Mini Review

Natural Immunomodulators Treat the Cytokine Storm in SARS-CoV-2

Introduction

The immune system consists of a collection of cells, chemicals and processes that protect various organs of the body from foreign antigens, cancer cells, and toxins. On the other hand, defects in one arm of the immune system resulting in an inappropriate response.¹

Cytokines are tiny glycoproteins generated by nearly every cell to control the immune response. They are classified according to the basis from which they are formed into pro-inflammatory cytokines (cytokines that alert the immune system due to the existence of infection and threat), anti-inflammatory cytokines (cytokines that induce feedback inhibition and return to an inactive non-inflammatory state and negatively control the inflammatory process), lymphokines (cytokines that are released by lymphocytes and adjust the immune response), chemokine (cytokines that recruit leukocytes to the site of infection or injury) and growth factor ( cytokines which aid the cell to be alive and cause structural modifications in the airways).²

Cytokines are essential in the adaptation of the inflammatory response to self-or not-self hazard molecules. For now, inflammation is a vital defense mechanism for health.³ Usually, the severe response is recognized by a rapid start and short periods. This response is supplemented by the stimulation of macrophages and liberation of cytokines like interleukin (IL)-1, tumor necrosis factor-α (TNF-α) and IL-6 that act on fibroblasts and endothelial cells and stimulate an increase in the vascular permeability of the cells. This cytokine also induces adhesion molecules expression that binds to different cells like lymphocytes, neutrophils and monocytes and enables these cells to infiltrate through the walls of the blood vessels to the tissue spaces and fight injury or infection. However, prolonged persistence of an antigen or uncontrolled acute inflammation which fails to end tissue injury may lead to chronic inflammatory response and enhance staffing of many cells, improving the release of pro-inflammatory cytokines and finally increased the microbicidal activity.⁴

The levels of produced cytokine determine the intensity of the inflammatory response. The pro-inflammatory cytokines are very important mediators to set up an anti-infectious response but an exacerbated production of these cytokines may be deleterious and lead to multi-organ failure and death. In addition to that, anti-inflammatory cytokines are suitable to control the cascade of pro-inflammatory cytokines but excessive production is associated with severe immune suppression.⁵ One of the life-threatening states is the cytokine storm that occurs when the level of circulating pro-inflammatory cytokines suddenly rises, causing a massive influx of lymphocytes into the infected area, and causes disruption of the vascular barrier, multi-organ failure, and, eventually, death.⁶

The acute to chronic progress should be prevented; the inflammatory response must be depressed to avoid the extra tissue damage. Stopping inflammation is a well-managed process involving the production of control mediators such as cytokine and chemokine. According to that, circulating white blood cells decrease recruitment to injury sites as well as induce a reduction in neutrophil infiltration and apoptosis of spent neutrophils, ultimately causing reverse-regulation of chemokine and cytokines.⁷ In this review, we explained the various types of natural immunomodulators, and their effect on cytokine storm syndrome, and the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Immunological features of COVID-19 associated cytokine storm

Coronavirus is a single-stranded RNA (+ssRNA), and enveloped that belongs to Coronaviridae. Many species of the CoV family infect mammals and birds, causing gastrointestinal infections and upper respiratory tract. It mostly induces the common cold in humans, but complications such as pneumonia and SARS-CoV-2 can happen.⁸ Most of COVID-19 patients have a high degree of pro-inflammatory response causing the cytokine release syndrome (CRS) with a notable rise in the degree of several pro-and anti-inflammatory cytokines and chemokines, such as interferon (IFN)-α, interferon-gamma induced protein 10 (IP-10), IL-1ra, IL-2ra, IL-6, IL-10, IL-18, hepatocyte growth factor (HGF) and monocyte chemotactic protein-3 (MCP-3). The pro-inflammatory effect of IL-6, which is a multifunctional cytokine, plays a role in the inflammatory storm’s modulation. The main functions of IL-6 are the activation of T cells and the promotion of B differentiation and antibody formation ().⁹

Close

Figure 1. Immunological features of COVID-19 associated cytokine storm.

Immunomodulation of the immune system with different natural products or drugs can restore the immune system and give some help in reversing the angry of lymphocytes and targeting cytokine to increase the chance of survival.

Natural products as immune system modulators

Natural products have a well-known therapeutic efficacy such as the metabolic disorders, cardiovascular diseases, inflammation, and viral infection. Herbal medicines, fatty acids, and probiotics are examples of natural products that play a role in the immune function. They regulate the immune system in a pleiotropic mode, and take a part in diverse adaptive and innate immunity processes. So, natural products have efficacy for directed immune modulators, in the management of definite kinds of immunological and inflammatory diseases, like prevention of Crohn’s disease, ulcerative plaque psoriasis and rheumatoid arthritis, colitis, among other immunological and inflammatory diseases.¹⁰

Polyphenols

Polyphenols are active natural products familiar with immunomodulatory activities. They control immunity by affecting the immune cell regulation, pro-inflammatory cytokines’ synthesis, and gene expression. They deactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and change mitogen-activated protein kinase (MAPK) and arachidonic acids pathways. Polyphenols are common in plants, since they are products of secondary metabolism and can be found as glycosides or free aglycones.¹¹ The polyphenol family has thousands of structural deviations (over 8000), and in vivo and vitro studies have shown that plant polyphenols have anti-inflammatory properties, indicating that they could be used as therapeutic implements for a variety of acute and chronic diseases.^10,12 Furthermore, polyphenols’ capability to modulate the development of many pro-inflammatory genes and the immune system contributes to the regulation of inflammatory signaling.^13,14 In vivo and in vitro reports, the murine and rat macrophages exhibited the resveratrol inhibited cyclooxygenase (COX), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and stimulated endothelial nitric oxide synthase (eNOS).^15,16

Curcumin and its chemical analogues cause inhibition of the of NF-κB stimulation by many diverse inflammatory stimuli.¹⁷ In the system of human cells, the curcumin and analogues decreased the expression of inflammatory cytokines such as tumour necrosis factor (TNF) and intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1).

Wang et al stated that the TNF-α and IL-6 secretion is reduced by polyphenols extracted from chamomile, and quercetin without 1L-1β alteration.¹⁸ A polyphenol-rich diet can help patients with COVID-19 to decrease inflammation due to the hyper-activation of cytokines as TNF-α, IL-1β, IL-6, and IL-8.¹⁹ In general, polyphenols modulate inflammatory cytokines, which is one of the most common mechanisms by which they use immune-modulator effects.

Diagram show polyphenols Effect on various steps of the SARS-CoV-2 life cycle. Polyphenols potentially block the binding of SARS-CoV-2 spike protein to host cell receptor angiotensin-converting enzyme 2 (ACE2), stop viral entry into the host cell, and block viral RNA replication and protein processing ().

Close

Figure 2. Polyphenols effect on various steps of the SARS-CoV-2 life cycle. Polyphenols potentially block the binding of SARS-CoV-2 spike protein to host cell receptor ACE2, stop viral entry into the host cell, and block viral RNA replication and protein processing

Effect of zinc on immunity

Zinc is a popular dietary supplement, which is discovered in 1961, and is necessary for human physiology.²⁰ Also, it can be used as single or in divided doses, and some formulations are designed to be administered intravenous or intramuscular.²¹ Zinc is prescribed in doses of 25–50 mg/d, and has few side effects. However, the higher doses of 200–400 mg/d cause epigastric pain, vomiting, and fatigue.^22,23

Zinc is involved in more than 10% of human proteins synthesis and plays a vital role in the immune function.²⁴ Also, it has an anti-inflammatory effect by reducing the production of cytokines and biomarkers of oxidative stresses.²⁵

However, zinc deficiency has an effect on immunity, making you more susceptible to infections and the symptoms of zinc deficiency includes cognitive impairment, growth delay, impaired immunity, loss of appetite, heavy hair loss, impotence, diarrhoea, skin, eye lesions, taste defects and postponed wound healing.^26-29 There are several literatures about the loss of taste or smell and zinc deficiency, which revealed that was due to the chemotherapy or insufficient nutrients.^30-34

Moreover, deficiency of zinc is accompanied by a decrease in antibodies secretion, impaired immune system function as low natural killer cell activity, decreased cytokine production, and decreased chemotaxis and oxidative rupture of neutrophils.³⁵ Antiviral properties of zinc are essentially via physical routes like virus attachment, infection, uncoating, and by hindering viral protease and polymerase enzymes.³⁶

Many hypotheses recommended zinc compounds as supporting treatment for elderly people with SARS-CoV-2 infection has an illness like diabetes, obesity, or cardiovascular diseases.^37-40 A recent study highlighted the role of zinc supplementation in SARS-CoV-2, which has promising antiviral effects but, still lack clinical data.⁴¹

Studies on cell cultures have shown that the high concentrations of zinc and the addition of pyrithione to stimulate cellular import of zinc ion will stop the replication of different RNA viruses, including several picornaviruses and influenza viruses.^42,43 Zinc modulates T-cell functions, and preventing immune system hyper-activation by modulating and balancing cytokines.⁴⁴

A recent study conducted in the United States using electronic medical records discovered a high recovery rate among patients treated with hydroxychloroquine and azithromycin with zinc sulphate.⁴⁵

Lactoferrin as a part of innate immunity

Understanding of lactoferrin antimicrobial efficiency, interaction with host cells, and immune modulation allows this promising protein as a possible antibiotic substitute. Lactoferrin antimicrobial effect directly or indirectly affects bacteria, viruses, and parasites. Lactoferrin can also modulate immune responses by interacting with different lactoferrin targets, like pathogen-associated molecular patterns and their receptors, glycosaminoglycans, and cell receptors. Lactoferrin can also act as an alarmin, allowing the production of neutrophils and monocytes as well as the activation and maturation of monocytes and immature dendritic cells (). Lactoferrin can also target other cells, such as epithelial cells, by interacting with the lactoferrin receptor, resulting in uptake and nuclear translocation or transcytosis of these cells.⁴⁶

Close

Figure 3. An overview of the main targets of lactoferrin.

Lactoferrin, or lactotransferrin is a globular glycoprotein of the transferrin family found in a variety of secretory fluids, like nasal secretions, milk, saliva, and tears. There is a high concentration of lactoferrin in human colostrum, human, and cow milk. Lactoferrin has antimicrobial activity and is part of the innate immunity, at mucosal surfaces. Lactoferrin exhibits some of its biological functions through interaction with DNA and RNA, polysaccharides, and heparin, to form complexes with them.⁴⁷ Lactoferrin inhibits many human and animal viruses with DNA and RNA genomes, including cytomegalovirus and HIV.^48-52 Lactoferrin binds to the same lipoproteins as many viruses, expelling the virus particles. Lactoferrin can interact with the cell membrane and bind directly to viral particles as in hepatitis viruses.⁵³ Further, an indirect antiviral effect is achieved by affecting natural killer cells, granulocytes, and macrophages that act in the early stages of viral infections.⁵⁴ No direct reaction occurred between host cell angiotensin-converting enzyme 2, which is the functional receptor for SARS-CoV, and SARS-CoV-2 and lactoferrin.^55,56

It is widely assumed that lactoferrin can prevent viral entry by interacting with heparan sulphate proteoglycans.⁵⁷ Recently, the study by Zwirzitz et al showed that lactoferrin regulate the activation of the plasminogen, which controls the coagulation stimulated by the virus.⁵⁸ Mesoporous silica nanomaterials have recently attracted researchers’ interest because of their potential biomedical applications, superior biocompatibility, and biodegradability. Furthermore, mesoporous silica nanoparticles are a promising nano-vehicle with high drug loading as well as time-dependent drug release.^59,60

Also, tannic acid was used to change the surface of mesoporous silica nanomaterials as a delivery nano-vehicle to accelerate bone healing and regeneration in bone fractures and disorders.⁶¹ This study of lactoferrin loaded on mesoporous silica could be a promising prospect in the treatment or prevention of SARS-CoV-2.⁶¹

The antivirals and immunomodulators efficacy of medicinal plants and essential oils

In addition to traditional therapies that control viral infection, antivirals that are cost- effective and extremely powerful as vaccines are urgently needed. Cheng et al showed that no specific CoV infection therapies are available. As a result, the condition explains the need to develop the right antiviral drugs to combat CoV infection.⁶² Saikosaponins (A, B2, C, and D), triterpene glycosides isolated from medicinal plants such as Bupleurum spp., Scrophularia scorodonia, and Heteromorphaspp., have previously been reported to exert antiviral action against HCoV-22E9.

Houttuynia cordata water extract has a number of antiviral effects on SARS-CoV, including prevention of 3CL viral protease and disrupting the activity of RNA-dependent viral RNA polymerase.⁶³ According to Li et al, co-challenge with the virus, extracts from Pyrrosia lingua, Lycoris radiata, Lindera aggregate, and Artemisia annua extracts effectively suppress the first stage of HCoV-22E9 invasion, including viral penetration and attachment, and induce anti-SARS-CoV effects.⁶⁴ Natural SARS-CoV enzyme inhibitors like 3CL protease and nsP13 helicase have also been reported, including myricetin, scutellarein and Isatis indigotica and Torreya nucifera phenolic compounds.

Many viruses are left lacking protective vaccinations and successful antiviral therapies. It seems impossible to end these viral diseases. Natural ingredients, however, are an excellent source of biodiversity for the detection of new antivirals, the discovery of new interactions between structure and operation, and the creation of efficient protective/therapeutic strategies against viral infections.⁶⁵ Because the several findings in this area are still preliminary, further research is encouraged in the characterization of bioactive ingredients, in the description of the underlying pathways, and in the evaluation of the effectiveness and possible use in vivo to help improve successful antiviral therapies. In addition to further trials, the feasibility of combination treatments with other natural substances or traditional medications should be studied in addition to further trials, as multi-target therapies could lead to eliminating the chance of drug-resistant viruses being produced. Natural ingredients, thus believed, will continue to play an important role in the development of antiviral drugs and will contribute to their development. COVID-19 has become a public health issue. Unsurprisingly, considering its high bioavailability against both the SARS-CoV-2 virus and its inflammatory consequences, there are only a few licensed medications available. The production of vaccines is being vigorously studied. However, it will take a year for it to be available to the public. Off-label therapies including dexamethasone, antimalarial (chloroquine/hydroxychloroquine), antivirals (remdesivir), and monoclonal antibodies that inhibit IL-6 receptors (tocilizumab) are used to treat COVID-19 in various combinations.⁶⁶

Essential oils (EOs) have long been reported to have anti-inflammatory, immunomodulatory, bronchodilator, and antiviral effects for a long time and SARS-CoV-2 virus activity is suggested. For a long time, EOs have been reported to have immunomodulatory, anti-inflammatory, bronchodilator, and antiviral effects. Clove dried leaves provided 4.8% of the oil for hydrodistillation. The oil study of gas chromatography (GC) and gas chromatography–mass spectrometry (GC-MS) led to the identification of 16 compounds. Eugenol (94.4%) followed by caryophyllene (2.9%) was the main compound.⁶⁷ Recent research performed by Merad and Martin found that there are lung defects in nearly all COVID-19 positive patients. The key causes of disease occurrence and mortality in COVID-19 patients are supposed to be pathological and overactive inflammatory responses to SARS-CoV-2. This hyper-inflammatory syndrome is characterized by an increase in inflammatory cytokines, profound lymphopenia, and significant mononuclear cell penetration in the lungs as well as other organs such as the brain, lymph nodes, spleen, and kidneys. Patients’ systemic cytokine profiles show higher levels of cytokines including IL-7, IL-6, and TNF, as well as a slew of other pro-inflammatory cytokines.⁶⁸

To investigate the effects of eucalyptol therapies and eucalyptus oils on the recruitment of macrophages and monocytes in response to infections and lung inflammation, many in vitro and ex vivo experiments have been performed. Data from these studies suggest that eucalyptus oil and its active part, eucalyptol, have marked immunomodulatory properties. Both therapies decreased the release of monocytes and macrophages of pro-inflammatory cytokines, but their phagocytic activities were not prevented. Eucalyptol is also a mucolytic and bronchodilator.^69,70 Oddly, it has also been demonstrated that eucalyptus oil has disinfection properties and prevents virus development on different utensils and filter instruments.⁷¹ Data from clinical studies suggests that eucalyptus oil and its active component, eucalyptol, have promising therapeutic potential for COVID-19 prevention and treatment. In this respect, however, further studies are critically required.

Molecular docking strategies were used by Kumar and colleagues to assess the anti-SARS-CoV-2 effectiveness of menthol, eugenol, and carvacrol, the main aspects of EOs, against various target proteins of SARS-CoV-2. SARS-CoV-2 spike enzyme, primary protease (Mpro), human ACE-2 proteins, and RNA-dependent RNA polymerase all have binding affinities, according to docking results. Kumar et al also found that carvacrol has the capacity to inhibit Mpro and thus disrupt viral replication.⁷²

A second notification letter (MARCS-CMS607753) was sent to a company alleging that a substance is known as “Nobel laurel” had immune-boosting and antiviral properties, as well as anti-corona effects. The FDA has also sent requests to other firms containing misleading statements about their diagnostic instruments or other information, with regard to these suppliers. Hypersensitivity reactions are another concern associated with using EOs. EOs such as linalool and pinene are known to cause a large spectrum of respiratory problems in allergic patients, including seasonal asthma and rhinitis.^71,72

In African green monkey and human lung cancer cells, chloroquine (CQ) and hydroxychloroquine (HCQ) have been shown to effectively prevent SARS-CoV-2 infection by blocking viral genome release.⁷³ Furthermore, CQ is thought to increase endosomal pH, blocking endosomal maturation and, as a result, the failure to transport and release SARS-CoV-2. In patients with COVID-19, HCQ was also shown to suppress the development of inflammatory cytokines.⁷⁴

Around the globe, the sunflower, Helianthus annuus L, has a variety of nutritional and medicinal advantages around the world. Antimicrobial, antioxidant, anti-inflammatory, anti-hypertensive, cardiovascular benefits, and wound-healing are given by polyunsaturated fatty acids, flavonoids, phenolic compounds, and vitamins.⁷⁵ In ethnomedicine, it is being used to cure a series of diseases, including cardiovascular disease, bronchial, laryngeal, and respiratory illnesses, cough, cold, and whooping cough.⁷⁶

Antioxidants such as phenolic acids, flavonoids, vitamins, and trace metals are abundant in the edible seeds and sprouts. Flavonoids are phenolic compounds found in a range of vascular plants that have antiallergic antimicrobial, anti-inflammatory, antiviral, anti-thrombotic, and vasodilator properties.^77,78

Tocopherols and vitamin E are the main constituents of sunflower oil. Tocopherols are fat-soluble antioxidant vitamins that can be used in both vivo and vitro.⁷⁹ Sunflower seeds and sprouts are high in niacin, as well as vitamins A, B, and C. Minerals such as iron, calcium, magnesium, arsenic, potassium, selenium, and zinc are abundant.⁸⁰ Enzymes (glutathione dehydrogenase, catalase, and guaiacol peroxidase), carotenoids, peptides, and phenolic compounds (flavonoids, tocopherols and phenolic acids) are all products of different antioxidants.⁸¹ Sunflower oil has anti-inflammatory properties, and it is thought to reduce paw edema caused by carrageenan by 79.5% as compared to indomethacin (56.2%), which is a popular anti-inflammatory product.⁸²

Helianthus annuus was used as an antimalarial, anti-inflammatory, anti-asthma, antioxidant and antimicrobial agent and antitumor. Numerous chemical compounds have been identified and characterized from different parts of the plant, including sabinene (monoterpene), heliangolides (sesquiterpene lactones), alpha-pinene, helikauranoside (diterpene), and the leaf alkaloid and phenolic group; helianthoside (triterpene) and the flower saponin group; fatty acids, tocopherol, tannins, and polyphenols of the leaf group. According to the findings, 96% of H. annuus root ethanol extract has the greatest antimalarial activity as compared to the other components. It was found to have more efficacy as a therapeutic antimalarial drug than a preventative antimalarial drug. Similarly, as it comes to the antimalarial mechanism of inhibiting blood detoxification, the 96% ethanol extract of H. annuus root has the greatest inhibitory effect when compared to the other components of H. annuus; the inhibition is also stronger than CQ, a typical medication. As a result, it’s safe to assume that ethanol extract of H. annuus root has a possible antimalarial drug, which may be a new target for the development of natural plant-based antimalarial agents.⁸³

Conclusion

COVID-19 is a serious infection that can cause pneumonia and other complications like sepsis and multi-organ failure. The majority of people with severe COVID-19 were found to have CRS, implying that COVID-19 complications result from a sudden severe immune response to the infection, releasing elevated levels of both pro- and anti-inflammatory cytokines and chemokines. Natural products have always been well-known for their medicinal value in different diseases. With the emergence of COVID-19 and the lack of specific therapies, they have begun to be extensively investigated for their antiviral and immunomodulatory activities Several natural products were found to have immunomodulation activity, anti-oxidant effect as well as an antiviral effect through interference with different stages in the life cycle of SARS-CoV-2. For instance, natural products containing polyphenols, such as chamomile that contains Quercetin, have an anti-inflammatory effect, antioxidant effect as well as antiviral effect. This suggests that a diet rich in polyphenols may help reducing inflammation in patients with COVID-19. A lot of natural products containing EOs were found to have anti-inflammatory, immune-modulatory and antiviral effects. Eucalyptus oil has also been mentioned, as an example of beneficial EOs, for its promising potential for COVID-19 prevention and treatment. The review has also presented the immune-modulatory and antiviral properties of zinc and lactoferrin that led to considering them promising in COVID-19 prevention and treatment.

In conclusion, natural products serve as excellent source of biodiversity for the development of new antiviral agents. Since a lot of findings in the potential antiviral activity of natural products are still preliminary, the review has highlighted the future perspectives on exploring natural immunomodulators, evaluating their effectiveness and assessing the possibility of their use in the treatment of cytokine storm in COVID-19.

Author Contributions

Conceptualization: Heba Salah Abbas.

Data curation: Manal Ahmed Nabil, Heba Salah Abbas.

Formal analysis: Manal Ahmed Nabil.

Investigation: Mona Mohamed Abd-elhakeem, Rania Mostafa Abd El Galil, Omar Ahmed Reyad, Heba Ahmed Mohamed, Salma Emad Saber Ismail.

Methodology: Heba S Abbas, Mona Mohamed Abd-elhakeem, Rania Mostafa Abd Elgalil, Manal Ahmed Nabil.

Resources: Heba S Abbas, Mona Mohamed Abd-elhakeem, Rania Mostafa Abd Elgalil, Manal Ahmed Nabil, Omar Ahmed Reyad, Heba Ahmed Mohamed, Salma Emad Saber Ismail.

Supervision: Heba Salah Abbas.

Writing original drafts: Heba Salah Abbas, Mona Mohamed Abd-elhakeem, Rania Mostafa Abd El Galil, Omar Ahmed Reyad, Heba Ahmed Mohamed, Salma Emad Saber Ismail, Manal Ahmed Nabil

Writing, reviewing and editing: Heba Salah Abbas, Manal Ahmed Nabil.

Ethical Issues

Not applicable.

Confilict of Interest

The authors declare that they have no competing interests.

References

1. Innate immunity. J Allergy Clin Immunol 2010; 125(2 Suppl 2):S24-32. doi: 10.1016/j.jaci.2009.07.016 [Crossref]
2. Cytokines and their role in health and disease: a brief overview. MOJ Immunol 2016; 4(2):00121. doi: 10.15406/moji.2016.04.00121 [Crossref]
3. Cytokines in inflammatory disease. Int J Mol Sci 2019; 20(23):6008. doi: 10.3390/ijms20236008 [Crossref]
4. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 2018; 9(6):7204-18. doi: 10.18632/oncotarget.23208 [Crossref]
5. Cytokine research in depression: principles, challenges, and open questions. Front Psychiatry 2019; 10:30. doi: 10.3389/fpsyt.2019.00030 [Crossref]
6. The deregulated immune reaction and cytokines release storm (CRS) in COVID-19 disease. Int Immunopharmacol 2021; 90:107225. doi: 10.1016/j.intimp.2020.107225 [Crossref]
7. Cytokine storm in COVID-19: the current evidence and treatment strategies. Front Immunol 2020; 11:1708. doi: 10.3389/fimmu.2020.01708 [Crossref]
8. Human coronaviruses: insights into environmental resistance and its influence on the development of new antiseptic strategies. Viruses 2012; 4(11):3044-68. doi: 10.3390/v4113044 [Crossref]
9. SARS-CoV-2 and coronavirus disease 2019: what we know so far. Pathogens 2020; 9(3):231. doi: 10.3390/pathogens9030231 [Crossref]
10. Immunomodulatory activity of polyphenols derived from Cassia auriculata flowers in aged rats. Cell Immunol 2011; 271(2):474-9. doi: 10.1016/j.cellimm.2011.08.017 [Crossref]
11. Separation and characterization of phenolic compounds from dry-blanched peanut skins by liquid chromatography-electrospray ionization mass spectrometry. J Chromatogr A 2014; 1356:64-81. doi: 10.1016/j.chroma.2014.06.027 [Crossref]
12. Phytochemical antioxidants modulate mammalian cellular epigenome: implications in health and disease. Antioxid Redox Signal 2012; 17(2):327-39. doi: 10.1089/ars.2012.4600 [Crossref]
13. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. ImmunopharmacolImmunotoxicol 2015; 37(1):35-41. doi: 10.3109/08923973.2014.976794 [Crossref]
14. Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of asthma. Mediators Inflamm 2015; 2015:538670. doi: 10.1155/2015/538670 [Crossref]
15. Nutritional antioxidants and adaptive cell responses: an update. Curr Mol Med 2011; 11(9):770-89. doi: 10.2174/156652411798062395 [Crossref]
16. Curcumin: a review of its effects on human health. Foods 2017; 6(10):92. doi: 10.3390/foods6100092 [Crossref]
17. Analgesic and anti-inflammatory plants: an updated review. Int J Pharm Sci Rev Res 2012; 12(2):114-9.
18. Molecular mechanisms underlying the in vitro anti-inflammatory effects of a flavonoid-rich ethanol extract from Chinese propolis (poplar type). Evid Based Complement Alternat Med 2013; 2013:127672. doi: 10.1155/2013/127672 [Crossref]
19. The implications of zinc therapy in combating the COVID-19 global pandemic. J Inflamm Res 2021; 14:527-50. doi: 10.2147/jir.s295377 [Crossref]
20. Rapid review protocol: zinc for the prevention or treatment of COVID-19 and other coronavirus-related respiratory tract infections. Integr Med Res 2020; 9(3):100457. doi: 10.1016/j.imr.2020.100457 [Crossref]
21. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc 2001; 101(3):294-301. doi: 10.1016/s0002-8223(01)00078-5 [Crossref]
22. Food poisoning involving zinc contamination. Arch Environ Health 1964; 8:657-60. doi: 10.1080/00039896.1964.10663736 [Crossref]
23. Zinc toxicity. Am J Clin Nutr 1990; 51(2):225-7. doi: 10.1093/ajcn/51.2.225 [Crossref]
24. Counting the zinc-proteins encoded in the human genome. J Proteome Res 2006; 5(1):196-201. doi: 10.1021/pr050361j [Crossref]
25. Zinc is an antioxidant and anti-inflammatory agent: its role in human health. Front Nutr 2014; 1:14. doi: 10.3389/fnut.2014.00014 [Crossref]
26. Zinc as a gatekeeper of immune function. Nutrients 2017; 9(12):1286. doi: 10.3390/nu9121286 [Crossref]
27. Zinc and immunity: an essential interrelation. Arch BiochemBiophys 2016; 611:58-65. doi: 10.1016/j.abb.2016.03.022 [Crossref]
28. Impact of the discovery of human zinc deficiency on health. J Trace Elem Med Biol 2014; 28(4):357-63. doi: 10.1016/j.jtemb.2014.09.002 [Crossref]
29. NIH Office of Dietary Supplements. Zinc Fact Sheet. Available from: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/. Accessed 2020.
30. A randomized, placebo controlled trial of oral zinc for chemotherapy-related taste and smell disorders. J Pain Palliat Care Pharmacother 2012; 26(2):111-4. doi: 10.3109/15360288.2012.676618 [Crossref]
31. A double blind study of the effects of zinc sulfate on taste and smell dysfunction. Am J Med Sci 1976; 272(3):285-99. doi: 10.1097/00000441-197611000-00006 [Crossref]
32. A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 1998; 82(10):1938-45. doi: 10.1002/(sici)1097-0142(19980515)82:10<1938::aid-cncr18>3.0.co;2-u [Crossref]
33. Zinc and taste disturbances in older adults: a review of the literature. Consult Pharm 2016; 31(5):267-70. doi: 10.4140/TCP.n.2016.267 [Crossref]
34. Zinc deficiency and taste disorders. Ann Pharmacother 1996; 30(2):186-7. doi: 10.1177/106002809603000215 [Crossref]
35. Zinc-altered immune function. J Nutr 2003; 133(5 Suppl 1):1452S-6S. doi: 10.1093/jn/133.5.1452S [Crossref]
36. Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. Arch Immunol Ther Exp (Warsz) 2008; 56(1):15-30. doi: 10.1007/s00005-008-0003-8 [Crossref]
37. The role of zinc in antiviral immunity. Adv Nutr 2019; 10(4):696-710. doi: 10.1093/advances/nmz013 [Crossref]
38. Potential interventions for novel coronavirus in China: a systematic review. J Med Virol 2020; 92(5):479-90. doi: 10.1002/jmv.25707 [Crossref]
39. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci 2018; 68(1):19-31. doi: 10.1007/s12576-017-0571-7 [Crossref]
40. The immune system and the impact of zinc during aging. Immun Ageing 2009; 6:9. doi: 10.1186/1742-4933-6-9 [Crossref]
41. Zinc and respiratory tract infections: perspectives for COVID-19 (Review). Int J Mol Med 2020; 46(1):17-26. doi: 10.3892/ijmm.2020.4575 [Crossref]
42. Antiviral activity of the zinc ionophores pyrithione and hinokitiol against picornavirus infections. J Virol 2009; 83(1):58-64. doi: 10.1128/jvi.01543-08 [Crossref]
43. Antiviral effects of pyrrolidine dithiocarbamate on human rhinoviruses. J Virol 2002; 76(12):6004-15. doi: 10.1128/jvi.76.12.6004-6015.2002 [Crossref]
44. Zinc-suppressed inflammatory cytokines by induction of A20-mediated inhibition of nuclear factor-κB. Nutrition 2011; 27(7-8):816-23. doi: 10.1016/j.nut.2010.08.010 [Crossref]
45. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients. J Med Microbiol 2020; 69(10):1228-34. doi: 10.1099/jmm.0.001250 [Crossref]
46. Lactoferrin, a versatile natural antimicrobial glycoprotein that modulates the host’s innate immunity. Biochem Cell Biol 2021; 99(1):61-5. doi: 10.1139/bcb-2020-0080 [Crossref]
47. Biological role of lactoferrin. Arch Dis Child 1992; 67(5):657-61. doi: 10.1136/adc.67.5.657 [Crossref]
48. Antiviral properties of lactoferrin--a natural immunity molecule. Molecules 2011; 16(8):6992-7018. doi: 10.3390/molecules16086992 [Crossref]
49. Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea. Arch Virol 1995; 140(8):1469-72. doi: 10.1007/bf01322673 [Crossref]
50. Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. J Infect Dis 1995; 172(2):380-8. doi: 10.1093/infdis/172.2.380 [Crossref]
51. Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection. Int J Biochem Cell Biol 1998; 30(9):1055-62. doi: 10.1016/s1357-2725(98)00066-1 [Crossref]
52. Natural products and chronic hepatitis C virus. Liver Int 2007; 27(1):17-25. doi: 10.1111/j.1478-3231.2006.01408.x [Crossref]
53. Identification of a lactoferrin-derived peptide possessing binding activity to hepatitis C virus E2 envelope protein. J Biol Chem 2003; 278(12):10162-73. doi: 10.1074/jbc.M207879200 [Crossref]
54. Expression profile of immune response genes in patients with severe acute respiratory syndrome. BMC Immunol 2005; 6:2. doi: 10.1186/1471-2172-6-2 [Crossref]
55. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One 2011; 6(8):e23710. doi: 10.1371/journal.pone.0023710 [Crossref]
56. Addendum: a pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 588(7836):E6. doi: 10.1038/s41586-020-2951-z [Crossref]
57. Virus movements on the plasma membrane support infection and transmission between cells. PLoSPathog 2009; 5(11):e1000621. doi: 10.1371/journal.ppat.1000621 [Crossref]
58. Lactoferrin is a natural inhibitor of plasminogen activation. J Biol Chem 2018; 293(22):8600-13. doi: 10.1074/jbc.RA118.003145 [Crossref]
59. Bioresponsive mesoporous silica nanoparticles for triggered drug release. J Am Chem Soc 2011; 133(49):19582-5. doi: 10.1021/ja206998x [Crossref]
60. Mesoporous silica nanoparticles with manipulated microstructures for drug delivery. Colloids Surf B Biointerfaces 2012; 95:274-8. doi: 10.1016/j.colsurfb.2012.03.012 [Crossref]
61. Lactoferrin-anchored tannylated mesoporous silica nanomaterials for enhanced osteo-differentiation ability. Pharmaceutics 2020; 13(1):30. doi: 10.3390/pharmaceutics13010030 [Crossref]
62. Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin Exp PharmacolPhysiol 2006; 33(7):612-6. doi: 10.1111/j.1440-1681.2006.04415.x [Crossref]
63. Immunomodulatory and anti-SARS activities of Houttuynia cordata. J Ethnopharmacol 2008; 118(1):79-85. doi: 10.1016/j.jep.2008.03.018 [Crossref]
64. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005; 67(1):18-23. doi: 10.1016/j.antiviral.2005.02.007 [Crossref]
65. Antiviral natural products and herbal medicines. J Tradit Complement Med 2014; 4(1):24-35. doi: 10.4103/2225-4110.124335 [Crossref]
66. COVID-19 and therapy with essential oils having antiviral, anti-inflammatory, and immunomodulatory properties. Inflammopharmacology 2020; 28(5):1153-61. doi: 10.1007/s10787-020-00744-0 [Crossref]
67. Essential oil composition of Syzygiumaromaticum leaf from Little Andaman, India. FlavourFragr J 2001; 16(5):334-6. doi: 10.1002/ffj.1005 [Crossref]
68. Author Correction: Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020; 20(7):448. doi: 10.1038/s41577-020-0353-y [Crossref]
69. New therapeutic strategy and innovative lubricating ophthalmic solution in minimizing dry eye disease associated with cataract surgery: a randomized, prospective study. Adv Ther 2020; 37(4):1664-74. doi: 10.1007/s12325-020-01288-z [Crossref]
70. Immune-modifying and antimicrobial effects of Eucalyptus oil and simple inhalation devices. Altern Med Rev 2010; 15(1):33-47.
71. Antiviral activity of tea tree and eucalyptus oil aerosol and vapour. J Aerosol Sci 2013; 59:22-30. doi: 10.1016/j.jaerosci.2013.01.004 [Crossref]
72. Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J Biomol Struct Dyn 2021; 39(10):3760-70. doi: 10.1080/07391102.2020.1772112 [Crossref]
73. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30(3):269-71. doi: 10.1038/s41422-020-0282-0 [Crossref]
74. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6:16. doi: 10.1038/s41421-020-0156-0 [Crossref]
75. Plants, medicines and man. J Sci Food Agric 2006; 86(12):1797-804. doi: 10.1002/jsfa.2598 [Crossref]
76. Chemistry, pharmacology and ethnomedicinal uses of Helianthus annuus (sunflower): a review. Pure Appl Biol 2015; 4(2):226-35. doi: 10.19045/bspab.2015.42011 [Crossref]
77. Anthocyanins, total polyphenols and antioxidant activity in amaranth and quinoa seeds and sprouts during their growth. Food Chem 2009; 115(3):994-8. doi: 10.1016/j.foodchem.2009.01.037 [Crossref]
78. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993; 342(8878):1007-11. doi: 10.1016/0140-6736(93)92876-u [Crossref]
79. Determination of microelements in sprouts grown on metal-enriched solutions by ion chromatography. Acta Chromatogr 2014; 26(4):739-47. doi: 10.1556/achrom.26.2014.4.14 [Crossref]
80. Effect of UV-B radiation on antioxidant defense system in sunflower cotyledons. Plant Sci 2002; 162(6):939-45. doi: 10.1016/s0168-9452(02)00051-1 [Crossref]
81. A review of phytochemistry, metabolite changes, and medicinal uses of the common sunflower seed and sprouts (Helianthus annuus L.). Chem Cent J 2017; 11(1):95. doi: 10.1186/s13065-017-0328-7 [Crossref]
82. Helianthus annuus (Asteracea): a review. International Journal of Pharma Professional’s Research 2011; 2(4):465-470.
83. Various parts of Helianthus annuus plants as new sources of antimalarial drugs. Evid Based Complement Alternat Med 2019; 2019:7390385. doi: 10.1155/2019/7390385 [Crossref]