, retinol, plays a remarkable role in invigorating the immune system including both innate and adaptive immune responses (Alpert, 2017) . It has been found that vitamin A also has antiviral effects (Elenius et al., 2017) . One of the most notable functions of vitamin A is that it assists in regulating IL-2 and TNF-α production, which then further promotes microbe killing and respiratory burst stimulation by macrophage activation (Gombart et al., 2020) (Table 1) . Vitamin A also increases the concentration of antibodies (Alpert, 2017) and is associated with the increased level of IFN-γ, which ultimately provides protection against viral afflictions by increasing the number of natural killer (NK) cells (Elenius et al., 2017; Maggini et al., 2007) . Its natural sources include Spinacia oleracea (spinach), Brassica oleracea (broccoli), Prunus armeniaca (apricot), Daucus carota (carrot), Ipomoea batatas (sweet potato), and Pistacia vera (pistachio) (Farhan Aslam et al., 2017) .

Pyridoxine or vitamin B 6 is a water-soluble vitamin that plays a significant role in maintaining the optimal levels of homocysteine in blood (Farhan Aslam et al., 2017) . Vitamin B 6 is utilized for the synthesis of serotonin and is also crucial for the absorption of vitamin B 12 . In addition, it has a vital role in stimulating the immune system (Farhan Aslam et al., 2017) , by regulating inflammation, lymphocyte multiplication, and differentiation (Gombart et al., 2020) . Vitamin B 6 also increases the antibody titer (Farhan Aslam et al., 2017) , modulates NK cell function, and Th1-mediated immune response (Table 1) . It is present in Thunnini (tuna), Salmo salar (salmon), Allium cepa (onions), Oryza sativa (rice), Cicer arietinum (chickpea), beef liver, and cereals (Farhan Aslam et al., 2017) .

Folic acid or vitamin B 9 plays an influential role in the human body in the form of tetrahydrofolate for the synthesis of proteins and nucleic acids (Alpert, 2017) . Deficiency in folic acid disrupts metabolic reactions and consequentially affects both innate and adaptive immune responses (Rosenthal et al., 2019) . It is a potent antioxidant (Zehra & Khan, 2020) , and it intensifies NK cell activity, crucial for Treg cell survival, and is important for the synthesis of antibodies (Gombart et al., 2020) . It expedites T-cell escalation, and its deficiency is associated with reduced CD8+ T-cell generation (Rosenthal et al., 2019) . The activity of neutrophils is also impaired due to the lack of vitamin B 9 (Ibrahim & El-Sayed, 2016 Vitamin B 12 , also named as cobalamin, plays a major role in protection against bacterial and viral afflictions by reinforcing the immune response (Farhan Aslam et al., 2017) . It promotes proliferation and multiplication of white blood cells (Alpert, 2017) . It has significant immunomodulatory effects on the activity of cytotoxic T-lymphocytes and NK cells, and promotes the growth of T-cells (Gombart et al., 2020) . Deficiency of vitamin B 12 is associated with neutropenia and leukopenia (Ibrahim & El-Sayed, 2016) and alters the CD4+/ CD8+ ratio and represses the activity of NK cells . Microbes in the intestine utilize vitamin B 12 for several metabolic reactions; thus, the gut barrier is also supported by vitamin B 12 (Gombart et al., 2020) . Natural sources of vitamin B 12 include milk, eggs, cheese, trout, and cereals (Farhan Aslam et al., 2017) .

Vitamin C, also known as ascorbic acid having astonishing antiviral and anticancer activity, also plays an astounding role in strengthening the immune system (Alpert, 2017) . It affects iron transport, (Table 1) . Calcitriol functions to stimulate the synthesis of proteins that have defensive action against certain microbes (Farhan Aslam et al., 2017) and therefore has a protective effect against pulmonary infections (Ibrahim & El-Sayed, 2016) . Calcitriol also influences antibody and cytokine generation (Ibrahim & El-Sayed, 2016) .

Vitamin D 3 is naturally produced by the human body in the presence of ultraviolet radiations, whereas vitamin D 2 is synthesized by plants (Farhan Aslam et al., 2017) . Deficiency of vitamin D is associated with respiratory tract infections and to ARDS. As COVID-19 has a link to SARS, vitamin D may play a role in providing resistance to coronavirus (Adams et al., 2020) . Natural sources of vitamin D include Thunnini (tuna), C. sinensis (orange), S. salar (salmon), milk, yogurt, egg, cheese, and cod liver oil (Farhan Aslam et al., 2017) .

Vitamin E, a cumulative term for four tocotrienols and four tocopherols, is well known for its exceptional antioxidant activity and signal transduction modulation role (Lee & Han, 2018) . Supplementation with antioxidants such as vitamin E has been shown to restore the action on both cell-mediated and innate immune responses (Ibrahim & El-Sayed, 2016) . Vitamin E causes lymphocytes multiplication, enhances NK cell functions and IL-2 synthesis, stimulates phagocytosis and averse infections by activating the Th1 immune response , decreases the formation of immunosuppressant agents like PGE 2 (Figure 1 ), prevents the oxidation of PUFAs, and facilitates the antibody response (Lee & Han, 2018) . Vitamin E deficiency causes retinopathy and ataxia. Vitamin E is present in Iron is an indispensable mineral because it plays a central role in the electron transport chain, citric acid cycle, nucleic acid synthesis (DNA), and oxygen transport by hemoglobin (Weiss, 2002) and can mitigate SARS-CoV-2 infections. Older red blood cells are recycled by macrophages, leading to the recycling of iron (Alpert, 2017) . Iron also plays a vital role in gene regulation, cellular proliferation, and maturation . In addition to these functions, iron also has a dominant role in modulating the immune response, as it activates neutrophils for bacterial destruction by hydroxyl radical, facilitates cytokines actions, causes T-cell escalation, and acts as a crucial element of enzymes required for the proper functioning of the immune system (Gombart et al., 2020; Weiss, 2002) . Iron also stimulates microbe-killing pathways of macrophages and promotes the multiplication of monocytes and NK cells (Theurl et al., 2005) . Iron-rich foods include Musa acuminata (banana), Solanum tuberosum (potato) ( Figure 2) , bread, grains, pasta, pork, eggs, fruits, vegetables, biscuits, beef, kumara, and milk (Menzies, 2019; Sandstead, 2000) .

Zinc is a vital trace element for catalyzing and restoring the humoral and cell-mediated immune responses (Maares & Haase, 2016) . The plasma level of zinc is 12-16 μm (Maares & Haase, 2016 ). Zinc has a major role in the structural regulation of proteins and transcription factors (Ibrahim & El-Sayed, 2016) , and it is essential for SOD activity, interferes with cytokine production growth, and activates the Th1-mediated immune response . It activates macrophages for phagocytosis, stimulates NK cells, causes the production of IL-6, IL-12, TNF-α, maintains the integrity of skin and mucosa, and has a defensive action against reactive oxygen species (Gombart et al., 2020) . Zinc improves the antibody response ( Figure 3 ), promotes CD8+ cells multiplication, causes NK cell production, and reduces NADPH oxidase actions, and ZIP10 inhibits the apoptosis of B cells (Alpert, 2017; Maares & Haase, 2016) . Zinc inhibits viral replication and RNA polymerase activity of SARS-CoV (Stipp, 2020) . Natural dietary sources of zinc include Anacardium occidentale (cashew), Brachyura (crab), C. arietinum (chickpea), P. amygdalus (almond), P. sativum (pea), cereals, oatmeal, pork chop, baked beans, yogurt, and kidney beans (Gu & Zhang, 2017) .

Selenium plays a phenomenal role in the development of body and has significant importance for immunosurveillance (Avery & Hoffmann, 2018 ). The immune system depends upon an appropriate amount of selenium intake as it supports the proliferation of Tlymphocytes and enhances IFN-γ production (Avery & Hoffmann, 2018; Ibrahim & El-Sayed, 2016) . It modulates the activities of NK cells and leukocytes, increases Th cells, maintains antibody levels, and counteracts ROS (Gombart et al., 2020) . The main mechanism by which selenoproteins protect against oxidative harm is via glutathione peroxidase (GPx), a selenium-dependent enzyme ( Table 1 ). The immune system requires selenium for efficient functioning of T-cells (Figure 3 ), macrophages, and neutrophils (Nkengfack et al., 2019) . Food sources of selenium include cereals, grains, fish, meat, milk, Morchella vulgaris (fungi),

and Boletus edulis (mushroom) (Falandysz, 2008; Olza et al., 2017) .

Copper is required for several physiological processes including the proper functioning of the immune system (Alpert, 2017) . It has potent antioxidant activity and is required for the conversion of superoxide free radical to O 2 and hydrogen peroxide . Copper interacts with macrophages to encounter the infections, promotes NK cell functions, modulates the actions of neutrophils and monocytes, enhances IL-2 production, and increases the concentration of neutrophils (Alpert, 2017) . It also promotes T-cell growth and differentiation (Gombart et al., 2020) Magnesium is an alkaline-earth element and the second most abundant mineral after potassium having a remarkable role in several physiological processes such as glycolysis, oxidative phosphorylation, and synthesis of nucleic acids and proteins (Malavolta, 2018) . It has a regulatory effect on the activation of leukocytes, acts as a cofactor for antibody synthesis, promotes antibody-dependent dissolution of cells,

facilitates IgM binding to lymphocytes, provides structural stability to DNA, shields DNA against oxidative harm, and lessens superoxide F I G U R E 1 A diagrammatic presentation and brief strategic plan of therapeutic targets in combating COVID-19 [Colour figure can be viewed at wileyonlinelibrary.com] production (Gombart et al., 2020) . It activates macrophages towards lymphokines and facilitates the adherence of helper T cells and B cells (Malavolta, 2018) . The deficiency of magnesium is associated with the enhanced production of free radicals, DNA damages, and lipid peroxidation (Malavolta, 2018) . Natural sources of magnesium include fruits, vegetables, fish, whole grain bread, dried fruit, walnuts, and legumes (Kokubo et al., 2018) . Andrographolide is isolated from medicinal herbaceous plant Andrographis paniculata (Ajaya Kumar et al., 2004) . Mechanistically, andrographolide boosts humoral immunity by increasing peripheral blood lymphocyte levels (Table 2) (Latief et al., 2016; Reckziegel et al., 2016; Reyes et al., 2018; Sarjit et al., 2015; Zhang, Ma, et al., 2019) . Gallic acid activates both humoral and cell-mediated immunity by boosting the activity of IL-12p70, TNF, INF-γ, MCP-1, and IL-6. The discharge of IL-12 stimulates the liberation of INF-γ, which, in turn, promotes the phagocytosis by activating macrophages (Figure 3 ). MCP-1 enhances the migration of monocytes including neutrophils and dendritic cells (Reyes et al., 2018) . IL-6 promotes the activation of helper T-lymphocytes to stimulate humoral immunity .

Another flavonoid, kaempferol, is significantly isolated from B. oleracea, Malus domestica, and C. sinensis (Chen & Chen, 2013) ( Table 2) . It has gained a great importance due to its biological implications including immunostimulant, antidiabetic, anticancer, and antioxidant activities (Alkhalidy et al., 2018; Bandyopadhyay et al., 2008; Kashyap et al., 2017; Liao et al., 2016) . Kaempferol displays immunostimulant activity by promoting the release of granulocytemacrophage colony-stimulating factor (GM-CSF), which, in turn, has gained a great attention by promoting the activation and chemotaxis of dendritic cells, enhancing the accumulation of neutrophils, and most significantly activating macrophages (Bandyopadhyay et al., 2008; Castellani et al., 2019) .

A potent phytochemical, plumieride belongs to a multiplex class, iridoid glycoside, and is obtained after extraction from Plumeria acutifolia, Plumeria alba, and Allamanda cathartica (Boeing et al., 2018; Gupta, 2016; Singh et al., 2017) . It possesses significant pharmacological activities including immune-boosting, antidepressant, and antioxidant functions (Boeing et al., 2018; Bonomini et al., 2017; Singh et al., 2017) . Plumieride boosts the humoral immunity as well as cellmediated immunity, and promotes the assembly and liberation of various cytokines including IL-2, IFN-γ, and IFN-α (Figure 1 ). Mechanistically, it activates CD 4 cells, which, in turn, enhance phagocytosis by promoting the proliferation of macrophages and also activates T and B-lymphocytes (Singh et al., 2017) (Figure 3 ).

An isoflavone glycoside, puerarin, a constituent of P. tuberosa and Pueraria lobata, functions as immunostimulant, reno protective, antioxidant, antidiabetic, anticancer, and hepatoprotective (Maji et al., 2014; Fu-Liang et al., 2006; Wang et al., 2013; Wu et al., 2013; Xia et al., 2013) . Puerarin plays a key role in boosting the immune response by promoting the level of monocytes and lymphocytes via enhancing their proliferation (Table 1 ). In addition, puerarin elevates the level of phagocytes and increases immunity by stimulating phagocytosis (Maji et al., 2014) . Table 2) is approved for varied pharmacological actions including immunostimulant, insecticidal, and antimicrobial functions (Özek et al., 2017; Pavela et al., 2020; Zomorodian et al., 2018 ). The immune system may be significantly enhanced by immune-boosting action of (Z)-propenylsec-butyl disulphide. This volatile oil enhances the killing action of neutrophils by promoting the Ca ++ influx in neutrophils, which leads to the effective generation of ROS from neutrophils, and, together with this, potentiates the phagocytosis by raising the level of phagocytes (Özek et al., 2017) .

A phytochemical, bromelain, known for its fibrinolytic, antithrombotic, and anticoagulant activities, is found in the enzymes of Ananas comosus (pineapple) (Setiasih et al., 2019) . Bromelain is an enzyme complex containing peroxidase, acid phosphatase, glycosidase, cellulose, and others (Setiasih et al., 2019; Whitworth et al., 2006) . Bromelain also enhances immune defense against infections as it promotes T-lymphocytes binding to antigens and also modulates the number of circulating CD4+ and CD8+ lymphocytes (Whitworth et al., 2006) . The major immunomodulatory effects involve the activation of T-lymphocytes and stimulation of (TNF-α, INF-γ, IL-1, IL-2, IL-6, and GM-SCF) production (Amini et al., 2016) .

A virus is a chunk of bad scoop swaddled in a protein coat (Sohail et al., 2011) . Viral infections are considered as one of the prime threats for human life (Arakawa et al., 2009 ). It has been recognized that NPs from different natural origins are the most important source of antivirals for the management of COVID-19 (Liu & Du, 2012;  Yonesi & Rezazadeh, 2020) ( Figure 4 ).

SARS-CoV-2 entry into the host cell depends upon angiotensinconverting enzyme-2 (ACE2), which is also known as the SARS-CoV receptor (Inhibitor et al., 2020) . The receptor-binding domain present in the SARS-CoV spike (S) protein has a major role in binding to ACE2 of the host cell (Ge et al., 2013) . The SARS-CoV S-protein causes viral attachment and pathogenesis (Du et al., 2009 ). However, for the entry of SARS-CoV, the association between SARS-CoV-2 S-protein and ACE-2 is the most crucial step (Du et al., 2009) (Figure 1) . Emodin, obtained from Rheum and Polygonum, baicalin obtained from Scutellaria baicalensis, and luteolin obtained from Veronica thymoides act by inhibiting the S1 domain of S-protein attachment to the host cell receptor ACE2 (Alves et al., 2004; Deng et al., 2012; Ho et al., 2007; Li-Weber, 2009; Lopez-Lazaro, 2008; Rane et al., 2020; Yeung et al., 2006) (Table 3 ). The S1 domain consists of two subdomains-N-terminal domain (NTD) and C-terminal domain (CTD)

both of which act as receptor-binding domains (RBDs) (Belouzard et al., 2012) . Thus, inhibiting the attachment of S-protein to ACE2 is essential for treating the SARS-CoV-2 infection .

Emodin also functions as hepato-protective and as an anticancer agent (Dong, Zeng, et al., 2020; Hsu & Chung, 2012) . S. baicalensis have multiple biological effects, such as treating respiratory infections, diarrhea, insomnia, and hypertension (Ding et al., 2019; Zhao et al., 2019) . Luteolin has other benefits, including antioxidant or prooxidant and anti-allergy activity (Kawai et al., 2007; Lin et al., 2008) .

The 

Matricaria chamomilla Blocks the proteolytic activity of SARS-CoV-2 3CLpro. (Baumann, 2008; Jo et al., 2020) Baicalin Flavonoid S. baicalensis Prevents viral attachment to the host cell. (Li-Weber, 2009) β-Sitosterol Phytosterol Isatis indigotica Blocks the SARS-3CLpro enzyme cleavage activity. (Lin et al., 2005) Dihydrotanshinone Biterpenoids Salvia miltiorrhiza Inhibits virus entry into the cell. Emodin Anthraquinone Rheum and polygonum Inhibits attachment of surface spike protein of SARS-CoV-2 with the host cell. (Alves et al., 2004; Ho et al., 2007) Epigallocatechin gallate Flavan C. sinensis Anti-SARS 3CLpro enzyme activity. (Jo et al., 2020; Westbrook et al., 2018) Gallocatechin gallate

Flavan Litchi chinensis sonn.

Anti-SARS 3CLpro enzyme activity. (Jo et al., 2020) Gnidicin Diterpene esters

Inhibit SARS-CoV-2 RdRp. (Bhandurge et al., 2013) Gniditrin Diterpene esters

Inhibit SARS-CoV-2 RdRp. (Bhandurge et al., 2013) Glycyrrhizin Saponin G. radix.

Active against viral adsorption and penetration. (Cinatl et al., 2003; Ong, 2002) Herbacetin Flavonol M. paniculata Anti-proteolytic activity of SARS-CoV 3CLpro. (Harborne, 1969; Jo et al., 2020) Hesperidin (Yi et al., 2004) Maco-flavanone E Flavonoid M. tanarius Blocks viral assembly and release. (Gupta et al., 2020) Pectolinarin Flavone Cirsium spp. Anti-SARS 3CLpro enzyme activity. Jo et al., 2020) Puerarin Iso-flavone Pueraria lobata Anti-SARS CoV 3CLpro proteolytic activity. (Jo et al., 2020; Zhou et al., 2014) Phaithanthrin Alkaloid Isatis indigotica Inhibition of PLpro activity. (Wu, Liu, et al., 2020) Phyllaemblicin Terpenoids P. emblica Inhibits helicase activity of SARS-CoV-2. (Wu, Liu, et al., 2020; Zhang, Kaunda, et al., 2019) Phyllaemblinol Terpenoids P. emblica Anti-SARS-CoV-2 helicase activity. (Wu, Liu, et al., 2020; Zhang, Kaunda, et al., 2019) Platycodin D Triterpenoidal saponin P. grandiflorum Inhibit PLpro activity of SARS-CoV-2. (Khan et al., 2016; Wu, Liu, et al., 2020) Quercetin Flavonol C. sinensis Inhibition of SARS-CoV-2 3CLpro. (Wu et al., 2015) Rhoifolin Flavone Citrus paradisi, Citrus aurantium, Citrus limon

Inhibits the enzymatic action of SARS-CoV-2 3CLpro. (Jo et al., 2020) Rutin Glycoside R. graveolens Inhibits the helicase of SARS-CoV-2. (Ganeshpurkar & Saluja, 2017; Wu, Liu, et al., 2020) (Continues) receptor complexes (Figure 1 ). Enveloped virus entrance into cells takes place by two main processes: Some of the viruses transfer their genomes into the cytosol where the envelope merges with the plasma membrane of the host cell, and some act on the endocytic mechanism of the cell ( Figure 5 ). In the latter process, endosomal acidic pHmediated endocytosed virus causes the activation shift in the (Cheng et al., 2006; Sinigrin Glucoside

Blocks the SARS-3CLpro enzyme cleavage activity. (Lin et al., 2005) Sugetriol-3,9-diacetate

Cyperus rotundus L.

Anti-SARS-CoV-2 PLpro activity. (Kim et al., 2013) Tetrandrine Alkaloid

Stephania tetrandra S. Blockage of spike and nucleocapsid protein expression in HCOV-OC43. Tetra-O-galloylβ-D-glucose

Galla chinensis Attaches with the surface spike protein of SARS-CoV-2 in an avid manner. (Yi et al., 2004) Theaflavin Flavonoid C. sinensis Inhibition of SARS-CoV-2 RdRp. (Leung et al., 2001) Vibsanol A Lignan V. odoratissimum Blocks viral assembly and release. (Gupta et al., 2020) Note endocytic mechanism is pH-dependent, but direct fusion with the membrane is independent of pH (Pelkmans & Helenius, 2003; Sieczkarski & Whittaker, 2002) . Glycyrrhizin obtained from

Glycyrrhizae radix, saikosaponins extracted from Radix bupleuri, and dihydrotanshinone obtained from Salvia miltiorrhiza block the entry of SARS-CoV-2 into the host cell by inhibiting the endocytosis of the virus into the host cell (Cheng et al., 2006; Cinatl et al., 2003; Kim et al., 2018; Li, Song, et al., 2018; Ong, 2002; (Table 3) . Along with virustatic activity, glycyrrhizin acts as a hepatoprotective agent and cough suppressor (Kamei et al., 2003; van Rossum et al., 1998) . Saikosaponin is used as a neuroregulatory agent given its anticonvulsant activity Yuan et al., 2017) . Dihydrotanshinone is used to treat Alzheimer's disease and as a cardioprotective agent Jiang et al., 2019) . 

Two viral proteases have a role in encoding the replicase polyproteins for SARS-CoV-2. One of the proteases, papain-like protease (PLpro), has a role in releasing the NSp1, NSp2, and NSp3 (necessary for the correction of viral replication) by the N-terminus cleavage of replicase poly-protein (Harcourt et al., 2004) . PLpro also has a crucial role in antagonizing the innate immunity of the host cell by blocking the interferon regulatory factor 3 (IRF3) pathway and IFN production (Chen et al., 2014; Yuan et al., 2015) . Platycodin D obtained from Platycodon grandiflorum, sugetriol-3,9-diacetate obtained from Cyperus rotundus L, and phaithanthrin D obtained from

Isatis indigotica may play a role as anti-COVID-19 agents by inhibiting the cleavage of N-terminus of polyproteins (Khan et al., 2016; Kim et al., 2013; Wu, Liu, et al., 2020) (Table 3 ).

4.3.2 | Inhibition of 3-chymotrypsin-like protease (3CLpro) 3CLpro, another viral protease called NSp5, undergoes the cleavage process to synthesize mature enzymes (Yang et al., 2005) . It is an interesting target (Figure 1 ) because it plays a key function in the translation of the viral genome by processing the polyproteins.

Accordingly, it is called as the main protease (M pro) (Zhang, Lin, Sun, et al., 2020) . CoV genome is comprised of six ORFs (open reading frames). Shifting between ORF1a and ORF1b causes the formation of polypeptides: pp1a and pp1ab that play a part in the formation of the replication transcription complex (RTC) (Chen, Liu, et al., 2020) . The natural antivirals, apigenin obtained from Matricaria chamomilla, epigallocatechin gallate obtained from C. sinensis, herbacetin obtained from Meconopsis paniculata, pectolinarin obtained from Cirsium spp., puerarin obtained from P. lobata, rhoifolin obtained from Citrus spp., and quercetin obtained from C. sinensis, may protect against the virus by inhibiting the 3CLpro enzyme activity of SARS-CoV-2 (Article, 2012; Baumann, 2008; Cho et al., 2016; Finger et al., 1991; Harborne, 1969; Jo et al., 2020; Nguyen et al., 2012; Westbrook et al., 2018; Zhou et al., 2014) ( Table 3 ). Apigenin has many potential benefits including antiplatelet and anticancer activity (Jang et al., 2008; Yan et al., 2017) . EGCG is widely used for treating obesity and inflammation (Li, Gao, et al., 2018; Riegsecker et al., 2013) . Herbacetin is a promising molecule for cancer prevention and bone loss Li, Sapkota, et al., 2016) . Pectolinarin reduces inflammation and also has analgesic property (Lim et al., 2008; Martínez-Vázquez et al., 1998) . Puerarin is used to treat endometriosis and chronic liver diseases (Yu et al., 2015; Zhao et al., 2016) . Rhoifolin functions as antidiabetic agent (Tzeng et al., 2011) . Quercetin has a broad range of pharmacological activities along with antiviral activity including anticarcinogenic and antiinflammatory activity (Li, Yao, et al., 2016) .

Accordingly, all these natural antivirals are maybe therapeutically of value in preventing and treating COVID-19.

RNA-dependent RNA polymerase or RNA replicase of SARS-CoV-2 is the most dominant focus for the anti-SARS activity (Xu et al., 2003) .

Among the ORFs, the biggest ORF called replicase has a role in the encoding of enzymes, which then further cause translation and form structural proteins (Sawicki et al., 2007) . NSp12 in coronavirus is an RNA-dependent RNA polymerase, which is a conserved protein. Thus, it is considered to be an essential enzyme transcription complex of coronavirus. The RdRp domain has a conserved Ser-Asp-Asp motif and location on the C-terminus (Subissi et al., 2014) . NSp8 is capable of catalyzing the synthesis of template-dependent oligoribonucleotides, which is primarily used as a primer for RNA synthesis and catalyzes the NSp12 activity (Imbert et al., 2006) .

Theaflavin obtained from C. sinensis and the plant Gnidia lamprantha from the Gnidia species include phytochemicals, gnidicin, and gniditrin (Table 3) , which have anti-SARS-CoV-2 activity, inhibiting the translation process of RNA-dependent RNA polymerase enzyme present in COVID-19 (Bhandurge et al., 2013; Leung et al., 2001; Wu, Liu, et al., 2020 ) ( Figure 5) . Thus, all these natural compounds may possess efficient antiviral activity against SARS-CoV-2.

SARS-associated helicase is regarded as one of the most important targeted proteins for anti-SARS agent evolution (Tanner et al., 2003) .

Virus requires helicase for the conversion of double-stranded RNA to single-stranded RNA for the manipulation of polynucleotides (Briguglio et al., 2011) . Helicase (NSp13) is a multifunctional protein that consists of the helicase domain (HEL) and the N-terminal metalbinding domain (MBD). NsP13 unwinds the double-stranded RNA in an NTP-dependent manner along the direction of 5 0 -3 0 . Because helicase has a central role in the uncoiling of duplex RNA and RNA capping (Shum & Tanner, 2008) and is essential for replication and proliferation of the virus, it is believed to be a target for antiviral agents Shum & Tanner, 2008) ( Figure 1 ). Hesperidin obtained from Citrus spp., rutin obtained from Ruta graveolens, and the plant Phyllanthus emblica containing phyllaemblicin B and phyllaemblinol are known to show activity against SARS-CoV-2 by inhibiting the helicase NSp13 activity of SARS-COV-2 (Ganeshpurkar & Saluja, 2017; Man et al., 2019; Wu, Liu, et al., 2020; Zhang, Kaunda, et al., 2019) (Table 3) .

Virion particle assembly is the last and essential step for viral infection (Thomas & Gorelick, 2008) . The generation of progenitors in coronavirus involves two major mechanisms: viral envelope assembly and helical nucleocapsid assembly (de Haan et al., 2000) . Four structural proteins: S-protein, E-protein, M-protein, and N-protein play a key role in CoV assembly and viral infection (DeDiego et al., 2007) . Among all the structural proteins, M-protein (membrane protein) is the protein, which is considered the main promoter for the assembly of COVID-19 and elucidates the envelope of the virus by the M-M protein interaction (Masters & Rottier, 2005; Neuman et al., 2011) . Nprotein acts by binding to the RNA genome of CoV, thus producing nucleocapsid (de Haan & Rottier, 2005) . Binding to the RNA of the virus is the major interest of N-protein (Masters, 2006) . Most SARS N-protein and RNA make a complex, called ribonucleoprotein complex, which is inserted into the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) with S-protein, M-protein, and E-protein.

Final virion assembly occurs in the intermediate compartment, and mature virions are released via smooth-walled vesicles by exocytosis (Nal et al., 2005) (Figure 5 ). The natural compound vibsanol A extracted from the flowers and leaves of Viburnum odoratissimum and macoflavanone E extracted from the leaves of Macaranga tanarius act by modifying the E-protein's normal ion channel activity, which factors in the pathogenesis of SARS-CoV-2 (Gupta et al., 2020; Kawakami et al., 2008; Shen et al., 2002) (Table 3 ). Natural antiviral compounds that inhibit the activity of N-protein have yet to be identified. (Table 4 summarizes the factors that serve as promising targets for SARS-CoV-2 particle assembly and release.

This review establishes the role of phytonutrients as immunity boosters, and different phytochemicals are also used against COVID-19 because of their antiviral activity. It is crystal clear with this study that an acceptable amount of nutraceuticals and phytochemicals can improve the resistance against several infections. So, the deficiency of immunity intensifiers can be disastrous for the immune system.

Unquestionably, the simplest way to reinvigorate the immune system is to intake nutrients that act as immunity-boosting tonics, and after nutrients, phytochemicals are the best, and both can be used as a powerful weapon against SARS-CoV-2. But if the immune system fails to cope with the virus, then antivirals serve as the marvelous therapy against the viral infections. The use of the antivirals is to solicit both direct antiviral impressions against viruses and specific immune cell activation. The present review posits that natural antivirals may act on different targets of SARS-CoV-2 to impede infection and afford efficient treatment. Compounds from natural origin may therefore play a significant role in the management of anti-SARS-CoV-2 therapy, but additional research is required to better understand their mechanisms in-depth.

The authors of this article have no conflict of interest.

Not applicable.

Host factor(s) HCoV (other CoV) Function References

HCoV-229E, HCoV-NL63, (TGEV) Binds to the cytosolic domain of S protein; facilitates the assembly and release of the virus. (Rüdiger et al., 2016) Β-Actin (IBV) Binds to M protein; promotes particle assembly and release. (Wang et al., 2009) Vimentin (TGEV) Binds to N protein; ease the process of viral assembly and release. Note: HCoV-229E, human coronavirus-229E; HCoV-NL63, human coronavirus-NL63; TGEV, transmissible gastroenteritis virus; IBV, infectious bronchitis virus.

Azhar Rasul https://orcid.org/0000-0001-9669-7364

Haroon Khan https://orcid.org/0000-0002-1736-4404

Myth busters: Dietary supplements and COVID-19

Resveratrol and Alzheimer's disease: Mechanistic insights

Anticancer and immunostimulatory compounds from Andrographis paniculata

Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice

The role of vitamins and minerals on the immune system. Home Health Care Management & Practice

Membranerelated effects underlying the biological activity of the anthraquinones emodin and barbaloin

Utility of bromelain and N-acetylcysteine in treatment of peritoneal dissemination of gastrointestinal mucin-producing malignancies

Cytotoxic C-methylated chalcones from Syzygium samarangense

Antiviral and virucidal activities of natural products

Selenium, Selenoproteins, and immunity

Kaempferol and quercetin stimulate granulocyte-macrophage colonystimulating factor secretion in human prostate cancer cells

Andrographolide: Antibacterial activity against common bacteria of human health concern and possible mechanism of action

Mechanisms of coronavirus cell entry mediated by the viral spike protein

The therapeutic potential of resveratrol: A review of clinical trials

The Gnidia genus: A review

Antihypertensive effect of caffeic acid and its analogs through dual renin-angiotensin-aldosterone system inhibition

Antioxidant and antiinflammatory effect of plumieride in dextran sulfate sodium-induced colitis in mice

Neuropharmacological and acute toxicological evaluation of ethanolic extract of Allamanda cathartica L. flowers and plumieride

Immunomodulatory effect of natural flavonoid chrysin (5, 7-dihydroxyflavone) on LPS stimulated RAW 264.7 macrophages via inhibition of NF-κB activation

Inhibition of RNA helicases of ssRNA + virus belonging to Flaviviridae, Coronaviridae and Picornaviridae families

A new clinical trial to test high-dose vitamin C in patients with COVID-19

G-CSF and GM-CSF modify neutrophil functions at concentrations found in cystic fibrosis

Boesenbergia pandurata Roxb., an Indonesian medicinal plant: Phytochemistry, biological activity, plant biotechnology

Application of phytochemicals as immunostimulant, antipathogenic and antistress agents in finfish culture

A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention

Anticancer effects of epigallocatechin-3-gallate nanoemulsion on lung cancer cells through the activation of AMP-activated protein kinase signaling pathway

Natural products for the prevention and treatment of kidney disease

Pharmacological activities of dihydrotanshinone I, a natural product from Salvia miltiorrhiza Bunge

SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex

Emerging coronaviruses: Genome structure, replication, and pathogenesis

Antiviral effects of saikosaponins on human coronavirus 229E in vitro

Determination of pectolinarin in Cirsium spp. using HPLC/UV analysis

Anticancer properties of low molecular weight oat beta-glucan -an in vitro study

Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus

Potential antivirals and antiviral strategies against SARS coronavirus infections

Molecular interactions in the assembly of coronaviruses

Assembly of the coronavirus envelope: Homotypic interactions between the M proteins

A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo

Inhibitory activities of baicalin against renin and angiotensin-converting enzyme

Biomedicine & Pharmacotherapy Baicalin relaxes vascular smooth muscle and lowers blood pressure in spontaneously hypertensive rats

Discovering drugs to treat coronavirus disease

Aloe-emodin: A review of its pharmacology, toxicity, and pharmacokinetics

The spike protein of SARS-CoV -A target for vaccine and therapeutic development

Natural products as antiviral agents

The relationship of serum vitamins A, D, E and LL-37 levels with allergic status, tonsillar virus detection and immune response

Selenium in edible mushrooms

Vitamins: Key role players in boosting up immune response-a mini-review

Flavonol glycosides in tea-kaempferol and quercetin rhamnodiglucosides

Puerarin protects rat pancreatic islets from damage by hydrogen peroxide

The pharmacological potential of Rutin

Coronavirus that uses the ACE2 receptor

A review of micronutrients and the immune system-working in harmony to reduce the risk of infection

Handbook of famine, starvation, and nutrient deprivation

Phytochemical screening of leaves of Plumeria alba and Plumeria acuminata

In-silico approaches to detect inhibitors of the human severe acute respiratory syndrome coronavirus envelope protein ion channel

Broad-spectrum antiviral properties of andrographolide

Gossypetin and herbacetin as taxonomic markers in higher plants

Identification of severe acute respiratory syndrome coronavirus Replicase products and characterization of papain-Like protease activity

Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction

Review article anticancer potential of emodin

Structural characterization and evaluation of antioxidant, anticancer and hypoglycemic activity of radiation degraded oat (Avena sativa) β-glucan. Radiation Physics and Chemistry

Potential role of nutrients on immunity

A second, non-canonical RNAdependent RNA polymerase in SARS coronavirus

SARS-CoV-2 Cell Entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven article SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

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

Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase

Human coronavirus 229E nonstructural protein 13: Characterization of duplex-unwinding, nucleoside Triphosphatase, and RNA 5 0 -Triphosphatase activities

Inhibition of cholinesterase and amyloid-&bgr; aggregation by resveratrol oligomers from Vitis amurensis

HIF-1α preconditioning potentiates antioxidant activity in ischemic injury: The role of sequential administration of dihydrotanshinone I and protocatechuic aldehyde in cardioprotection

Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors

Inhibition of SARS-CoV 3CL protease by flavonoids

Anti-platelet effects of epigallocatechin-3-gallate in addition to the concomitant aspirin, clopidogrel or ticagrelor treatment

Antitussive principles of Glycyrrhizae radix, a main component of the Kampo preparations Bakumondo-to (Mai-men-dong-tang)

Kaempferol -A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements

Flavonoids and related compounds as anti-allergic substances

Macaflavanones A-G, prenylated flavanones from the leaves of Macaranga tanarius

Killing cancer with platycodin D through multiple mechanisms

Immunomodulatory and cellular anti-oxidant activities of caffeic, ferulic, and p-coumaric phenolic acids: A structure-activity relationship study

Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus oc43 infection of mrc-5 human lung cells

Herbacetin is a novel allosteric inhibitor of ornithine decarboxylase with antitumor activity

Safe, high-throughput screening of natural compounds of MERS-CoV entry inhibitors using a pseudovirus expressing MERS-CoV spike protein

Sesquiterpenes from the rhizomes of Cyperus rotundus and their potential to inhibit LPS-induced nitric oxide production

Dietary magnesium intake and risk of incident coronary heart disease in men: A prospective cohort study

Influenza vaccine uptake, COVID-19 vaccination intention and vaccine hesitancy among nurses: A survey

Prevalence and clinical relevance of occult hepatitis B in the fibrosis progression and antiviral response to INF therapy in HIV-HCV-Coinfected patients

The enhancement of immune function and activation of NF-κB by resveratrol-treatment in immunosuppressive mice

Flavonoids as antiviral agents for enterovirus A71 (EV-A71)

Prevention and treatment of viral infections by natural therapies

Hepatoprotective efficacy of gallic acid during nitrosodiethylamineinduced liver inflammation in Wistar rats

The role of Vitamin E in immunity

Theaflavins in black tea and Catechins in green tea are equally effective antioxidants

EGCG reduces obesity and white adipose tissue gain partly through AMPK activation in mice

Herbacetin inhibits RANKL-mediated osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo

SARS coronavirus papain-like protease inhibits the TLR7 signaling pathway through removing Lys63-linked polyubiquitination of TRAF3 and TRAF6

Saikosaponins: A review of pharmacological effects

A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins

Molecular immune pathogenesis and diagnosis of COVID-19

Andrographolide and its potent derivative exhibit anticancer effects against imatinib-resistant chronic myeloid leukemia cells by downregulating the Bcr-Abl oncoprotein

Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells

Anti-inflammatory activity of pectolinarigenin and pectolinarin isolated from Cirsium chanroenicum

Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol

Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds

Antiviral natural products and herbal medicines

Luteolin, a flavonoid with potential for cancer prevention and therapy. Current Cancer Drug Targets

Antiviral properties of phytochemicals

The anti-diabetic activity of oat β-D-glucan in streptozotocinnicotinamide induced diabetic mice

Microwave-assisted synthesis and antioxidant activity of palmitoylepigallocatechin gallate

New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin

Distribution and biological activities of the flavonoid Luteolin

Vaccines, antivirals, and the beneficial uses of viruses

Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases

Andrographolide ameliorates oxidative stress, inflammation and histological outcome in complete Freund's adjuvant-induced arthritis

Zinc and immunity: An essential interrelation

Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses

In-vivo immunomodulatory potential of standardized Pueraria tuberosa extract and its isoflavonoids

Trace elements and minerals in health and longevity

Benefits of hesperidin for cutaneous functions. Evidence-Based Complementary and Alternative Medicine

Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action

A comparative study of the analgesic and anti-inflammatory activities of pectolinarin isolated from Cirsium subcoriaceum and linarin isolated from Buddleia cordata

Coronavirus reverse genetics by targeted RNA recombination

The molecular biology of coronaviruses

Antimicrobial activity of resveratrol-derived monomers and dimers against foodborne pathogens

Beta-glucan: An ideal immunostimulant in aquaculture (a review)

Iron intakes and food sources of iron in New Zealand adolescent females

The pro-fibrotic properties of transforming growth factor on human fibroblasts are counteracted by caffeic acid by inhibiting myofibroblast formation and collagen synthesis

No 主観的健康感を中心とした 在宅高齢者における 健康関連指標に関する共分散;造分析Title. Block Caving -A Viable Alternative?

Naturally occurring immunomodulators with antitumor activity: An insight on their mechanisms of action

Divergent effects of Daidzein and its metabolites on estrogeninduced survival of breast Cancer cells

Immunostimulant activity of an enzymatic protein hydrolysate from green microalga Chlorella vulgaris on undernourished mice

Synthesis and biological evaluation of quercetin and resveratrol peptidyl derivatives as potential anticancer and antioxidant agents

Hepatoprotective activity of Andrographis paniculata and Swertia chiriiayita

Differential maturation and subcellular localization of severe acute respiratory syndrome coronavirus surface proteins S, M and E

Cardamonin: A new player to fight cancer via multiple cancer signaling pathways

A structural analysis of M protein in coronavirus assembly and morphology

Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris

Selenium and immunity

Pharmacologic therapy for COVID-19 infection

Reported dietary intake and food sources of zinc, selenium

Chemical assay of glycyrrhizin in medicinal plants by pressurized liquid extraction (PLE) with capillary zone electrophoresis (CZE)

Chemical composition and phagocyte immunomodulatory activity of Ferula iliensis essential oils

The volatile oils from the oleo-gumresins of Ferula Asafoetida and Ferula gummosa: A comprehensive investigation of their insecticidal activity and eco-toxicological effects

Insider information: What viruses tell us about endocytosis

Antioxidant potential ethanolic extract of Glycine max (l.) Merr. Var. Detam and daidzein

Effect of chrysin on hepatoprotective and antioxidant status in dgalactosamine-induced hepatitis in rats

Chrysin induces antidiabetic, antidyslipidemic and antiinflammatory effects in athymic nude diabetic mice

Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: An in silco study for drug development

Antioxidant protection of gallic acid against toxicity induced by Pb in blood, liver and kidney of rats

Effects of gallic acid on signaling kinases in murine macrophages and immune modulation against Brucella abortus 544 infection in mice

A mouse modelbased screening platform for the identification of immune activating compounds such as natural products for novel cancer immunotherapies

Potential benefits of green tea polyphenol EGCG in the prevention and treatment of vascular inflammation in rheumatoid arthritis

Role of IL-12 in overcoming the low responsiveness of NK cells to missing self after traumatic brain injury

Tubulins interact with porcine and human S proteins of the genus Alphacoronavirus and support successful assembly and release of infectious viral particles

Symposium: Dietary zinc and Iron -Recent perspectives regarding growth and cognitive development dietary zinc and Iron sources, Physical growth and cognitive development

Biochanin A: A novel bioactive multifunctional compound from nature

Antimicrobial activity of gallic acid against thermophilic campylobacter is strain specific and associated with a loss of calcium ions

Immunomodulatory potential of hesperetin and chrysin through the cellular and humoral response

Minireview: A contemporary view of coronavirus transcription

Dissolution study of purified bromelain from pineapple cores

Merr) encapsulated in alginate-chitosan microcapsule

New vibsane diterpenes and Lupane triterpenes from Viburnum odoratissimum

Copper, manganese, iron and zinc contents of Nigerian foods and estimates of adult dietary intakes

Differential inhibitory activities and stabilisation of DNA aptamers against the SARS coronavirus helicase

Dissecting virus entry via endocytosis

Immunostimulatory activity of plumieride an iridoid in augmenting immune system by targeting Th-1 pathway in balb/c mice

Plant as a source of natural antiviral agents

SARS-CoV-2: Micronutrient optimization in supporting host immunocompetence

SARS-CoV ORF1b-encoded nonstructural proteins 12-16: Replicative enzymes as antiviral targets

Variation in the activity of distinct cytochalasins as autophagy inhibitors in human lung A549 cells

The severe acute respiratory syndrome (SARS) coronavirus NTPase fhelicase belongs to a distinct class of 5 0 to 3 0 viral helicases

The macrophage: A cellular factory at the interphase between iron and immunity for the control of infections

Nucleocapsid protein function in early infection processes

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

Insulin-mimetic action of rhoifolin and cosmosiin isolated from Citrus grandis (L.) osbeck leaves: Enhanced adiponectin secretion and insulin receptor phosphorylation in 3T3-L1 cells. Evidence-Based Complementary and Alternative Medicine

Antiviral properties of the natural polyphenols delphinidin and epigallocatechin gallate against the flaviviruses West Nile virus, Zika virus, and dengue virus

Chrysin pretreatment improves angiotensin system, cGMP concentration in L-NAME induced hypertensive rats

Vitamin C and the Immune System j SpringerLink

Interaction of the coronavirus infectious bronchitis virus membrane protein with β-Actin and its implication in Virion assembly and budding

Synthesis, biological evaluation and structureactivity relationships of glycyrrhetinic acid derivatives as novel antihepatitis B virus agents

In vitro and in vivo anticancer activity of a novel puerarin nanosuspension against colon cancer, with high efficacy and low toxicity

Hepato-protective effect of resveratrol against acetaminophen-induced liver injury is associated with inhibition of CYP-mediated bioactivation and regulation of SIRT1-p53 signaling pathways

Protective effect of daidzein against streptozotocin-induced Alzheimer's disease via improving cognitive dysfunction and oxidative stress in rat model

Curcumol: From plant roots to cancer roots

Iron and immunity: A double-edged sword

Improving distributed sensing with continuous gratings in single and multi-core fibers

This article is protected by copyright. All rights 1 reserved

Contribution of selected vitamins and trace elements to immune function

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

A new coronavirus associated with human respiratory disease in China

Anti-diabetic effects of puerarin, isolated from Pueraria lobata (Willd.), on streptozotocin-diabetogenic mice through promoting insulin expression and ameliorating metabolic function. Food and Chemical Toxicology

Quercetin as an antiviral agent inhibits influenza a virus (IAV) entry. Viruses

Hepatoprotective activity of puerarin against carbon tetrachlorideinduced injuries in rats: A randomized controlled trial

Molecular model of SARS coronavirus polymerase: Implications for biochemical functions and drug design

Neuroprotection of andrographolide against microglia-mediated inflammatory injury and oxidative damage in PC12 neurons

Apigenin in cancer therapy: Anti-cancer effects and mechanisms of action

Design of wide-spectrum inhibitors targeting coronavirus main proteases

Severe acute respiratory syndrome coronavirus entry into host cells: Opportunities for therapeutic intervention

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

Plants as a prospective source of natural anti-viral compounds and oral vaccines against COVID-19 coronavirus

The effects and possible mechanisms of puerarin to treat endometriosis model rats

A systematic review of the active saikosaponins and extracts isolated from Radix bupleuri and their applications

P53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling

Flavonoids: Promising natural compounds against viral infections

Dietary folic acid requirement of fingerling Channa punctatus ( Bloch ) based on growth , protein productive value and liver folic acid concentrations

α-Glucosidase inhibitory effect of resveratrol and piceatannol

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

In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Potential interventions for novel coronavirus in China: A systematic review

Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non-small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway

Identification of the interaction between vimentin and nucleocapsid protein of transmissible gastroenteritis virus

The genus Terminalia (Combretaceae): an ethnopharmacological, phytochemical and pharmacological review

Protective effects of Genistein and Puerarin against chronic alcoholinduced liver injury in mice via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms

Scutellaria baicalensis Georgi. (Lamiaceae): A review of its traditional uses, botany, phytochemistry, pharmacology and toxicology

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

Puerarin: A review of pharmacological effects

The composition, antibiofilm and antimicrobial activities of essential oil of Ferula Assa-foetida oleo-gum-resin

Combination of natural antivirals and potent immune invigorators: A natural remedy to combat COVID-19