A Review on the Antiviral Activity of Functional Foods Against COVID-19 and Viral Respiratory Tract Infections
Received 3 February 2022
Accepted for publication 12 April 2022
Published 10 May 2022 Volume 2022:15 Pages 4817—4835
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Scott Fraser
Abdullah Khalid Omer,1,2 Sonia Khorshidi,1 Negar Mortazavi,1 Heshu Sulaiman Rahman3,4
1Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran; 2Razga Company, Sulaimaniyah, Kurdistan Region, Iraq; 3Department of Physiology, College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq; 4Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaimaniyah, Iraq
Correspondence: Abdullah Khalid Omer; Heshu Sulaiman Rahman, Tel +964 772 860 3692 ; +964 772 615 9598, Email [email protected]; [email protected]
Abstract: Due to the absence of successful therapy, vaccines for protection are continuously being developed. Since vaccines must be thoroughly tested, viral respiratory tract infections (VRTIs), mainly coronaviruses, have seriously affected human health worldwide in recent years. In this review, we presented the relevant data which originated from trusted publishers regarding the practical benefits of functional foods (FFs) and their dietary sources, in addition to natural plant products, in viral respiratory and COVID-19 prevention and immune-boosting activities. As a result, FFs were confirmed to be functionally active ingredients for preventing COVID-19 and VRTIs. Furthermore, the antiviral activity and immunological effects of FFs against VRTIs and COVID-19 and their potential main mechanisms of action are also being reviewed. Therefore, to prevent COVID-19 and VRTIs, it is critical to identify controlling the activities and immune-enhancing functional food constituents as early as possible. We further aimed to summarize functional food constituents as a dietary supplement that aids in immune system boosting and may effectively reduce VRTIs and COVID-19 and promote therapeutic efficacy.
Keywords: functional foods, COVID-19, immune-boosting, viral respiratory infection
The worldwide pandemic coronavirus disease 2019 (COVID-19), which started in December 2019 in a food market in Wuhan, Republic of China, has been linked to a highly contagious novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2).1–3 The global rate of morbidity and mortality associated with COVID-19 continues to be high despite considerable progress over the past two years. The worldwide morbidity rate due to COVID-19 is 472,816,657 confirmed cases, and its mortality rate reaches 6,099,380 confirmed deaths until 23 March 2022.4 In addition, the application of FFs provides significant benefits in discovering new approaches for safer and more effective medicine of COVID-19 and boost immunity.5 FFs have been applied for an extended time, supplying necessary for individual life and used as natural alternative medications to manage disease.6,7 Different nations have recognized the significance of functional food, which is necessary for human survival and enhances functional processes and immune enhancements.8,9 The application of FFs, including polyphenols, flavonoids, propolis, curcumin, prebiotic and probiotic, and also food supplements such as zinc (Zn), vitamin C, D, and E, has been increasing over the past few years for modulating immunity and to boost biological function.10,11
Vitamin D offers a wide range of health benefits, including possible involvement in preventing pulmonary inflammation. Pneumonia and acute respiratory distress syndrome are more expected when vitamin D deficiency is in the bloodstream.12 Hariyanto et al12 reviewed the relationship between vitamin D and COVID-19. The authors indicated that taking more vitamin D decreased the number of COVID-19 cases referred to the critical care unit, reduced the need for mechanical ventilation, and reduced the death rate. The microbiota influences the human body’s function; SARS-COV-2 in the older may be linked to a reduced variety of the gut microbiota. Due to various changes in gut microbiota composition-related inflammation, the aged are more prone to illness, dysfunction, weakness, and even early death than the general population.13
The complexities that go into defining functional foods are still questionable or controversial. In the early 1980s, the word “functional food” was introduced in Japan. Since there is no universal definition of FFs, one of the most prevalent and fundamental definitions is “processed foods that have disease-prevention and/or health-promoting effects in addition to their nutritional value”.10,14,15 The term “functional food” originated in Japan; furthermore, in 1991, Japan was the first nation to establish the term “foods of specified health use” (FOSHU). Products that follow such guidelines (Table 1) will carry the FOSHU label, as stated by the Japanese Ministry of Health.10,16 There is, however, no agreement on an accurate description between both the United States and Europe at this time. There is also clearly no globally accepted definition of FFs; furthermore, numerous organizations have created their meanings (Table 2). The new model is that FFs are now intended to improve health by focusing on specific biological functions that contribute to preventive medicine. Therefore, they positively impact human health and are essential for most diets.10 Functional foods are classified into the plant, animal, microbial, and miscellaneous (algae, mushrooms, etc.) functional foods based on their source of origin (Figure 1).17
Table 2 Functional Foods Definitions by Different Nations and Organizations
Figure 1 Classification of functional foods based on their sources of origin.
Several FFs with antiviral, antimicrobial, and anti-inflammatory activities have been classified across the preceding years.9,18 The previous studies of naturally occurring compounds suppressing coronaviruses were based on the similarity of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Unfortunately, there are currently no recognized treatments for COVID-19, and protective vaccines are continuously being made and must be thoroughly tested. As a result, the condition highlights the importance of effective immune-boosting and antivirals to be developed for prophylaxis of COVID-19.19 Moreover, the ingestion of a healthy meal will aid in the improvement of human immune systems, which is also a positive start in fighting COVID-19. It’s fair to say that no studies have been done on the influence of food substitutes in combating COVID-19 in particular. However, previous research has found that consuming certain FFs can improve our health and help our bodies to combat some infective pathogens.17 Several FFs (Table 3) from various dietary sources have already been confirmed for antiviral efficacy against multiple viruses. This review documented a list of the essential FFs that seem to have antiviral activity, besides their anti-inflammatory, antioxidant, and antibacterial characteristics, along with FFs used to enhance and boost immunity.
Table 3 Functional Foods and Their Antiviral Properties with the Primary Dietary Sources
Functional Foods as Antiviral Substances
Because of their rapid outbreaks, viral infections are life-threatening, whereas managing viral infections is a big task due to quick adaptation, the resistance of viruses, and the development of new strains of the virus, and ineffective drugs.20,21 Firstly, COVID-19 symptoms are not well-defined, but fever, cough, nausea/vomiting, diarrhoea, sneezing, and shortened breathing can be considered initial symptoms of CoVID-19 and respiratory viral infection, while severe symptoms include pneumonia.22 Furthermore, in histopathological studies, individuals with COVID-19 had diffused alveolar lesions in their lungs, oedema; also, the lungs appear congested, with patches of hemorrhagic necrosis, while inflammation of alveoli with atrophy, proliferation, and desquamation of alveolar epithelial cells, with the appearance of exudate macrophages and monocytes, are prominent features microscopically.22,23
In this article, various common and readily available FFs were documented the antiviral characteristics, particularly those FFs effective against VRTIs. Cinatl et al24 showed the antiviral activity of glycyrrhizin against SARS-coronavirus. Glycyrrhizin was the most effective treatment in preventing the multiplication of the SARS-associated virus based on the medication of two clinical isolates of coronavirus from SARS cases hospitalized to the Clinical Center of Frankfurt University in Germany. The results of Hoever et al25 were very comparable. According to studies, liquorice has high immunomodulation activity and is helpful, especially in improving the body’s immune system’s ability to combat microbial diseases. Krawitz et al26 recorded the antiviral action of elderberry extract against common cold and influenza viruses; the author also showed elderberry’s antibacterial activity against pathogens responsible for upper respiratory tract infections. Antiviral effects of Sambucol, a black elderberry extract, were demonstrated against several influenza virus strains in another study by Barak et al.27 The flu symptoms were shortened to 3–4 days using Sambucol and their practical actions in vitro against ten influenza virus strains.
Ground garlic, whether with or without honey, is thought to improve immunity and has antiviral activities, which may be attributed to some bioactive sulfur-containing substances such as proteins, polyphenols, and sulfoxide.21,28 Garlic’s immunostimulatory properties may be helpful in clinical settings as it can increase innate and specific cell immunity while increasing host resistance. Garlic and its organosulfur compounds (Allium sativum L.) were shown to have antiviral effects against common cold, influenza, and acute respiratory viral infections in various clinical studies.29,30
Antiviral compounds in various fruits and plants can prevent infection by acting on viruses and host cells. For example, the pomegranate peel extract and its parts can avoid replicating the influenza A virus (IAV) in vitro.31 Similarly, in another vitro investigation, Nikolaeva-Glomb et al32 investigated the antiviral action of numerous berry extracts and realized that berry fruit extracts prevented the replication of IAV.
Immunomodulatory and Anti-Inflammatory Effects of Functional Foods
The body’s most potent natural response towards infection is the individual immune response. Personal life depends significantly on defending against various external causative microorganisms, such as viruses. Man’s innate and adaptive immune systems could serve a defensive role on SARS-COV-2 since no medical interventions have been presented.9,21 Different nations introduced the concepts of FFs to stimulate biological functions and immune reactions besides their vital role in life.8,33 Numerous researches have revealed the immune-modulating and antiviral activities of FFs. Flavonoids, curcumin, and quercetin are examples of FFs that can modulate and support immunity, act as antioxidants, have anti-inflammatory and antiviral activities.34,35 Vitamin A and C are easily accessible in the food, act as antioxidants and protect immune cells from destruction;10 vitamin D supplements decrease the threat of VRTIs, flu, and COVID-19.5,36 Sambucol dramatically boosted the formation of inflammatory cytokines (IL-1, TNF-alpha, IL-6, and IL-8). Sambucol can thus be helpful in the activation of the immunity and the inflammatory response in healthy people and individuals with different illnesses. In addition, when combined with chemotherapeutic or other drugs, Sambucol may have immunoprotective or immunostimulatory impacts in cancer or AIDS patients.27
Herbs may be used to cure various diseases, which is not a new concept. In ancient times, herbs and spices were used to treat infectious diseases, including pneumonia and flu.37,38 Several medicinal mushrooms have been studied to learn more about their immune-boosting properties, and ˃ 270 identified mushroom species have been identified as having immune-boosting effects.39 The antiviral action of honey has been studied, and it has antiviral activity against the Rubella virus. It’s also used topically to treat herpes simplex virus-induced chronic lesions. Because of its antiviral properties, this compound will effectively prevent influenza virus replication.40,41 Fresh ginger (Zingiber officinale) has been found to have antiviral action and is effective against the respiratory syncytial virus (RSV).42 Salem & Hossain43 reported the antiviral impact of black seed oil from Nigella sativa against murine cytomegalovirus. Lemon balm (Melissa officinalis L.) extracts were found to prevent influenza virus duplication at different steps of the multiplication cycle, specifically during direct interaction with virus particles, also their antiviral action against human immunodeficiency virus type 1 (HIV-1).44,45
Antiviral Defence Mechanisms of Functional Foods
The term “nutritional immunity” was first coined to describe iron (Fe), but it was later expanded to include other essential trace elements, including selenium (Se) and Zn. According to in vitro studies, elevated intracellular Zn2+ concentrations can interfere with replicating various RNA viruses, including influenza virus and poliovirus. It also impacts a common step in the cell replication cycle.46 The immune system comprises two main types of cells: innate (speedy to respond) and adaptive immune cells. The cells are sustained mainly by granulocytes and macrophages, specifically entrap pathogens, including viruses and bacteria.47,48 There is a decrease in the synthesis of antibodies when Zn is depleted. The innate immune system is also affected by a decline in the activity of natural killer cells in this condition. Mononuclear cells produce fewer cytokines when Zn deficiency is present, and neutrophil chemotaxis and respiratory burst are both diminished as a result.49 As mentioned above, upon the onset of disease, the immune system plays a critical function in defending our bodies from infectious particles such as viruses. Therefore, numerous abundant substances in various herbs, fruits, and vegetables may help improve the body’s immunity, reduce the risk of contagious diseases, and aid in disease care. These substances are polyphenols, fatty acids, fibres, flavonoids, soy proteins, minerals, vitamins, and pre-and pro-biotics.
Intake of FFs of a wide range of plant, animal, and fungal resources, consumed through various diets and cultural aspects, would boost antiviral immunity. Traditional herbal medicines like teas, roots, mushrooms, and dried plants and leaves, along with olive oils, fish oil, nuts, fruits, and vegetables, are among these functional foods. Most of the products mentioned above contain natural vitamins (such as vitamins A, C, and D) and minerals (like Zn, Fe, and Se) and other phenols that are particularly immunoprotective due to their antioxidant and anti-inflammatory effects.10,50 Innate immunological responses are improved, immune-modulatory effects are achieved by boosting T cell activities, and immunoglobulin synthesis is increased due to vitamin C intake.51,52 According to Rayman,53 Se deficiency is linked to reduced immunological activity. Se has long been known to have immune-stimulant effects, including increased T- and natural killer- cells. Se deficiency is frequent in immunocompromised people, which could explain their greater susceptibility to pathogens (eg bacterial and viral) infections.54
Glycyrrhizin has immunomodulatory and anti-inflammatory properties.55 The antiviral activity of glycyrrhizin was investigated in an animal model study. Glycyrrhizin could protect mice following lethal doses of influenza virus A2 infection by stimulating interferon-gamma production via T cells, as T cells are interferon-gamma producer cells when enabled with glycyrrhizin.56 The mechanism of glycyrrhizin antiviral activity seems to be induced through antiviral functions of the host.56
Polyphenols act as immunomodulators, improving T cell function and increasing anti-influenza virus IgG and IgA antibody formation. They also suppress viral replication, inhibit viral hemagglutination, reduce viral replication, increase secretion of type I interferon and pro-inflammatory cytokines.57,58 Polyphenols were shown to inhibit viral RNA and protein synthesis, viral hemagglutination, viral binding to and penetration into host cells.59,60 Various researches have shown the management and protection of influenza, common cold, and acute upper respiratory tract infections with FFs, such as vitamin C, probiotics, garlic, and others. Vitamin C and garlic reduce the duration and severity of colds while also boosting the immune system.61,62 Yoghurt ingestion has been shown to raise the synthesis of cytokines, principally interferon γ, and enhance monocyte cytokine production.10,16
Probiotics boost innate immunity by improving natural killer cell activity. Further, they enhance gut and respiratory, immune responses by increasing influenza-specific IgA and IgG antibodies and modifying the host’s innate immunity. Probiotics have been shown to prevent viral attachment to target cells, boost the activity of natural killer cells, and enhance cytokine responsiveness.63,64 In addition, probiotics boost immunity by indirectly stimulating cytokines and modulating the intestinal microbiota. Probiotics also interact with the gut microbiota to increase immunity, stimulate specific immunological pathways, and enhance immunity, and all have functional and therapeutic significance.65,66 Lipopeptides like subtilisin (Bacillus amyloliquefaciens), curvacin A (Lactobacillus curvatus), sakacin P (Lactobacillus sakei), lactococci Gb (Lactococcus lactis) derived from different probiotic strain have demonstrated that have an affinity to bind with S-protein of SARS-CoV-2 and human angiotensin-converting enzyme II receptor (ACE2) for entry into the expressing cells.67,68 Furthermore, the study of Verma’s group69 has shown that the human ACE2 is expressed and secreted in Lactobacillus paracasei.69 Therefore, the binding of this secreted ACE2 to COVID-19 binding protein could represent a way of blocking SARS-COV-2 entry into cells.70
Functional Food Ingredients Were Effective in Virus Infections
All stages of the virus lifecycle depend on the host; therefore, immune cells, as the first line of defence, play a vital role in protecting our body against pathogens and viruses. Due to the inadequacy of vaccines, drugs, and increased mutation rates in the viral genomes, boosting the immune system could be a reasonable alternative to fight COVID-19.71 The food sector has been affected since the inception of COVID-19, and the demand for functional, organic, and sustainable foods has increased.72 Many functional food ingredients have been claimed to have potentially immunomodulatory and antiviral properties.73 Here, we will highlight the possible advantages of flavonoids, propolis, elderberry, resveratrol, curcumin, pre-and probiotics, and supplementing nutrients including vitamin D, vitamin C, and Zn. Various investigations have demonstrated a link between these substances’ ingestion and the protection, delay, or management of viral infections and immune disorders.65,74,75 The studies also indicate that micronutrient supplements alone or with antiviral and anti-inflammatory medications may be modestly valuable in preventing COVID-19 and improving their clinical course. Therefore, this review also discusses the relationship between these compounds and their antiviral properties.
Flavonoids are an important group of secondary plant metabolites present in the diet. They have numerous biologically beneficial activities in the human body, including anti-inflammatory, antioxidant, anti-mutagenic, and antiviral properties.76 Flavonoids can be found in various plants such as grapes, apples, onions, and cherries. In addition, it has also been discovered that multiple flavonoids inhibit other viral targets, such as the coronaviridae family.72,77,78 There are various mechanisms that flavonoids can prevent, treat, and interact with the immune system to help fight off viruses. For example, flavonoids can lower the viral load by interfering with host components essential for infection or regulating immunity. In addition, flavonoids act as inhibitors of viral adhesion or penetration into host cells, bind to viruses, and alter their structures. The virus can still enter the body, but the process of viral uncoating has slowed down considerably.77 The basic molecular mechanisms of flavonoid antiviral actions are the suppression of viral neuraminidase, proteases, and DNA/RNA polymerases and the alteration of numerous viral proteins.79
A molecular docking study was conducted to recognize the anti-inflammatory and antiviral properties of 10 flavonoid substances. This work described that flavonoid naringin has the highest binding affinity with spike protein compared with COVID-19 common medications.80,81 In addition, other flavonoids such as curcumin,82 herbacetin, quercetin, kaempferol,83–85 luteolin86 have been proposed as potential interactions with the above-mention receptor in similar studies.
3CLpro and PLpro of SARS-COV-2 are efficient targets in discovering anti-SARS drugs and play essential roles in translating and replicating COVID-19.87 Furthermore, it was reported that flavonoids such as tangertin, rhoifolin, pectolinarint, herbactin, helichristetine, and narigenin could attach firmly to MERS-COV and SARS-COV-2 protease 3CLpro, as well as nutritional flavonoids, namely kaempferol, quercetin, and isoliquiritigenin, have a synergistic impact on 3CLpro and PLpro in vitro.88,89 RNA-dependent RNA-polymerase (RdRp) is one of the significant druggable targets of SARS-COV-2.90,91 Many investigations have been conducted to analyze the role of flavonoids concerning RdRp. For example, Singh et al92 used a molecular docking method to target RdRp of SARS-COV-2. They revealed that epigallocatechin gallate, hesperidin, and quercetin could inhibit RdRp activity and, in this way, block replication and prevent viral transcription. Studies demonstrated that flavonoids (herbacetins, rhoifolins, and pectolinarins) have an antiviral effect against coronavirus. SARS-COV 3CLpro enzymatic activity was effectively blocked by the flavonoids mentioned above.93 In another similar recent study, the proteolytic activity of SARS-COV-2 3CLpro has been discovered to be blocked by flavonoids, including baicalin, herbacetin, and pectolinarin.94
Based on the reports, VRTIs can be treated more effectively when vitamin D and C are combined with quercetin.95,96 Moreover, flavonoids could relieve the respiratory symptoms of COVID-19 in the case of individuals managed with hydroxychloroquine.97 In addition, the use of combination curcumin and Zn have also been proposed to modulate the immune system to combat coronavirus infections.98 However, as potent anti-inflammatory agents, flavonoids are valuable biomarkers for assessing human health. Therefore, administering flavonoids alone or in combination with other natural medicines should be addressed.
Propolis (bee glue) is a bee-metabolized sticky material of various plant sources. It has a wide application with antioxidant, anticancer, anti-parasite, immunomodulatory, antimicrobial, and anti-inflammatory properties. In addition, propolis and its constituents possess antiviral activity toward different viruses and several biological activities. Most of these properties are attributed to the presence of several natural compounds,99,100 and this variety is significantly dependent on plants, climatic regions, environmental conditions, and collection seasons. Moreover, flavonoids and esters of phenolic acid are commonly considered bioactive compounds with antimicrobial activity. They are also proposed as a potentially promising alternative in therapy against pathogens that cause severe respiratory syndromes.100,101 Several investigations accepted the antiviral action of propolis, which was found to block the viral entrance toward the host cells and inhibit virus duplication.100,102 In March 2020, responding to the current pandemic scenario of COVID-19, propolis is considered a functional food and a possible complementary treatment that could help reduce infection during this lethal outbreak.103
It was reported that caffeic acid (the bioactive ingredient of propolis) and caffeic acid phenethyl ester (CAPE) could bind strongly to angiotensin-converting enzyme II receptor (ACE2) as compared to nelfinavir.104 Furthermore, the obtained results in the other study revealed that the propolis components had higher values of ACE inhibition among samples tested.105 Moreover, the ability of various active ingredients from honeybee and propolis to prevent SARS-COV-2 main protease was investigated. It was observed that CAPE, galangin, and chrysin have a strong binding with COVID-19 main protease, and they might be used as an effective virus inhibitor.106,107
Based on results, propolis is identified to boost immunity; therefore, it could be accepted as an adjuvant treatment to reduce the inflammatory response and inhibit cytokines storm that cause damage to extrapulmonary tissues and organs during the pathogenic coronavirus infection. Furthermore, CAPE has also been proven to have anti-inflammatory and immunomodulatory properties as an essential active component of propolis. It has been reported that it prevents infection with the coronavirus. Thus, inhibiting or reducing lung fibrosis with this therapy may be successful. In addition, quercetin, hesperidin, kaempferol, chrycin, rutin, myricetin, and artepillin C (is a significant constituent of Brazilian green propolis) can also be able to alleviate the violence of inflammatory agents caused by SARS-COV-2.108–111 Although data specifically on SARS-COV-2 randomized controlled studies have not been conducted, the enumerated evidence from the literature strongly suggested that propolis and its constituents can be a promising source of pharmacological for prevention and symptomatic treatment in patients infected with COVID-19.
Various practical antiviral protection actions against VRTIs have been reported for probiotics, along with increased interferon-gamma and alpha production, increased secretory immunoglobulin A production, decreased expression of pro-inflammatory cytokines, enhanced anti-inflammatory cytokine production, increased regulatory T-cells, and enhanced natural killer cell activity.112,113 It has been shown that viral infections in the respiratory tract, such as coronaviruses, by increasing permeability of the gastrointestinal tract, cause destructive impacts on the gut microbiota and increase pathogenic bacteria in the host.114–116 Furthermore, Xu et al117 suggested that the intestinal damage caused by COVID-19 is even more significant and more prolonged than the lungs. Additionally, SARS-COV-2 RNA has been identified in the stools of COVID-19 cases even after improving respiratory symptoms.118 Therefore, the gut may act as a reservoir for the virus.119 Thus, probiotics have a crucial role in the restoration of the composition of human gut microflora, protection of the gut barrier function, reducing duration and symptoms of VRTI, competition with pathogens for adhesion to gut epithelium and nutrition, and playing a regulatory role on the gut-lung axis.92,120,121 In addition, probiotic bacteria can directly bind to the virus, prevent entry into the host’s respiratory and gastrointestinal tract epithelial cells, and prevent the pathogen-host cell receptor interaction.122
Baud et al123 compiled the commonest probiotics that could affect the COVID-19 pandemic scenario, including Lactobacillus casei, Lactobacillus gasseri, Bifidobacterium breve, Pediococcus pentosaceus, and Leuconostoc mesenteroides. Based on clinical studies and human trials, some of the species mentioned above significantly reduce the risk of upper respiratory infections, common cold, the symptoms of influenza viral infection, and preventing antibiotic-associated diarrhoea by 40% to 70%.122 In addition, it was recently discovered that medication with probiotic bacteria using Bifidobacteria and Lactobacillus offers a strong possibility of restoration from COVID-19.124
Currently, it has been shown that probiotics modulate intestinal epithelial defence responses by producing various antiviral compounds.125 In addition, a computational docking analysis has demonstrated that metabolites derived from Lactobacillus Plantarum are more responsible for adhering to the S-protein of SARS-COV-2 and preventing entrance by attaching to ACE2 receptors.126 d’Ettorre et al127 published a recent cohort study in which individuals hospitalized with COVID-19 treated with a probiotic were compared to those who did not receive a probiotic and found that the probiotic group had alleviation of COVID-19 related symptoms, an 8-fold reduction in respiratory complications, and no deaths were observed in this group (compared to those who did not receive the probiotic).
Prebiotics contribute to short-chain fatty acid production that can modulate the immune system by enhancing anti-inflammatory cytokine production and decreasing pro-inflammatory cytokine development.128,129 It was also revealed that some compounds such as unsaturated fatty acids, polyphenols, fibre, inulin, glycan, and polysaccharides are included in prebiotics and have therapeutic effects in infections.130–132 In addition, several recent reviews described the importance of pro-and prebiotics as an adjuvant therapeutic option to aid COVID-19 management.113,126,133
Some pro-and prebiotics indicates that they can be considered adjuvant vaccines and may modulate responses to vaccinations.134,135 Therefore, they could be used to develop anti-coronavirus vaccines.136 Thus, despite the lack of clinical data, these data indicate that pro-and prebiotics could benefit individuals with COVID-linked gastrointestinal manifestations and a potential immunomodulatory strategy for COVID-19.
Zn is a vital micronutrient and a critical factor for innate (non-specific) and adaptive (specific) antiviral immune responses. In addition, Zn is a crucial cofactor for numerous viral enzymes, proteases, and polymerase; therefore, Zn is a critical factor to inhibit viral replication and dissemination.137,138 It seems that Zn exhibits antiviral effects by enhancing the cell’s resistance to the entry of the virus, inhibition of viral replication, viral attachment, destabilizing the viral envelope, RNA synthesis, DNA polymerase, and reverse transcriptase.139,140
Several studies showed that Zn supplementation as a general stimulant of antiviral immunity affected the role of innate immunity such as natural killer cells, improved the secretion of pro-inflammatory cytokines and macrophages,49,115 reduced the levels of reactive oxygen species141 decreased apoptosis of lymphocytes;142 thus it leads to reduce the susceptibility to systemic inflammation, lung injury and minimize secondary infections.143,144 In addition, it has also been shown that Zn administration leads to positive impacts on clinical outcomes such as shortened infectivity, amelioration of clinical symptoms, duration of the common cold, and reduction of rates of acute respiratory infection up to 45%.75,145,146 Therefore, Zn deficiency can decrease resistance to viral infection in susceptible persons (eg, old age) linked with the elevated mortality risk.147,148
It was recently reported that the specimens obtained from the non-surviving COVID-19 cases had notably low Zn levels.149,150 According to similar studies, adding Zn to the combination of hydroxychloroquine or chloroquine and azithromycin for treating individuals with COVID-19 may help lower the mortality rate and hospitalization and improve clinical practice outcomes in high-risk patients.151,152 Clinical studies on serum Zn content in COVID-19 patients observed a strong correlation between low serum Zn levels and the severity of COVID-19, as well as mortality.153,154 On the other hand, Zn intake has been shown in earlier research to be beneficial in inhibiting entrance into the host cell.155 A vivo model reported that a high level of Zn inhibited the expression of ACE2; thus, it can be assumed that Zn administration can block SARS-COV-2 cellular entry.143 It could also act synergistically when co-administered with azithromycin and triclabendazole or emetine on the expression of ACE-2.156,157
A molecular docking study suggested that a high intracellular concentration of Zn could interact with the enzymatic activities of 3CLpro and RdRp of SARS-COV-2; therefore, it can be recommended that Zn show action against viral replication of SARS-COV-2.158 Zn supplementation has been recommended to improve antibody titers and viral vaccination responses during the social vaccination program to enhance the adaptive immune response against SARS-CoV-2 and a better humoral immune response after vaccination.137,159 Zn intake alone or in conjunction with hydroxychloroquine is being studied in clinical studies to prevent and treat COVID-19. Men should consume 11 milligrams of zinc daily, while non-pregnant women should take 8 milligrams. In registered clinical trials, zinc sulfate 220 mg (50 mg of elemental zinc) twice daily is the maximal dose for patients with COVID-19. Zinc treatment for COVID-19 is currently not supported by enough evidence to provide a recommendation for or against its usage.160 Deficiency of Zn availability may impair immunization outcomes. However, when combined with other antiviral and anti-inflammatory medicines, these properties make Zn an excellent potential candidate for use in the case of a viral infection.
Elderberry’s antiviral activity is attributed to increasing inflammatory cytokine production.161 It was discovered that elderberry juice has a considerable antiviral effect against influenza virus infection in humans when tested on the human IAV using concentrated elderberry juice.162 Besides, some studies have shown that the elderberry’s flavonoid components inhibit neuraminidase;163 and bind to the envelope of influenza.164 Furthermore, it was proved that elderberry syrup is effective against IAV infections. Zakay-Rones et al165 conducted a study on patients suffering influenza-like symptoms. Following the onset of influenza-like symptoms in the trial participants, the author gave them 15 mL of elderberry or placebo syrup four times a day for five days (within 48 hours of the symptoms). The severity of their symptoms was measured using a visual analogue scale, and the duration was practically as short as that of the placebo syrup.
On the other hand, air travellers consumed elderberry capsules in a double-blind, placebo-controlled, randomized study (600 mg daily, ten days before the travel). The dosage was increased two days before departure and 4–5 days after arrival (900 mg daily). The results of this study, on the other hand, showed that elderberry could shorten the duration and severity of a cold by two days (p=0.05).166 In addition, the study conducted by Krawitz et al26 showed that elderberry liquid extract is active against pathogenic respiratory bacteria and influenza viruses.
In the aggregate, black elder contains many valuable compounds for general health and may be beneficial to control COVID-19. Recently, Schön et al167 demonstrated that elderberry extract has antiviral activity and inhibits the release of pro-inflammatory cytokines TNF- and α, IFN-γ, and IL-2, indicating that elderberries act as immunomodulators. Additionally, the elderberry extract possesses substantial antiviral bioavailability, as demonstrated by its high virucidal efficacy against the modified vaccinia virus Ankara, which is reduced by up to 95%. Thus, the proprietary elderberry extract’s anti-inflammatory and antiviral properties recommend its usage as an immunomodulatory health product.
Resveratrol is a natural polyphenol compound derived from grapes, red wine, mulberry, peanuts, and other plant sources. Resveratrol has antioxidant, anticancer, antiviral, and free radical scavenging activities.168 In addition, resveratrol’s antiviral activity may be connected to its immunomodulatory impacts on IFN-a, IL-2, and IL-12.169 The coagulation disorders and thrombotic events are the consequences of COVID-19, which increases inflammatory cytokines. For these reasons, speculated that resveratrol, as a natural substance with anti-thrombotic characteristics, could effectively protect against COVID-19.170 Resveratrol has been reported to significantly inhibit MERS-Coronavirus replication and reduce cell death (25%) after virus infection. This study also found that resveratrol treatment inhibited MERS-Coronavirus nucleocapsid as well as RNA expression.171
In vivo study showed that ACE2 levels were increased in resveratrol-fed mice.172 Moreover, the addition of resveratrol to the diet can reduce the adverse effects of high fat on ACE2 gene expression.173 In addition, resveratrol destroyed the pseudorabies virus by inhibiting intracellular viral reproduction.174
Researchers discovered that resveratrol had a beneficial impact on the Duck enteritis virus (DEV), a member of the alphaherpesvirinae family. In addition, they found that resveratrol may considerably reduce DEV replication. A recent study by Beijers et al175 found a reduction of inflammation and oxidative stress in the lungs due to chronic obstructive pulmonary disease after treatment with resveratrol because of the drop in the activation of several inflammatory cytokines, including nuclear factor kappa B, tumour necrosis factor, and matrix metalloprotease-9 protein expression in lymphocytes. Due to the limitations of resveratrol’s bioavailability, stability, and solubility, the combination of this compound with a β-glucan improves the stability of resveratrol.176 The study conducted by Baldassarre et al177 proved that a solution containing resveratrol plus carboxymethyl-β-glucan reduces some respiratory signs in infants with the common cold. The above studies demonstrate that resveratrol can be used as a novel therapy for COVID-19. However, further investigations are needed to prove it.
Low vitamin D levels drop immune system function due to vitamin D’s immunomodulatory activity.178 When exposed to infections, macrophages, dendritic cells, and the active form of vitamin D begin to be synthesized.179 Therefore, vitamin D is an integral part of innate immunity, and vitamin D deficiency can cause immune system disorders.180 Furthermore, vitamin D affects interferon γ and tumour necrosis factor α and subsequently decreases the cytokine storm.181 Moreover, vitamin D regulates T cells and IL-4, and it has an inhibitory effect on IFN-γ, IL-17.182
In patients with chronic hepatitis C virus, correcting vitamin D deficiency resulted in a considerable reduction in interferon gamma-induced protein 10 and enzyme dipeptidyl peptidase-4, both linked to inflammatory reactions in the condition.183 Furthermore, a study of elderly COVID-19 patients who received a combination of 1000 IU of vitamin D, 500 µg of vitamin B12, and 150 mg of magnesium found that they were considerably less likely to necessitate oxygen therapy.184 In addition, a retrospective observational study in Belgium demonstrated that vitamin D insufficiency enhanced the risk factor for COVID-19.185
Vitamin D decreases the danger of contagions by several mechanisms, including inducing defensins and cathelicidins, which reduce virus replication. Reducing pro-inflammatory concentration and increasing cytokine’s anti-inflammatory concentration are considered other mechanisms.186 Taking 10,000 IU/d of vitamin D for a few weeks was suggested by Grant et al186 for people at risk of influenza and coronavirus infection. In addition, results obtained from a retrospective study in the mainland of the USA recommended that sunshine and vitamin D possibly reduce the risk of disease and mortality associated with COVID-19.2 Due to the effects of vitamin D on various organs, we hypothesized that vitamin D has effects against VRTIs. However, the evidence obtained is not sufficient to prove this point and to prove it, a more detailed study is needed.
Vitamin C possesses immunomodulatory and antiviral effects.187 In addition, antioxidants were found to prevent lung inflammation and injury induced by viruses.188 However, according to the findings of the other study, early use of high-dose vitamin C can improve respiratory problems caused by COVID-19.189 Intravenous using vitamin C can reduce the risk of cytokine storms in the late stages of COVID-19.190 In vitro study demonstrated that vitamin C inhibits the formation of IVA nucleoproteins and neuraminidase. This suppression effect was dose-dependent.191
Furthermore, it was found that 1–2 g/day of vitamin C inhibits VRTIs.138 Thus, a high dose of vitamin C may be a therapeutic agent for improving oxidative stress and inflammation caused by coronavirus infection, preventing virus replication, improving the antiviral immune system and adrenal function.192 A daily intake of 1 g vitamin C and 30 mg Zn can help to prevent viral symptoms in flu patients.193 The other study indicated that dietary-rich vitamin C enhances macrophage function.194 Furthermore, combining vitamin C, curcumin, and glycyrrhizic acid can protect against viral infection by boosting interferon synthesis, modulating the innate immune response, activating and balancing T-cells.195
Antioxidants in vitamin C improve the production of interleukin-2, natural killer cell activity, and T lymphocyte response.196 Vitamin C and quercetin have synergistic antiviral action. They can be used to treat COVID-19 as adjunctive for promising agents such as Remdesivir or convalescent plasma.96 Vitamin C appears to potentially affect oxidative stress and the generation of free radicals caused by burning and helps decrease overall fluid requirements and improve endothelial function.197
FFs have been shown to have antiviral properties in clinical trials. Since vitamin C is well-known for preventing respiratory infection, it has been used extensively in clinical trials. According to the findings of a clinical investigation, vitamin C can be used as a therapeutic medicine to reduce the severity of lung inflammation caused by viral infection.198 Study participants (n=214) with SARS-COV-2 infection were given zinc gluconate (50 mg), vitamin C (8000 mg), or a combination of the two supplements, and the duration of symptoms did not differ substantially across groups compared with standard of care in a randomized clinical trial study.199 In a pilot therapeutic trial in China, 56 patients with COVID-19 in the critical care unit were randomly assigned to receive 24 g of intravenous vitamin C per day or a placebo for 7 days. Unfortunately, the trial was halted early due to a decrease in COVID-19 cases in China. However, the paper identifies no variations in mortality and mechanical ventilation time.200 Short three-arm pilot research evaluated two IV vitamin C doses (50 and 200 mg/kg per day) to placebo in 24 sepsis patients. During the 4-day investigation, individuals who received vitamin C (either 50 or 200 mg/kg per day) showed lower proinflammatory markers than those who received placebo.201
Curcumin possesses antiviral properties against numerous viruses, such as vesicular stomatitis virus, parainfluenza virus type 3, and RSV.202 For COVID-19 management, there is a suggestion that curcumin may have a beneficial effect on viral encapsulation, cytokine storm protection, and cellular signalling pathways by blocking virus entry and viral protease encapsulation.203 Furthermore, curcumin also alters the structure of viral surface proteins, making it difficult for the virus to enter the host cell.204 Moreover, the ACE2 binding site for viral spike protein is better bound by curcumin.205 While this may be the case, curcumin is anticipated to inhibit the spike protein’s receptor-binding area.206
Moreover, the coronaviruses also use the dipeptidyl peptidase 4 to enter the host cell.207 Therefore, it has been suggested that topical application of curcumin as an emulsion can effectively prevent entering the SARS-COV2 to the human body through ACE2 receptors distributed in the nasal cells, respiratory mucosa, and eyes.208 Furthermore, curcumin prevents the replication of SARS-COV-2 by targeting the virus to penetrate the cell and attack the components that the virus needs to replicate.209 Additionally, the spread of viral particles from infected cells is inhibited by curcumin.210
Curcumin suppresses the transcription factor of activated B cells (NF-κB) by inhibiting Ang II-stimulated angiotensin AT1 receptor signalling in COVID-19.211 Furthermore, the study results show that curcumin can reduce the inflammatory response caused by IAV in the lung by inhibiting NF-κB.117 Further, curcumin has been reported to inhibit the release of critical cytokines IL-6, IL-10, interferon γ and reverse the fatal cytokine storm.212 Collectively, according to anti-fibrotic, pulmonoprotective and inhibitory effects on NF-κB and several pro-inflammatory cytokines by curcumin on the lung tissue, making it helpful in treating patients with COVID-19.
Due to the lack of a viable medicine, VRTIs, particularly coronaviruses, have significantly influenced people worldwide. Vaccines for protection are continuously being developed and must be carefully and systematically tested. Considerable scientific evidence supports FFs as a strategy to get health benefits from a food-based diet. FFs have also been shown to have antiviral activity, becoming increasingly apparent. Boosting the immune system is another way to combat viral infection. Polyphenols, flavonoids, propolis, curcumin, prebiotics, probiotics, and food supplements like Zn, vitamin C, D, and E are examples of functional food ingredients that might be referred to as natural immune boosters. The data suggested several processes by which FFs combat viruses that cause respiratory illness. In addition, the use of dietary supplements to prevent and cure VRTI was also found to be effective. Therefore, research into the potential role of FFs and functional food ingredients in the prevention and treatment of VRTIs, particularly in cases with COVID-19, is highly suggested in the future.
The authors express their thanks to Urmia University, Iran, for its support. The work was supported financially by the Razga Company for Trading, General Contracting and Quality Control.
The authors report no conflicts of interest in this work.
1. Eastin C, Eastin T. Clinical Characteristics of Coronavirus Disease 2019 in China. J Emerg Med. 2020;58(4):711–712. doi:10.1016/j.jemermed.2020.04.004
2. Li H, Liu S-M, Yu X-H, Tang S-L, Tang C-K. Coronavirus disease 2019 (COVID-19): current status and future perspectives. Int J Antimicrob Agents. 2020;55(5):105951. doi:10.1016/j.ijantimicag.2020.105951
3. WHO. WHO Director-General’s opening remarks at the media briefing on COVID-19-11 March 2020; 2020. Available from: https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020.
4. WHO. Coronavirus disease (COVID-19) pandemic; 2021. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019?gclid=Cj0KCQjwhr2FBhDbARIsACjwLo0FJkdT5PTcunihUBPJyFtwDQEt3PpdwrruMFnty373l3vGntvloH4aAlqlEALw_wcB.
5. Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020;12(4):988. doi:10.3390/nu12040988
6. Sheikh BY, Sarker MMR, Kamarudin MNA, Ismail A. Prophetic medicine as potential functional food elements in the intervention of cancer: a review. Biomed Pharmacother. 2017;95:614–648. doi:10.1016/j.biopha.2017.08.043
7. Liao SC, Hsu WH, Huang ZY, et al. Bioactivity evaluation of a novel formulated curcumin. Nutrients. 2019;11(12):2982. doi:10.3390/nu11122982
8. Quero J, Mármol I, Cerrada E, Rodríguez-Yoldi MJ. Insight into the potential application of polyphenol-rich dietary intervention in degenerative disease management. Food Funct. 2020;11(4):2805–2825. doi:10.1039/d0fo00216j
9. Mehany T, Khalifa I, Barakat H, Althwab SA, Alharbi YM, El-Sohaimy S. Polyphenols as promising biologically active substances for preventing SARS-CoV-2: a review with research evidence and underlying mechanisms. Food Biosci. 2021;40:100891. doi:10.1016/j.fbio.2021.100891
10. López-Varela S, González-Gross M, Marcos A. Functional foods and the immune system: a review. Eur J Clin Nutr. 2002;56(3):S29–S33. doi:10.1038/sj.ejcn.1601481
11. Calder PC, Kew S. The immune system: a target for functional foods? Br J Nutr. 2002;88(S2):S165–S176. doi:10.1079/BJN2002682
12. Hariyanto TI, Intan D, Hananto JE, Harapan H, Kurniawan A. Vitamin D supplementation and Covid-19 outcomes: a systematic review, meta-analysis and meta-regression. Rev Med Virol. 2022;32(2):e2269. doi:10.1002/rmv.2269
13. Lugito NPH, Kurniawan A, Damay V, Chyntya H, Sugianto N. The role of gut microbiota in SARS-CoV-2 infection: focus on angiotensin-converting enzyme 2. Curr Med Issues. 2020;18(3):261.
14. Vukasović T. Chapter 20 - Functional foods in line with young consumers: challenges in the marketplace in Slovenia. In: Bagchi D, editor. Nair SBT-DNFF and NP. San Diego: Academic Press; 2017:391–405. doi:10.1016/B978-0-12-802780-6.00020-1
15. Varzakas T, Kandylis P, Dimitrellou D, Salamoura C, Zakynthinos G, Proestos C. 6 - Innovative and fortified food: probiotics, prebiotics, GMOs, and superfood. Ali ME; Nizar NNABT-P and P of R and CF, editor. Woodhead Publishing Series in Food Science, Technology and Nutrition;Woodhead Publishing. 2018. 67–129. doi:10.1016/B978-0-08-101892-7.00006-7
16. Roberfroid MB. 1 - Defining functional foods. In: Gibson GR, Williams CMBT-F-F editors. Woodhead Publishing Series in Food Science, Technology and Nutrition. Woodhead Publishing; 2000:9–27. doi:10.1533/9781855736436.1.9.
17. Hasler CM. Functional Foods: benefits, Concerns and Challenges—A Position Paper from the American Council on Science and Health. J Nutr. 2002;132(12):3772–3781. doi:10.1093/jn/132.12.3772
18. Yang Y, Islam MS, Wang J, Li Y, Chen X. Traditional Chinese Medicine in the Treatment of Patients Infected with 2019-New Coronavirus (SARS-CoV-2): a Review and Perspective. Int J Biol Sci. 2020;16(10):1708–1717. doi:10.7150/ijbs.45538
19. Maryam M. Antiviral activity of traditional Chinese medicinal plants Dryopteris crassirhizoma and Morus alba against dengue virus. J Integr Agric. 2020;19(4):1085–1096. doi:10.1016/S2095-3119(19
20. Amber R, Adnan M, Tariq A, Mussarat S. A review on antiviral activity of the Himalayan medicinal plants traditionally used to treat bronchitis and related symptoms. J Pharm Pharmacol. 2017;69(2):109–122. doi:10.1111/jphp.12669
21. Yang F, Zhang Y, Tariq A, et al. Food as medicine: a possible preventive measure against coronavirus disease (COVID-19). Phytother Res. 2020;34(12):3124–3136. doi:10.1002/ptr.6770
22. Larsen JR, Martin MR, Martin JD, Kuhn P, Hicks JB. Modeling the Onset of Symptoms of COVID-19. Front Public Heal. 2020;8:473. doi:10.3389/fpubh.2020.00473
23. Vasquez-Bonilla WO, Orozco R, Argueta V, et al. A review of the main histopathological findings in coronavirus disease 2019. Hum Pathol. 2020;105:74–83. doi:10.1016/j.humpath.2020.07.023
24. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361(9374):2045–2046. doi:10.1016/S0140-6736(03
25. Hoever G, Baltina L, Michaelis M, et al. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem. 2005;48(4):1256–1259. doi:10.1021/jm0493008
26. Krawitz C, Mraheil MA, Stein M, et al. Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses. BMC Complement Altern Med. 2011;11:16. doi:10.1186/1472-6882-11-16
27. Barak V, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based natural product, on the production of human cytokines: i. Inflammatory cytokines. Eur Cytokine Netw. 2001;12(2):290–296.
28. Anywar G, Kakudidi E, Byamukama R, Mukonzo J, Schubert A, Oryem-Origa H. Medicinal plants used by traditional medicine practitioners to boost the immune system in people living with HIV/AIDS in Uganda. Eur J Integr Med. 2020;35:101011. doi:10.1016/j.eujim.2019.101011
29. Rouf R, Uddin SJ, Sarker DK, et al. Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: a systematic update of pre-clinical and clinical data. Trends Food Sci Technol. 2020;104:219–234. doi:10.1016/j.tifs.2020.08.006
30. Lissiman E, Bhasale AL, Cohen M. Garlic for the common cold. Cochrane Database Syst Rev. 2014;2014(11):CD006206–CD006206. doi:10.1002/14651858.CD006206.pub4
31. Moradi M-T, Karimi A, Shahrani M, Hashemi L, Ghaffari-Goosheh M-S. Anti-Influenza Virus Activity and Phenolic Content of Pomegranate (Punica granatum L.) Peel Extract and Fractions. Avicenna J Med Biotechnol. 2019;11(4):285–291.
32. Nikolaeva-Glomb L, Mukova L, Nikolova N, et al. In Vitro Antiviral Activity of a Series of Wild Berry Fruit Extracts against Representatives of Picorna-, Orthomyxo- and Paramyxoviridae. Nat Prod Commun. 2014;9(1):1934578X1400900116. doi:10.1177/1934578X1400900116
33. Del Bo C, Bernardi S, Marino M, et al. Systematic Review on Polyphenol Intake and Health Outcomes: is there Sufficient Evidence to Define a Health-Promoting Polyphenol-Rich Dietary Pattern? Nutrients. 2019;11(6):1355. doi:10.3390/nu11061355
34. Yao LH, Jiang YM, Shi J, et al. Flavonoids in food and their health benefits. Plant Foods Hum Nutr. 2004;59(3):113–122. doi:10.1007/s11130-004-0049-7
35. González-Gallego J, García-Mediavilla MV, Sánchez-Campos S, Tuñó MJ. Fruit polyphenols, immunity and inflammation. Br J Nutr. 2010;104(SUPPL.3):S15–S27. doi:10.1017/S0007114510003910
36. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583
37. Wang Z, Yang L. Turning the Tide: natural Products and Natural-Product-Inspired Chemicals as Potential Counters to SARS-CoV-2 Infection. Front Pharmacol. 2020;2:11.
38. Wang Z, Yang L. Chinese herbal medicine: fighting SARS-CoV-2 infection on all fronts. J Ethnopharmacol. 2021;270:113869. doi:10.1016/j.jep.2021.113869
39. Standish LJ, Wenner CA, Sweet ES, et al. Trametes versicolor mushroom immune therapy in breast cancer. J Soc Integr Oncol. 2008;6(3):122–128.
40. Watanabe K, Rahmasari R, Matsunaga A, Haruyama T, Kobayashi N. Anti-influenza Viral Effects of Honey In Vitro: potent High Activity of Manuka Honey. Arch Med Res. 2014;45(5):359–365. doi:10.1016/j.arcmed.2014.05.006
41. Al-Waili NS. Topical honey application vs. Acyclovir for the treatment of recurrent herpes simplex lesions. Med Sci Monit. 2004;10(8):MT94–MT98.
42. Chang JS, Wang KC, Yeh CF, Shieh DE, Chiang LC. Fresh ginger (Zingiber officinale) has anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. J Ethnopharmacol. 2013;145(1):146–151. doi:10.1016/j.jep.2012.10.043
43. Salem ML, Hossain MS. Protective effect of black seed oil from Nigella sativa against murine cytomegalovirus infection. Int J Immunopharmacol. 2000;22(9):729–740. doi:10.1016/S0192-0561(00
44. Pourghanbari G, Nili H, Moattari A, Mohammadi A, Iraji A. Antiviral activity of the oseltamivir and Melissa officinalis L. essential oil against avian influenza A virus (H9N2). Virusdisease. 2016;27(2):170–178. doi:10.1007/s13337-016-0321-0
45. Geuenich S, Goffinet C, Venzke S, et al. Aqueous extracts from peppermint, sage and lemon balm leaves display potent anti-HIV-1 activity by increasing the virion density. Retrovirology. 2008;5:27. doi:10.1186/1742-4690-5-27
46. Velthuis AJW, Worml SHE, Sims AC, Baric RS, Snijder EJ, Hemert MJ. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6:11. doi:10.1371/journal.ppat.1001176
47. Rink L, Kirchner H. Zinc-Altered Immune Function and Cytokine Production. J Nutr. 2000;130(5):1407S–1411S. doi:10.1093/jn/130.5.1407S
48. Turvey SE, Broide DH. Innate immunity. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S24–S32. doi:10.1016/j.jaci.2009.07.016
49. Quiles JL, Rivas-García L, Varela-López A, Llopis J, Battino M, Sánchez-González C. Do nutrients and other bioactive molecules from foods have anything to say in the treatment against COVID-19? Environ Res. 2020;191(August):54. doi:10.1016/j.envres.2020.110053
50. Hemilä H. Vitamin C and SARS coronavirus. J Antimicrob Chemother. 2003;52(6):1049–1050. doi:10.1093/jac/dkh002
51. Abobaker A, Alzwi A, Alraied AHA. Overview of the possible role of vitamin C in management of COVID-19. Pharmacol Reports. 2020;72(6):1517–1528. doi:10.1007/s43440-020-00176-1
52. Carr AC, Rowe S. The emerging role of vitamin C in the prevention and treatment of COVID-19. Nutrients. 2020;12(11):3286.
53. Rayman MP. The importance of selenium to human health. Lancet. 2000;356(9225):233–241. doi:10.1016/S0140-6736(00
54. Nkengfack G, Englert H, Haddadi M. Selenium and immunity. In: Nutrition and Immunity. Springer; 2019:159–165.
55. Michaelis M, Geiler J, Naczk P, et al. Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages. Med Microbiol Immunol. 2010;199(4):291–297. doi:10.1007/s00430-010-0155-0
56. Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother. 1997;41(3):551–556. doi:10.1128/AAC.41.3.551
57. Sriwilaijaroen N, Fukumoto S, Kumagai K, et al. Antiviral effects of Psidium guajava Linn. (guava) tea on the growth of clinical isolated H1N1 viruses: its role in viral hemagglutination and neuraminidase inhibition. Antiviral Res. 2012;94(2):139–146. doi:10.1016/j.antiviral.2012.02.013
58. Sundararajan A, Ganapathy R, Huan L, et al. Influenza virus variation in susceptibility to inactivation by pomegranate polyphenols is determined by envelope glycoproteins. Antiviral Res. 2010;88(1):1–9. doi:10.1016/j.antiviral.2010.06.014
59. Ding Y, Dou J, Teng Z, et al. Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase. Arch Virol. 2014;159(12):3269–3278. doi:10.1007/s00705-014-2192-2
60. Ho J-Y, Chang H-W, Lin C-F, Liu C-J, Hsieh C-F, Horng J-T. Characterization of the anti-influenza activity of the Chinese herbal plant Paeonia lactiflora. Viruses. 2014;6(4):1861–1875. doi:10.3390/v6041861
61. Nahas R, Balla A. Complementary and alternative medicine for prevention and treatment of the common cold. Can Fam Physician. 2011;57(1):31–36.
62. Moyad MA, Robinson LE, Zawada ET, et al. Effects of a modified yeast supplement on cold/flu symptoms. Urol Nurs. 2008;28(1):50–55.
63. Wakabayashi H, Oda H, Yamauchi K, Abe F. Lactoferrin for prevention of common viral infections. J Infect Chemother. 2014;20(11):666–671.
64. Leyer GJ, Li S, Mubasher ME, Reifer C, Ouwehand AC. Probiotic effects on cold and influenza-like symptom incidence and duration in children. Pediatrics. 2009;124(2):e172–e179.
65. Singh P, Tripathi MK, Yasir M, Khare R, Tripathi MK, Shrivastava R. Potential Inhibitors for SARS-CoV-2 and Functional Food Components as Nutritional Supplement for COVID-19: a Review. Plant Foods Hum Nutr. 2020;75(4):458–466. doi:10.1007/s11130-020-00861-9
66. Yan F, Polk DB. Probiotics and immune health. Curr Opin Gastroenterol. 2011;27(6):496–501. doi:10.1097/MOG.0b013e32834baa4d
67. Manna S, Chowdhury T, Chakraborty R, Mandal SM. Probiotics-Derived Peptides and Their Immunomodulatory Molecules Can Play a Preventive Role Against Viral Diseases Including COVID-19. Probiotics Antimicrob Proteins. 2020. doi:10.1007/s12602-020-09727-7
68. Li J, Zhao J, Wang X, et al. Novel Angiotensin-Converting Enzyme-Inhibitory Peptides From Fermented Bovine Milk Started by Lactobacillus helveticus KLDS.31 and Lactobacillus casei KLDS.105: purification, Identification, and Interaction Mechanisms. Front Microbiol. 2019;10:2643. doi:10.3389/fmicb.2019.02643
69. Verma A, Xu K, Du T, et al. Expression of Human ACE2 in Lactobacillus and Beneficial Effects in Diabetic Retinopathy in Mice. Mol Ther. 2019;14(September):161–170. doi:10.1016/j.omtm.2019.06.007
70. Rizzo P, Sega F, Fortini F, Marracino L, Rapezzi C, Ferrari R. COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm? Basic Res Cardiol. 2020;115(3):1–8. doi:10.1007/s00395-020-0791-5
71. Gorji A, Khaleghi Ghadiri M. Potential roles of micronutrient deficiency and immune system dysfunction in the coronavirus disease 2019 (COVID-19) pandemic. Nutrition. 2021;2:82. doi:10.1016/j.nut.2020.111047
72. Galanakis CM, Aldawoud TMS, Rizou M, Rowan NJ, Ibrahim SA. Food Ingredients and Active Compounds against the Coronavirus Disease (COVID-19) Pandemic: a Comprehensive Review. Foods. 2020;9(11):1701. doi:10.3390/foods9111701
73. Lange KW. Food science and COVID-19. Food Sci Hum Wellness. 2021;10(1):1–5. doi:10.1016/j.fshw.2020.08.005
74. Mrityunjaya M, Pavithra V, Neelam R, Janhavi P, Halami PM, Ravindra PV. Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19. Front Immunol. 2020;2:11. doi:10.3389/fimmu.2020.570122
75. Thirumdas R, Kothakota A, Pandiselvam R, Bahrami A, Barba FJ. Role of food nutrients and supplementation in fighting against viral infections and boosting immunity: a review. Trends Food Sci Technol. 2021;110:
76. Wang Z, Yang L, Zhao X-E. Co-crystallization and structure determination: an effective direction for anti-SARS-CoV-2 drug discovery. Comput Struct Biotechnol J. 2021;19:4684–4701. doi:10.1016/j.csbj.2021.08.029
77. Lalani S, Poh CL. Flavonoids as Antiviral Agents for Enterovirus A71 (EV-A71). Viruses. 2020;12:2. doi:10.3390/v12020184
78. Pastor N, Collado MC, Manzoni P. Phytonutrient and nutraceutical action against COVID-19: current review of characteristics and benefits. Nutrients. 2021;13(2):1–10. doi:10.3390/nu13020464
79. Ninfali P, Antonelli A, Magnani M, Scarpa ES. Antiviral properties of flavonoids and delivery strategies. Nutrients. 2020;12(9):2534.
80. Ubani A, Agwom F, RuthMorenikeji O, et al. Molecular docking analysis of some phytochemicals on two SARS-COV-2 targets: potential lead compounds against two target sites of SARS-COV-2 obtained from plants. bioRxiv. 2020. doi:10.1101/2020.03.31.017657
81. Jain AS, Sushma P, Dharmashekar C, et al. In silico evaluation of flavonoids as effective antiviral agents on the spike glycoprotein of SARS-CoV-2. Saudi J Biol Sci. 2021;28(1):1040–1051. doi:10.1016/j.sjbs.2020.11.049
82. Yudi Utomo R, Meiyanto E. Revealing the Potency of Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection. Aging. 2020;1(March):1–8. doi:10.20944/preprints202003.0214.v1
83. Sekiou O, Bouziane I, Bouslama Z, Djemel A. In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine against. ChemRxiv. 2020;2(1):56. doi:10.26434/chemrxiv.12181404.v1
84. Pandit M. In silico studies reveal potential antiviral activity of phytochemicals from medicinal plants for the treatment of COVID-19 infection. J Med. 2020;2:1–38. doi:10.21203/rs.3.rs-22687/v1
85. Sargiacomo C, Sotgia F, Lisanti MP. COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of Corona virus infection? Aging. 2020;12(8):6511–6517. doi:10.18632/AGING.103001
86. Yi L, Li Z, Yuan K, et al. Small Molecules Blocking the Entry of Severe Acute Respiratory Syndrome Coronavirus into Host Cells. J Virol. 2004;78(20):11334–11339. doi:10.1128/jvi.78.20.11334-11339.2004
87. Dai W, Zhang B, Jiang XM, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368(6497):1331–1335. doi:10.1126/science.abb4489
88. Paraiso IL, Revel JS, Stevens JF. Potential use of polyphenols in the battle against COVID-19. Curr Opin Food Sci. 2020;32:149–155. doi:10.1016/j.cofs.2020.08.004
89. Zhang D, Wu K, Zhang X. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med. 2020;18(2):152–158. doi:10.1016/j.joim.2020.02.005
90. Wang Z, Yang L. Broad-spectrum prodrugs with anti-SARS-CoV-2 activities: strategies, benefits, and challenges. J Med Virol. 2022;94(4):1373–1390. doi:10.1002/jmv.27517
91. Yang L, Wang Z. Natural Products, Alone or in Combination with FDA-Approved Drugs, to Treat COVID-19 and Lung Cancer. Biomed. 2021;9:6. doi:10.3390/biomedicines9060689
92. Singh S, Sk MF, Sonawane A, Kar P, Sadhukhan S. Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2 via RNA‐dependent RNA polymerase (RdRp) inhibition: an in-silico analysis. J Biomol Struct Dyn. 2020;1:1–16. doi:10.1080/07391102.2020.1796810
93. Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem. 2020;35(1):145–151. doi:10.1080/14756366.2019.1690480
94. Jo S, Kim S, Kim DY, Kim M-S, Shin DH. Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro. J Enzyme Inhib Med Chem. 2020;35(1):1539–1544.
95. Derosa G, Maffioli P, D’Angelo A, Di Pierro F. A role for quercetin in coronavirus disease 2019 (COVID-19). Phyther Res. 2020;1(September):1–7. doi:10.1002/ptr.6887
96. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: an Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol. 2020;11(June):1–11. doi:10.3389/fimmu.2020.01451
97. Schettig R, Sears T, Klein M, et al. COVID-19 Patient with Multifocal Pneumonia and Respiratory Difficulty Resolved Quickly: possible Antiviral and Anti-Inflammatory Benefits of Quercinex (Nebulized Quercetin-NAC) as Adjuvant. Adv Infect Dis. 2020;10(03):45–55. doi:10.4236/aid.2020.103006
98. Roy A, Sarkar B, Celik C, et al. Can concomitant use of zinc and curcumin with other immunity-boosting nutraceuticals be the arsenal against COVID-19? Phyther Res. 2020;34(10):2425–2428. doi:10.1002/ptr.6766
99. Anjum SI, Ullah A, Khan KA, et al. Composition and functional properties of propolis (bee glue): a review. Saudi J Biol Sci. 2019;26(7):1695–1703. doi:10.1016/j.sjbs.2018.08.013
100. Kwon MJ, Shin HM, Perumalsamy H, Wang X, Ahn YJ. Antiviral effects and possible mechanisms of action of constituents from Brazilian propolis and related compounds. J Apic Res. 2020;59(4):413–425. doi:10.1080/00218839.2019.1695715
101. Bachevski D, Damevska K, Simeonovski V, Dimova M. Back to the basics: propolis and COVID-19. Dermatol Ther. 2020;33:4. doi:10.1111/dth.13780
102. Debiaggi M, Tateo F, Pagani L, Luini M, Romero E. Effects of propolis flavonoids on virus infectivity and replication. Microbiologica. 1990;13(3):207–213.
103. Berretta AA, Silveira MAD, Cóndor Capcha JM, De jong D. Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: running title: propolis against SARS-CoV-2 infection and COVID-19. Biomed Pharmacother. 2020;131(August):65. doi:10.1016/j.biopha.2020.110622
104. Ş A, Eyupoglu V, Sarfraz I, et al. Caffeic acid derivatives (CAFDs) as inhibitors of SARS-CoV-2: cAFDs-based functional foods as a potential alternative approach to combat COVID-19. Phytomedicine. 2020;1(April):153310. doi:10.1016/j.phymed.2020.153310
105. Osés SM, Marcos P, Azofra P, et al. Phenolic Profile, Antioxidant Capacities and Enzymatic Inhibitory Activities of Propolis from Different Geographical Areas: needs for Analytical Harmonization. J Med. 2020;1:20–35. doi:10.3390/antiox9010075
106. Kumar V, Dhanjal JK, Kaul SC, Wadhwa R, Sundar D. Withanone and caffeic acid phenethyl ester are predicted to interact with main protease (Mpro) of SARS-CoV-2 and inhibit its activity. J Biomol Struct Dyn. 2020;1:1–13. doi:10.1080/07391102.2020.1772108
107. Hashem HE. IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors. Eurasian J Med Oncol. 2020;4(3):196–200. doi:10.14744/ejmo.2020.36102
108. Kumar A, Kubota Y, Chernov M, et al. Potential role of zinc supplementation in prophylaxis and treatment of COVID-19. Antimicrob Agents Chemother. 2009;1865(April):783–790. doi:10.1128/AAC.48.3.783-790.2004
109. Sun S, He J, Liu M, Yin G, Zhang X, Great Concern A. Regarding the Authenticity Identification and Quality Control of Chinese Propolis and Brazilian Green Propolis. J Drug. 2019;7(10):725–735. doi:10.12691/jfnr-7-10-6
110. Hori JI, Zamboni DS, Carrão DB, Goldman GH, Berretta AA. The Inhibition of Inflammasome by Brazilian Propolis (EPP-AF). J med. 2013;1:54.
111. Maruta H, He H. Medicine in Drug Discovery PAK1-blockers: potential Therapeutics against COVID-19. Med Drug Discov. 2020;6:100039. doi:10.1016/j.medidd.2020.100039
112. Oyeniran A, Gyawali R, Aljaloud SO, Krastanov A, Ibrahim SA. Probiotic Characteristics and Health Benefits of the Yogurt Bacterium Lactobacillus delbrueckii sp. Handb Mod Dairy Sci Technol. 2020;2:1–11.
113. Hu J, Zhang L, Lin W, Tang W, Chan FKL, Ng SC. Review article: probiotics, prebiotics and dietary approaches during COVID-19 pandemic. Trends Food Sci Technol. 2021;108(November2020):187–196. doi:10.1016/j.tifs.2020.12.009
114. Dhar D, Mohanty A. Gut microbiota and Covid-19- possible link and implications. Virus Res. 2020;285(April):198018. doi:10.1016/j.virusres.2020.198018
115. Costagliola G, Spada E, Comberiati P, Peroni DG. Could nutritional supplements act as therapeutic adjuvants in COVID-19? Ital J Pediatr. 2021;47(1):32.
116. Olaimat AN, Aolymat I, Al-Holy M, et al. The potential application of probiotics and prebiotics for the prevention and treatment of COVID-19. Npj Sci Food. 2020;4:1. doi:10.1038/s41538-020-00078-9
117. Xu Y, Liu L. Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway Background: influenza A viruses (IAV) result in severe public health problems with. Influ Other Respi Viruses. 2017;11:457–463. doi:10.1111/irv.12459
118. Ahlawat S, Asha SKK. Immunological co-ordination between gut and lungs in SARS-CoV-2 infection. Virus Res. 2020;286(June):198103. doi:10.1016/j.virusres.2020.198103
119. Lin L, Jiang X, Zhang Z, et al. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut. 2020;69(6):997–1001. doi:10.1136/gutjnl-2020-321013
120. Su M, Jia Y, Li Y, Zhou D, Jia J. Probiotics for the prevention of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials. Respir Care. 2020;65(5):673–685. doi:10.4187/respcare.07097
121. Dumas A, Bernard L, Poquet Y, Lugo-Villarino G, Neyrolles O. The role of the lung microbiota and the gut–lung axis in respiratory infectious diseases. Cell Microbiol. 2018;20(12):1–9. doi:10.1111/cmi.12966
122. Singh K, Rao A. Probiotics: a potential immunomodulator in COVID-19 infection management. Nutr Res. 2021;87:1–12. doi:10.1016/j.nutres.2020.12.014
123. Baud D, Dimopoulou Agri V, Gibson GR, Reid G, Giannoni E. Using Probiotics to Flatten the Curve of Coronavirus Disease COVID-2019 Pandemic. Front Public Heal. 2020;8:186. doi:10.3389/fpubh.2020.00186
124. Fanos V, Pintus MC, Pintus R, Marcialis MA. Lung microbiota in the acute respiratory disease: from coronavirus to metabolomics. J Pediatr Neonatal Individ Med. 2020;9(1):1–10. doi:10.7363/090139
125. Wan LYM, Chen ZJ, Shah NP, El-Nezami H. Modulation of Intestinal Epithelial Defense Responses by Probiotic Bacteria. Crit Rev Food Sci Nutr. 2016;56(16):2628–2641. doi:10.1080/10408398.2014.905450
126. Anwar F, Altayb HN, Al-Abbasi FA, Al-Malki AL, Kamal MA, Kumar V. Antiviral effects of probiotic metabolites on COVID-19. J Biomol Struct Dyn. 2020;1:1–10. doi:10.1080/07391102.2020.1775123
127. d’Ettorre G, Ceccarelli G, Marazzato M, et al. Challenges in the Management of SARS-CoV2 Infection: the Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19. Front Med. 2020;7:389. doi:10.3389/fmed.2020.00389
128. Trompette A, Gollwitzer ES, Yadava K, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20(2):159–166. doi:10.1038/nm.3444
129. Sanchez HN, Moroney JB, Gan H, et al. B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived short-chain fatty acids. Nat Commun. 2020;11:1. doi:10.1038/s41467-019-13603-6
130. Chan CKY, Tao J, Chan OS, Bin LH, Pang H. Preventing respiratory tract infections by synbiotic interventions: a systematic review and meta-analysis of randomized controlled trials. Adv Nutr. 2021;11(4):979–988. doi:10.1093/ADVANCES/NMAA003
131. Ashaolu TJ, Saibandith B, Yupanqui CT, Wichienchot S. Human colonic microbiota modulation and branched chain fatty acids production affected by soy protein hydrolysate. Int J Food Sci Technol. 2019;54(1):141–148. doi:10.1111/ijfs.13916
132. Shahramian I, Kalvandi G, Javaherizadeh H, et al. The effects of prebiotic supplementation on weight gain, diarrhoea, constipation, fever and respiratory tract infections in the first year of life. J Paediatr Child Health. 2018;54(8):875–880. doi:10.1111/jpc.13906
133. Gohil K, Samson R, Dastager S, Dharne M. Probiotics in the prophylaxis of COVID-19: something is better than nothing. Biotech. 2021;11(1):1–10. doi:10.1007/s13205-020-02554-1
134. Wu M, Feng H, Song J, et al. Structural elucidation and immunomodulatory activity of a neutral polysaccharide from the Kushui Rose (Rosa setate x Rosa rugosa) waste. Carbohydr Polym. 2020;232(December2019):115804. doi:10.1016/j.carbpol.2019.115804
135. Te LW, Shih PC, Liu SJ, Lin CY, Yeh TL. Effect of probiotics and prebiotics on immune response to influenza vaccination in adults: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 2017;9:11. doi:10.3390/nu9111175
136. Vitetta L, Saltzman ET, Thomsen M, Nikov T, Hall S. Adjuvant Probiotics and the Intestinal Microbiome: enhancing Vaccines and Immunotherapy Outcomes. Vaccines. 2017;5:4. doi:10.3390/vaccines5040050
137. Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The Role of Zinc in Antiviral Immunity. Adv Nutr. 2019;10(4):696–710. doi:10.1093/advances/nmz013
138. Zabetakis I, Lordan R, Norton C, Tsoupras A. Covid-19: the inflammation link and the role of nutrition in potential mitigation. Nutrients. 2020;12(5):1–28. doi:10.3390/nu12051466
139. Bagheri M, Haghollahi F, Shariat M, Jafarabadi M, Aryamloo P, Rezayof E. Supplement Usage Pattern in a Group of COVID- 19 Patients in Tehran. J Fam Reprod Heal. 2020;14(3):158–165. doi:10.18502/jfrh.v14i3.4668
140. Razzaque MS. COVID-19 pandemic: can zinc supplementation provide an additional shield against the infection? Comput Struct Biotechnol J. 2021;19:1371–1378. doi:10.1016/j.csbj.2021.02.015
141. Celik C, Gencay A, Ocsoy I. Can food and food supplements be deployed in the fight against the COVID 19 pandemic? Biochim Biophys Acta. 2021;1865(2):129801. doi:10.1016/j.bbagen.2020.129801
142. Kolenko VM, Uzzo RG, Dulin N, Hauzman E, Bukowski R, Finke JH. Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes. Apoptosis. 2001;6(6):419–429. doi:10.1023/A:
143. Wessels I, Rolles B, Rink L. The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis. Front Immunol. 2020;11(July):1–11. doi:10.3389/fimmu.2020.01712
144. Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. 2017;9:6. doi:10.3390/nu9060624
145. Mossink JP. Zinc as nutritional intervention and prevention measure for COVID–19 disease. BMJ Nutr Prev Heal. 2020;3(1):111–117. doi:10.1136/bmjnph-2020-000095
146. Rerksuppaphol S, Rerksuppaphol L, Randomized Controlled A. Trial of Zinc Supplementation in the Treatment of Acute Respiratory Tract Infection in Thai Children. Pediatr Rep. 2019;11(2):15–20. doi:10.4081/pr.2019.7954
147. Yalcin Bahat P, Aldikactioglu Talmac M, Bestel A, Topbas Selcuki NF, Aydın Z, Polat İ. Micronutrients in COVID-19 Positive Pregnancies. Cureus. 2020;12(9):10–14. doi:10.7759/cureus.10609
148. Joachimiak MP. Zinc against covid-19? Symptom surveillance and deficiency risk groups. PLoS Negl Trop Dis. 2021;15(1):1–17. doi:10.1371/journal.pntd.0008895
149. Jothimani D, Kailasam E, Danielraj S, et al. COVID-19: poor outcomes in patients with zinc deficiency. Int J Infect Dis. 2020;100:343–349. doi:10.1016/j.ijid.2020.09.014
150. Vogel-González M, Talló-Parra M, Herrera-Fernández V, et al. Low zinc levels at admission associates with poor clinical outcomes in sars-cov-2 infection. Nutrients. 2021;13(2):1–13. doi:10.3390/nu13020562
151. Derwand R, Scholz M. Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win todays battle against COVID-19? Med Hypotheses. 2020;142(April):109815. doi:10.1016/j.mehy.2020.109815
152. Dubourg G, Lagier J-C, Brouqui P, et al. Low blood zinc concentrations in patients with poor clinical outcome during SARS-CoV-2 infection: is there a need to supplement with Zinc COVID-19 patients? J Microbiol Immunol Infect. 2021;1:3. doi:10.1016/j.jmii.2021.01.012
153. Heller RA, Sun Q, Hackler J, et al. Prediction of survival odds in COVID-19 by zinc, age and selenoprotein P as composite biomarker. Redox Biol. 2021;38(August2020):101764. doi:10.1016/j.redox.2020.101764
154. Ali N, Fariha KA, Islam F, et al. Assessment of the role of zinc in the prevention of COVID-19 infections and mortality: a retrospective study in the Asian and European population. J Med Virol. 2021;1(March):54w. doi:10.1002/jmv.26932
155. Kumar A, Kubota Y, Chernov M, Kasuya H. Potential role of zinc supplementation in prophylaxis and treatment of COVID-19. Med Hypotheses. 2020;144(April):109848. doi:10.1016/j.mehy.2020.109848
156. Lee MC, Chen Y-K, Hsu Y-J, Lin B-R. Zinc supplement augments the suppressive effects of repurposed drugs of NF-kappa B inhibitor on ACE2 expression in human lung cell lines in vitro. bioRxiv. 2021;3456(7):428372.
157. Chang C-W, Lee M-C, Lin B-R, et al. Azithromycin Plus Zinc Sulfate Rapidly and Synergistically Suppresses IκBα-Mediated In Vitro Human Airway Cell ACE2 Expression for SARS-CoV-2 Entry. bioRxiv. 2021. doi:10.1101/2021.01.19.427206
158. Pormohammad A, Monych NK, Turner RJ. PORMOHAMMAD A. Zinc and SARS-CoV-2: a molecular modeling study of Zn interactions with RNA-dependent RNA-polymerase and 3C-like proteinase enzymes. Int J Mol Med. 2021;47(1):326–334. doi:10.3892/ijmm.2020.4790
159. Provinciali M, Montenovo A, Di Stefano G, et al. Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial. Age Ageing. 1998;27(6):715–722. doi:10.1093/ageing/27.6.715
160. Health NI of. Office of Dietary Supplements. Zinc Fact Sheet for Health Professionals. Health NI of. Office of Dietary Supplements; 2020.
161. Torabian G, Valtchev P, Adil Q, Dehghani F. Anti-influenza activity of elderberry (Sambucus nigra). J Funct Foods. 2019;54:353–360. doi:10.1016/j.jff.2019.01.031
162. Kinoshita E, Hayashi K, Katayama H, Hayashi T, Obata A. Anti-influenza virus effects of elderberry juice and its fractions. Biosci Biotechnol Biochem. 2012;76(9):1633–1638. doi:10.1271/bbb.120112
163. Wright CI, Van-buren L, Kroner CI, Koning MMG. Herbal medicines as diuretics: a review of the scientific evidence. J Ethnopharmacol. 2007;114(1):1–31. doi:10.1016/j.jep.2007.07.023
164. Liu A-L, Wang H-D, Lee SM, Wang Y-T, Du G-H. Structure–activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities. Bioorg Med Chem. 2008;16(15):7141–7147. doi:10.1016/j.bmc.2008.06.049
165. Zakay-Rones Z, Thom E, Wollan T, Wadstein J. Randomized Study of the Efficacy and Safety of Oral Elderberry Extract in the Treatment of Influenza A and B Virus Infections. J Int Med Res. 2004;32(2):132–140. doi:10.1177/147323000403200205
166. Tiralongo E, Wee SS, Lea RA. Elderberry Supplementation Reduces Cold Duration and Symptoms in Air-Travellers: a Randomized, Double-Blind Placebo-Controlled Clinical Trial. Nutrients. 2016;8:4. doi:10.3390/nu8040182
167. Schön C, Mödinger Y, Krüger F, Doebis C, Pischel I, Bonnländer B. A new high-quality elderberry plant extract exerts antiviral and immunomodulatory effects in vitro and ex vivo. Food Agric Immunol. 2021;32(1):650–662.
168. Marinella MA. Indomethacin and resveratrol as potential treatment adjuncts for SARS-CoV-2/COVID-19. Int J Clin Pract. 2020;74(9):25–27. doi:10.1111/ijcp.13535
169. Zhao X, Tong W, Song X, et al. Antiviral Effect of Resveratrol in Piglets Infected with Virulent Pseudorabies Virus. Viruses. 2018;10:9. doi:10.3390/v10090457
170. Giordo R, Zinellu A, Eid AH, Pintus G. Therapeutic Potential of Resveratrol in COVID-19-Associated Hemostatic Disorders. Molecules. 2021;26:4. doi:10.3390/molecules26040856
171. Lin SC, Ho CT, Chuo WH, Li S, Wang TT, Lin CC. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect Dis. 2017;17(1):1–10. doi:10.1186/s12879-017-2253-8
172. Horne J. SARS-CoV illness severity. JournalsPhysiology. 2020;2(418):1–15.
173. Oliveira Andrade JM, Paraíso AF, Garcia ZM, et al. Cross talk between angiotensin-(1–7)/Mas axis and sirtuins in adipose tissue and metabolism of high-fat feed mice. Peptides. 2014;55:158–165. doi:10.1016/j.peptides.2014.03.006
174. Zhao X, Xu J, Song X, et al. Antiviral effect of resveratrol in ducklings infected with virulent duck enteritis virus. Antiviral Res. 2016;130:93–100. doi:10.1016/j.antiviral.2016.03.014
175. Beijers RJHCG, Gosker HR, Schols AMWJ. Resveratrol for patients with chronic obstructive pulmonary disease: hype or hope? Curr Opin Clin Nutr Metab Care. 2018;21(2):138–144. doi:10.1097/MCO.0000000000000444
176. Franciosoa A, Mastromarino P, Masci A, d’Erme M, Mosca L. Chemistry, Stability and Bioavailability of Resveratrol. Med Chem. 2014;10(3):237–245. doi:10.2174/15734064113096660053
177. Baldassarre ME, Di Mauro A, Labellarte G, et al. Resveratrol plus carboxymethyl-β-glucan in infants with common cold: a randomized double-blind trial. Heliyon. 2020;6(4):e03814. doi:10.1016/j.heliyon.2020.e03814
178. Greiller CL, Martineau AR. Modulation of the Immune Response to Respiratory Viruses by Vitamin D. Nutrients. 2015;7(6):4240–4270. doi:10.3390/nu7064240
179. Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab. 2010;95(7):3111–3117. doi:10.1210/jc.2009-2673
180. Hewison M. Vitamin D and the intracrinology of innate immunity. Mol Cell Endocrinol. 2010;321(2):103–111. doi:10.1016/j.mce.2010.02.013
181. Meftahi GH, Jangravi Z, Sahraei H, Bahari Z. The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”. Inflamm Res. 2020;69(9):825–839. doi:10.1007/s00011-020-01372-8
182. Cantorna MT, Snyder L, Lin YD, Yang L. Vitamin D and 1,25(OH)2D Regulation of T cells. Nutrients. 2015;7(4):3011–3021. doi:10.3390/nu7043011
183. Komolmit P, Charoensuk K, Thanapirom K, et al. Correction of Vitamin D deficiency facilitated suppression of IP-10 and DPP IV levels in patients with chronic hepatitis C: a randomised double-blinded, placebo-control trial. PLoS One. 2017;12(4):1–14. doi:10.1371/journal.pone.0174608
184. Tan CW, Ho LP, Kalimuddin S, et al. Cohort study to evaluate effect of vitamin D, magnesium, and vitamin B12 in combination on severe outcome progression in older patients with coronavirus (COVID-19). Nutrition. 2020;79-80:111017. doi:10.1016/j.nut.2020.111017
185. Martens GA. Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics. J med. 2020;1:435. doi:10.1101/2020.05.01.20079376
186. Grant WB, Baggerly CA, Lahore H. Reply: “Vitamin D Supplementation in Influenza and COVID-19 Infections. Comment on: evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths Nutrients 2020, 12(4),988”. Nutrients. 2020;12(6):453. doi:10.3390/nu12061620
187. Colunga Biancatelli RML, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert Rev Anti Infect Ther. 2020;18(2):99–101. doi:10.1080/14787210.2020.1706483
188. Castro SM, Guerrero-Plata A, Suarez-Real G, et al. Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation. Am J Respir Crit Care Med. 2006;174(12):1361–1369. doi:10.1164/rccm.200603-319OC
189. Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discov. 2020;5:100028. doi:10.1016/j.medidd.2020.100028
190. Boretti A, Banik BK. Intravenous vitamin C for reduction of cytokines storm in acute respiratory distress syndrome. PharmaNutrition. 2020;12:100190. doi:10.1016/j.phanu.2020.100190
191. Jariwalla RJ, Roomi MW, Gangapurkar B, Kalinovsky T, Niedzwiecki A, Rath M. Suppression of influenza A virus nuclear antigen production and neuraminidase activity by a nutrient mixture containing ascorbic acid, green tea extract and amino acids. BioFactors. 2007;31(1):1–15. doi:10.1002/biof.5520310101
192. Hoang BX, Shaw G, Fang W, Han B. Possible application of high-dose vitamin C in the prevention and therapy of coronavirus infection. J Glob Antimicrob Resist. 2020;23:256–262. doi:10.1016/j.jgar.2020.09.025
193. Wintergerst ES, Maggini S, Hornig DH. Immune-enhancing role of Vitamin C and zinc and effect on clinical conditions. Ann Nutr Metab. 2006;50(2):85–94. doi:10.1159/000090495
194. Patel V, Dial K, Wu J, et al. Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1. Int J Mol Sci. 2020;21:3. doi:10.3390/ijms21030977
195. Chen L, Hu C, Hood M, et al. A Novel Combination of Vitamin C, Curcumin and Glycyrrhizic Acid Potentially Regulates Immune and Inflammatory Response Associated with Coronavirus Infections: a Perspective from System Biology Analysis. Nutrients. 2020;12:4. doi:10.3390/nu12041193
196. Stipp M. SARS-CoV-2: micronutrient Optimization in Supporting Host Immunocompetence. Int J Clin Case Reports Rev. 2020;2(2):1–10. doi:10.31579/2690-4861/024
197. Rizzo JA, Rowan MP, Driscoll IR, Chung KK, Friedman BC. Vitamin C in Burn Resuscitation. Crit Care Clin. 2016;32(4):539–546. doi:10.1016/j.ccc.2016.06.003
198. Fowler Iii AA, Kim C, Lepler L, et al. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome. World J Crit Care Med. 2017;6(1):85–90. doi:10.5492/wjccm.v6.i1.85
199. Thomas S, Patel D, Bittel B, et al. Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: the COVID A to Z Randomized Clinical Trial. JAMA Netw open. 2021;4(2):e210369–e210369. doi:10.1001/jamanetworkopen.2021.0369
200. Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intensive Care. 2021;11(1):5. doi:10.1186/s13613-020-00792-3
201. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. doi:10.1186/1479-5876-12-32
202. Zorofchian Moghadamtousi S, Abdul Kadir H, Hassandarvish P, Tajik H, Abubakar S, Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int. 2014;2014:53. doi:10.1155/2014/186864
203. Zahedipour F, Hosseini SA, Sathyapalan T, et al. Potential effects of curcumin in the treatment of COVID-19 infection. Phyther Res. 2020;34(11):2911–2920. doi:10.1002/ptr.6738
204. Chen T-Y, Chen D-Y, Wen H-W, et al. Inhibition of Enveloped Viruses Infectivity by Curcumin. PLoS One. 2013;8(5):1–11. doi:10.1371/journal.pone.0062482
205. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271–280.e8. doi:10.1016/j.cell.2020.02.052
206. Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. VirusDisease. 2020;31(2):179–193. doi:10.1007/s13337-020-00598-8
207. Hirano T, Murakami M. COVID-19: a New Virus, but a Familiar Receptor and Cytokine Release Syndrome. Immunity. 2020;52(5):731–733. doi:10.1016/j.immuni.2020.04.003
208. Jia HP, Look DC, Shi L, et al. ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia. J Virol. 2005;79(23):14614–14621. doi:10.1128/jvi.79.23.14614-14621.2005
209. Mathew D, Hsu W-L. Antiviral potential of curcumin. J Funct Foods. 2018;40:692–699. doi:10.1016/j.jff.2017.12.017
210. Ting D, Dong N, Fang L, et al. Multisite Inhibitors for Enteric Coronavirus: antiviral Cationic Carbon Dots Based on Curcumin. ACS Appl Nano Mater. 2018;1(10):5451–5459. doi:10.1021/acsanm.8b00779
211. Soni VK, Mehta A, Ratre YK, et al. Curcumin, a traditional spice component, can hold the promise against COVID-19? Eur J Pharmacol. 2020;886:173551. doi:10.1016/j.ejphar.2020.173551
212. Sordillo PP, Helson L. Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections. Vivo (Brooklyn). 2015;29(1):1–4.
213. Iwatani S, Yamamoto N. Functional food products in Japan: a review. Food Sci Hum Wellness. 2019;8(2):96–101. doi:10.1016/j.fshw.2019.03.011
214. Regulation EC. No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Off J Eur Union. 2007;50:3–18.
215. Hasler CM, Bloch AS, Thomson CA, Enrione E, Manning C. Position of the American Dietetic Association: functional foods. J Am Diet Assoc. 2004;104(5):814–826.
216. Bagchi D. Nutraceuticals and functional foods regulations in the United States and around the world. Toxicology. 2006;221(1):1–3. doi:10.1016/j.tox.2006.01.001
217. Henry CJ. Functional foods. Eur J Clin Nutr. 2010;64(7):657–659. doi:10.1038/ejcn.2010.101
218. Martirosyan DM, Singh J. A new definition of functional food by FFC: what makes a new definition unique? Funct Foods Heal Dis. 2015;5(6):209–223.
219. Hu N, Li Q-B, Zou S-Y. Effect of vitamin A as an adjuvant therapy for pneumonia in children: a Meta analysis. Zhongguo Dang Dai Er Ke Za Zhi. 2018;20(2):146–153. doi:10.7499/j.issn.1008-8830.2018.02.013
220. Imdad A, Mayo-Wilson E, Herzer K, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev. 2017;3(3):CD008524–CD008524. doi:10.1002/14651858.CD008524.pub3
221. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013;1:45.
222. Hemilä H, Louhiala P. Vitamin C for preventing and treating pneumonia. Cochrane Database Syst Rev. 2013;8:53.
223. Bergman P, Åu L, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013;8(6):e65835.
224. Zhou Y-F, Luo B-A, Qin -L-L. The association between vitamin D deficiency and community-acquired pneumonia: a meta-analysis of observational studies. Medicine (Baltimore). 2019;98:38.
225. Lee GY, Han SN. The role of vitamin E in immunity. Nutrients. 2018;10(11):1614.
226. Mao S, Zhang A, Huang S. Meta-analysis of Zn, Cu and Fe in the hair of Chinese children with recurrent respiratory tract infection. Scand J Clin Lab Invest. 2014;74(7):561–567. doi:10.3109/00365513.2014.921323
227. Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. Cmaj. 2012;184(10):E551–E561.
228. Hemilä H. Zinc lozenges and the common cold: a meta-analysis comparing zinc acetate and zinc gluconate, and the role of zinc dosage. JRSM Open. 2017;8(5):2054270417694291.
229. Wu W, Li R, Li X, et al. Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry. Viruses. 2016;8(1):6.
230. Li Y, Yao J, Han C, et al. Quercetin, inflammation and immunity. Nutrients. 2016;8(3):167.
231. Ali A, Banerjea AC. Curcumin inhibits HIV-1 by promoting Tat protein degradation. Sci Rep. 2016;6(1):1–9.
232. Colpitts CC, Schang LM, Rachmawati H, et al. Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Gut. 2014;63(7):1137–1149.
233. Kaihatsu K, Yamabe M, Ebara Y. Antiviral mechanism of action of epigallocatechin-3-O-gallate and its fatty acid esters. Molecules. 2018;23(10):2475.
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