Functional foods and immune system: A sustainable inhibitory approach against SARS-COV-2

Abstract

Background: COVID-19 has become the center of attention since its outbreak in December 2019. Despite the discovery of its preventive vaccine, role of healthy immune system is undebatable. Functional foods are continuously hunted as a promising option for a safe natural therapeutic treatment.

Purpose: This review demonstrates how functional foods can boost host immune system, promote antiviral operation, and synthesize biologically effective molecules against SARS-COV-2.

Research Methodology: For current review, online search was conducted for nature-based functional immune boosters against SARS-COV-2.

Conclusion: Functional foods, alongside a healthy lifestyle, fortifies the human immune system and could all help to dramatically lower the cost burden of COVID-19, the suffering of the patients, and the mortality rates worldwide.

Keywords

COVID-19 immunity booster functional nutrients healthy lifestyle minerals public health vitamins

Introduction

Coronavirus was first originated in the city of Wuhan, China causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV2).^1,2 A significant risk to public health has been posed by COVID-19 leading to global lockdown. The term “corona,” which originated from the Latin word for “crown,” refers to the viral particle’s crown-like configuration.³ Therefore, well-balanced diet is prerequisite for strong immune response against infections. Nutrition has a huge impact in maintaining human fitness leading towards prevention as well as control of infections.⁴ Various functional foods have immune-boosting properties which is crucial in the modulation of immunological function.⁵ Flavonoids, polyphenols, terpenoids, sterols, alkaloids, unsaturated fats, minerals, as well as vitamins contribute significantly in building immune system.⁶ For this reason, in early COVID-19 wave elderly and immune-compromised people were hit the most.⁷ An individual’s dietary status has a significant impact on the severity of SARS-CoV-2 infection. Consequently, vitamin and mineral supplements are beneficial for both treatment and preventive purposes.⁸ They play significant role to reduce the levels of Reactive Oxygen Species (ROS) and function as powerful antioxidants along with cellular stress. Minerals themselves have an immune-protective effect due to their ability to induce autophagy, cytokine synthesis, antiviral function, and boost the efficacy of antiviral drugs.⁹ Keeping in view the importance of health, this review article describes functional food immunity boosters.

Methodology

The information on the role of functional food components in the COVID-19 pandemic was acquired by searching several online databases such as PubMed, Web of Science, and Google Scholar using the search terms Immune-Booster, diet, Functional Nutrients, lifestyle, COVID-19 causes, and treatment. Some data was also acquired through examining the websites of various government as well as international agencies, such as the World Health Organization and the Central Intelligence Agency. Articles featured were based on the beneficial effects of several dietary elements, as well as those including accounts of the COVID-19 pandemic. All of the studies found via the comprehensive search were assessed by title or abstract before being subjected to a full-text review. Titles and abstracts were screened from an informational database search. The entire texts of all publications deemed potentially relevant were subsequently reviewed.

Results

Behavior of coronavirus

Coronaviruses are members of the Coronaviridae family. The coronavirus subfamily orthocoronavirinae belongs to the order nidovirales.¹ Orthocoronavirinae are categorized into four genera: Alpha coronavirus (-CoV), Delta coronavirus (-CoV), Gamma coronavirus (-CoV), and Beta coronavirus (-CoV).¹⁰ These four structural proteins participate in SARS-CoV-2 assembly and infection processing. The virus COVID-19 (SARS-CoV-2) is the seventh human-infecting member of the CoVs family. Common cold-like upper respiratory tract infections are motivated by four humans CoVs (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-NL63), whereas SARS-CoV and MERS-CoV is the reason for causing atypical pneumonia in humans.¹ Under the 2-D transmission electron microscopy, coronaviruses appeared as enveloped, non-segmented, single-stranded ribonucleic acid (ssRNA) with club-shaped protein (spikes).^11,12 The coronavirus particles spread through the respiratory tract.⁹ There is rapid replication of virus after entering into alveolar epithelial cells which elicits cytokine storm syndromes as well as pulmonary tissue destruction. Hypercytokinaemia is another term for cytokine storm syndrome. It is characterized by unregulated synthesis of pro-inflammatory cytokines in a variety of organs, such as the heart, lungs, gut and blood vessels.^13,14 In order for symptoms to manifest, an incubation period of 2–14 days is required. The utmost typical signs are a fatigue, dry cough along with fever. Losses of flavor and odor, headache, persistent cough, diarrhea, discomfort as well as pains are the less frequent symptoms. Breathing difficulties accompanied by loss of speech as well as movement after facing chest pain or pressure, are symptoms in critical condition. Out of total cases, 80% had mild symptoms while 15% had moderate and 5% required ventilation.^15–17

Immunity booster functional foods

According to Functional Food Center (FFC), “functional food” is defined as processed or natural foods that contain unknown or known biologically active compounds. Foods that are specified, efficient, and present in non-toxic proportions provide clinically established recorded data regarding health benefits for the management, or cure of chronic disease.¹⁸ The term “functional food” was firstly defined as food that despite nutrient supply, gastronomic pleasure and energy, has many other functions.¹⁹ The various functional food has the potential to provide immunomodulatory and antiviral properties, such as black pepper, ginger, garlic, turmeric, licorice, elderberry, and pomegranate.²⁰ According to studies, polyphenols are capable to regulate immune cells, reducing pro-inflammatory gene expression, and inhibiting cytokine generation.²¹ The probiotics, prebiotics, and ayurvedic products booster our body’s immunological defenses by reducing the body’s level of stress as well as keeping the gut fit through preserving microflora as well as bacterial colonies.^19,22

Role of food ingredients in supporting human immune system to fight against COVID-19

Functions of immune system can be sustained and regulated by using different nutraceuticals. Nutraceuticals are present in a variety of functional foods and supplementation.^23,24 For human nutrition and health, fruits and vegetables play a significant role due to abundance of functional compounds fibers.²⁵ Bioactive extracts from fruits as well as their byproducts might be utilized to create novel products with favorable pharmacological effects that can promote and enhance wellbeing.²⁶

Vitamins

In the vitamin category, vitamins A, B, C, D, and E are the most operative on the immune system and have an essential capability in the treatment of numerous viral diseases, like COVID-19.^27,28 Natural food sources of immune-promoting vitamins and their key mechanism to fight against COVID-19 are represented in Table 1.

Table 1.

Immune promoting vitamins: natural food sources and their mode of action.

Vitamin	Natural food sources	Key mechanism of actions	References
A	Orange, carrots, potatoes, broccoli, pumpkin, squash, kale, oily fish, liver, eggs, papaya, peaches, mango, tomato juice, spinach, milk, and cheese	• Aids in the T lymphocyte proliferation	^29,30
		• Participates in the treatment and control of respiratory infections
		• Involves in the differentiation as well as synthesis of T lymphocytes, results in resistance to infection
B6	Whole grain cereals, sunflower seeds, garlic, cloves, walnut, oyster mushroom, fish, eggs, fortified cereals, fruits, tofu, soya beans, sugarcane, and pistachio nut	• Participates in the formation of antibodies and cytokines	^31,32
		• Improves differentiation, proliferation, and maturation of T lymphocytes
		• Aids in the control of inflammatory response
		• Promotes activity of NK cells
B9	Green leafy vegetables for instance broccoli, sprouts, chickpeas brussels, peas, and fortified cereals	• Involves in the expansion of T lymphocytes	³³
B9		• Participates in the maintenance of innate immunity	³³
B12	Meat, fish, shellfish, milk, yeast extract, eggs, cheese, and fortified breakfast cereals	• Participates in antibodies production and its metabolism	^32,34
		• Involves in T lymphocytes production
		• Maintains NK cells functions
		• Works as immunomodulator
C	Kiwi, broccoli, potatoes, cherry, oranges, lemon, red and green peppers	• Involves in the modulation of inflammatory cytokines	^35–37
		• Participates in the prevention and management of respiratory infection
		• It promotes antibody production, replication, and specificity
		• Involves in the improvement of motility and phagocyte chemotaxis
		• Participates in positive regulation of the aging phase
		• Involves in the modulation of the inflammatory pathways in a positive manner
		• Participates in the reduction of pathogens bacteria, viruses, and other pathogens (parasites and fungi)
D	Eggs, oily fish, fortified foods, liver, and some breakfast cereals	• Plays a key role in mechanisms of pathogen elimination	³⁸
		• Involves in antibacterial protein synthesis
		• Promotes the division of monocytes into macrophages
		• Involves in the inhibition of viral replication
		• Stimulates innate immune response in bronchial epithelial cells
E	Seeds, nuts, wheat germ, and vegetable oils	• Have anti-inflammatory functions (against pneumonia and colds)	^39,40
		• Enhances NK cell activity
		• Involves in membrane anti-oxidant protection
		• Improves lymphocyte protection

Vitamin A

Vitamin A can act against inflammations and it has a significant impact in intensifying immune performance. It plays various principal functions in the human body such as mucus integrity, vision maintenance, and epithelium prevention.^5,41 The 9-cis retinoic acid metabolite of vitamin A is essential for the appropriate activity of B lymphocytes, particularly antibody production as well as lymphocyte survival and proliferation. Vitamin A supplements given to kids under the age of 5 can minimize the risks of having infections.⁴²

Vitamin B

Vitamin B serves as a key function in helping appropriate commencement of natural as well as adaptive immune retaliations. It minimizes the proportions of pro-inflammatory cytokines, enhances the intention of respiratory system, maintains endothelial rectitude, and forbids hypercoagulability, which can reduce hospitalization time for people suffering from viral diseases. Considering the advantages indicated earlier, vitamin B levels in COVID-19 patients should be monitored, plus it can also be employed as a non-pharmaceutical alternative to present therapies.^43,44 Vitamin B1 is recognized to have an impact on the oxidative effect, suppression of oxidative intensity and concerned in the modulation of natural killer cells of immune system.⁴⁵

Vitamin B₆ is considered an important factor for balancing lymphoid tissues and their immunological functions, that is, reactions mediated by cells and antibodies.⁴⁶ During COVID-19 infection, the functional state of vitamin B₆ “Pyridoxal 52-phosphate” helped in the control of cytokine storm and inflammation caused due to ejection of pro-inflammatory cytokines along with excessive T cell response.⁴⁷ Vitamin B₉ (folate) contributes an important function in synthesis of nucleic acid as well as the typical cellular function with potential pathogenic consequences.⁴⁸

Vitamin B₁₂ and its functional constituents hydroxo-, adenosyl- along with methylcobalamin have many vital roles in the body of humans which counts red blood cell synthesis, cellular growth, nervous system health, quick amalgamation of DNA, myelin synthesis.⁴³ The previous study has reported that vitamin B₁₂ therapy can minimize the oxidative intensity and organ damage with the support of methylcobalamin supplements.⁴⁹

Vitamin C

Vitamin C has many pharmacological qualities such as antiviral, antioxidant, and anti-inflammatory. Its immunomodulatory effects on relocation of white blood cells to infection area, phagocytosis, activity of natural killer cell, T lymphocyte along with the formulation of antibodies.^42,50 About 200 mg of vitamin C can be easily obtained by combining several foods like cooked cabbage and cauliflower, strawberries, grapefruit, oranges, green peppers, and red pepper.⁵¹ A single case-report from China described a 34 years old healthy young male patient without any comorbidities during the fight with COVID-19-associated symptoms (fatigue, poor appetite, dry cough, and subjective fever) who had received 3 g dose of vitamin C once on daily basis along with antiviral and antimicrobial treatments.⁵²

Vitamin E

Vitamin E is a powerful antioxidant as well as a key critical nutriment for immune system stability, particularly within aged individuals.⁵³ It is a vital component for natural killer cells and interleukins production, which contribute considerably to acceleration of white blood cells as well as to the induction of a potent immune response facing infections.^54,55

Vitamin D

1, 25-dihydroxy Vit D₃ (1,25(OH)₂D₃ is the dynamic variety of vitamin D that contributes in bone genesis by maintaining the phosphorus as well as calcium metabolisms. It also induces immunomodulation by influencing monocytes, dendritic cells, macrophages, T-cells, as well as B-cells, which have a significant impact on innate as well as adaptive immune responses.^56,57

Minerals

Several numbers of trace elements iron, selenium, zinc, and copper are essential for appropriate immune system function and play critical roles in biological operations including cell proliferation, oxygen transportation, oxidative stress protection as well as cell differentiation while their insufficiency can disrupt cellular activity for instance natural killer cells, antibody response, and cell-mediated immunity.⁵ Functional immune-promoting mineral food sources and their impact on the respiratory system are shown in Table 2.

Table 2.

Immune boosting minerals: natural sources and their impact on respiratory system.

Mineral	Food sources	The key mechanism of action	References
Zinc	Meat, shellfish, cheese, seeds, grains, cereals, and wholegrain bread	• Deficiency of zinc leads to a reduction in innate immunity	^58,59
		• It acts as central part during immune cell differentiation as well as maturation
		• Boosts up the production of NK cells
		• Involves in regulation of inflammatory cytokine
		• Participates in anti-inflammatory pathways
Selenium	Shellfish, fish, eggs, meat, nuts like Brazil nuts	• Necessary for the action of selenoproteins, which is crucial for the host’s anti-oxidant resistance	⁶⁰
Iron	Meat, liver, nuts, beans, fortified cereals, dried fruit, and dark green leafy vegetables (kale, spinach), and whole grains	• Iron is required for the development and accomplishment of inflammatory cytokines	^33,61
		• Helps to control generation of reactive oxygen species (ROS) that infects immune organization
		• It is concerned in the management for cytotoxic T cells as well as helper T cells
Copper	Shellfish, nuts, liver, and some vegetables	• Specifically engaged during protection against reactive oxygen species (ROS) via making association with superoxide dismutase (SOD) enzyme	^5,32,34,62
		• It maintains intracellular anti-oxidant balance by working as a free radical scavenger
		• It has participated in T cell differentiation as well as proliferation, antibody formation, plus cellular immunity in the animal study
Magnesium	Whole grains, dark chocolate, avocados, and black beans	• Involves in the modulation of NK cells • Maintains the reliability of lymphocytes	^63,64

Zinc

Zinc is considered an adjunct therapeutic agent for COVID-19 patients because of its immunological response and antiviral properties. In COVID-19 patients, zinc supplementation possesses the capability to lessen the seriousness of this illness.⁶⁵ It functions as a cofactor for thymulin, and that controls cytokine secretion as well as promotes propagation.^57,66

Iron

In hemoglobin, iron is the component of heme protein and it is responsible for providing oxygen to tissues in the human body. As a component of cytochromes, it is essential for the transit of mitochondrial electrons and has broad-spectrum effects such as impairing respiratory burst, killing germs, T-cell proliferation, and cytokine production.^67,68 Because of the positive benefits of iron chelation therapy on the inflammatory processes, it might be assessed during inappropriate scenario of critically sick individuals having COVID-19 to enhance survival and overall long-term outcome.⁶⁹ For preparing nano-particles in nanotechnology, ferrous/ferric oxide acts as an inert material and these nanoparticles are frequently used for developing personal protective equipment (PPE) diagnostic tests and manufacturing effective vaccinations or antiviral medications for worldwide war facing COVID-19.^70,71

Selenium

Selenium is essential micronutrients that involves in up-regulation of IL-2 receptors and boosting up the immune system by B lymphocytes to promote antibody production and enhance the production of antibody by increasing cytotoxicity of killer cells.⁵⁷ Selenium seems needed for productive as well as systematic operations of immune association. It improves cytotoxic effector cells’ efficiency, plus plays a vital part in maturation as well as function of T cell and T cell-dependent development of antibodies.⁷² Selenium is use against the recent COVID-19 battle reported by previous study.⁷³ There is connection between deficiency of selenium and mortality due to COVID-19. It is also essential for recuperation for illness.^60,74

Copper

Copper bears micronutrient that is required for B cells, helper T cells, natural killer (NK) cells, neutrophils as well as macrophages to operate properly.⁷⁵ The transmission and replication of SARS-CoV2, influenza as well as additional respiratory viruses are inhibited by copper, which helps to diminish the transmission of several infectious diseases. The copper oxide may be used in the preparation of nano-based face masks, filters, clothing, etc.⁷⁶

Magnesium

Magnesium, as an electrolyte, helps our bodies increase their natural killer cells and lymphocytes. It also serves as an important source of energy for adenosine triphosphate (ATP). Magnesium also supports the hemoglobin in our blood. Whole grains, avocados, dark chocolate, and black beans are among the foods high in magnesium.^62,64

Phenolic compounds

Phenolic compounds are recognized as dietary secondary metabolites which are commonly found in vegetables, fruits, seeds, flowers, food grains, tea, honey, wine as well as forage.⁷⁷ The exclusive antioxidant action of plants is linked with phenolic compounds.⁷⁸ Conventionally, consequential folk medication from polyphenol-rich plants are utilized to treat diseases of the bloodstream including stomach disorders, systolic, antiviral consequences, direct-acting mutagens, as well as burns dressing. They are also effective against various viruses such as hepadnavirus, influenza virus, retrovirus, herpesvirus, HIV, dengue virus, herpes simplex virus, poliovirus, and so on.⁷⁹ Phenol and polyphenolic-rich plants are most effective against COVID-19.^80–83 The consumption of polyphenols can ameliorate the physiological activities influenced by COVID-19 as indicated in Figure 1.

Figure 1.

COVID-19 and related diseases disrupt physiological activities, which can be ameliorated with polyphenols consumption.⁸⁴

Polyphenols can have the ability to counteract the detrimental excitability of unwanted or excessive reactive oxygen and nitrogen species (ROS and RNS) produced by an organism’s metabolic activities.⁸⁵ Furthermore, polyphenols have anti-arthritic, pro-apoptotic, anti-proliferative, hormonal modulation as well as prebiotic characteristics.^86,87 Versatile diet resources for immune-encouraging phenolic compounds as well as their methods for accomplishment against COVID-19 are represented in Table 3.

Table 3.

Food sources of natural phenolic compounds and their mode of action.

Bioactive compounds	Natural food sources	Key mechanism of action	References
Polyphenols	Tomato, berries, pumpkin, spinach, broccoli, orange, pomegranate, aonla, apricots, papaya, peaches, mango, and apple	• Prevent and control inflammation by mitigating inflammatory response to macrophages and adipocytes	^88–91
Quercetin	Brassica vegetables, onions, grapes, apples, berries, tomatoes, and tea	• Involves in pro-metabolic and anti-inflammatory pathways	⁹²
		• Have antiviral properties
Anthocyanins	Berries and pomegranate	• Act as an anti-oxidant, anti-inflammatory, antiplatelet and anti-carcinogenic	⁹³
		• Involves in cardio protection
Resveratrol	Berries, mulberry, peanuts, and grapes	• Play a great role in inhibition of viral RNA replication	⁸⁵
		• Involves in cell death reduction and inhibition of apoptosis
Catechins(−)-epigallocate- chin-3-gallate (EGCG)	Grape seeds, kiwi, strawberries, red wine, gooseberries, apples, blue berries, and herbal tea	• Enveloped DNA, (−) –RNA as well as (−) -RNA viruses may be inhibited by natural catechins, nevertheless, by blocking in vitro as well as in vivo reverse transcriptase function, EGCG has shown high potential for preventing the early phases of infection, consist of binding, post-adsorption penetration, as well as genomic replication through the disruption of viral protein complexes and biological processes	^94,95
Curcumin	Turmeric	• Function as an immunomodulator	⁹⁶
		• Involves in the modulation of dendritic cells
		• Have anti-inflammatory properties

Conclusion

The body’s immune system plays a central role in our survival and fights against a huge number of pathogens and antigens. Therefore, enhancing the immune system’s ability is highly beneficial in preventing many health disorders. COVID-19 held the world with an inevitable threat to humans to rethink about maintenance of healthy immune system. Therefore, maintaining a nutritious diet having natural bioactive compounds has become vital for protection against viral invasion.

Footnotes

Author contributions

HRK and RS designed the study and retrieved the data as well as write the first draft. MJ assisted in the write up, HY edited and supervised while IA and SJ critically read and finalized the draft.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Humaira Yasmeen

References

Liu

, et al. 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.

El-Mageed

HRA

Abdelrheem

Ahmed

, et al. Combination and tricombination therapy to destabilize the structural integrity of COVID-19 by some bioactive compounds with antiviral drugs: insights from molecular docking study. Struct Chem 2021; 32: 1415–1430. DOI: 10.1007/s11224-020-01723-5.

Lei

Jiang

, et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID19 infection. EClinicalMedicine 2020; 21: 100331. DOI: 10.1016/j.eclinm.2020.100331.

de Faria Coelho-Ravagnani

Corgosinho

Sanches

FLFZ

, et al. Dietary recommendations during the COVID-19 pandemic. Nutr Rev 2020; 79(4): 382–393. DOI: 10.1093/nutrit/nuaa067.

Thakur

Joshi

Thakur

. Immunology and its relation with food components: an overview. Int J Food Ferment Technol 2019; 9(1): 1–16. DOI: 10.30954/2277-9396.01.2019.3.

Alkhatib

. Antiviral functional foods and exercise lifestyle prevention of Coronavirus. Nutrients 2020; 12(9): 2633. DOI: 10.3390/nu12092633.

Hyams

Challen

Begier

, et al. Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: a prospective cohort study. Lancet Reg Health Eur 2022; 21: 100473.

Farzana

Shahriar

Jeba

, et al. Functional food: complementary to fight against COVID-19. Beni Suef Univ J Basic Appl Sci 2022; 11(1): 33.

Banerjee

Somasundaram

Das

, et al. Functional foods: a promising strategy for restoring gut microbiota diversity impacted by SARS-CoV-2 variants. Nutrients 2023; 15(11): 2631.

10.

Ahmed

Abdelrheem

El-Mageed

HRA

, et al. Destabilizing the structural integrity of COVID-19 by caulerpin and its derivatives along with some antiviral drugs: an in silico approaches for a combination therapy. Struct Chem 2020; 31: 2391. DOI: 10.1007/s11224-020-01586-w.

11.

Fehr

Perlman

. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 2015; 1282: 1–23. DOI: 10.1007/978-1-4939-2438-71.

12.

Singh

Tripathi

Yasir

, et al. Potential inhibitors for SARS-CoV-2 and functional food components as nutritional supplement for COVID-19: a review. Plant Foods Hum Nutr 2020; 75: 458–466. DOI: 10.1007/s11130-020-00861-9.

13.

Seyed Hosseini

Riahi Kashani

Nikzad

, et al. The novel coronavirus Disease-2019 (COVID-19): mechanism of action, detection and recent therapeutic strategies. Virology 2020; 551: 1–9. DOI: 10.1016/j.virol.2020.08.011.

14.

Rasmi

Hatamkhani

Naderi

, et al. Molecular signaling pathways, pathophysiological features in various organs, and treatment strategies in SARS-CoV2 infection. Acta Histochem 2022; 124: 151908.

15.

Ailioaie

Litscher

. Implications of SARS-CoV-2 infection in systemic juvenile idiopathic arthritis. Int J Mol Sci 2022; 23(8): 4268.

16.

Chilkoti

Mohta

Ahmad

, et al. Awake prone-positioning in patients on non-invasive ventilation for management of SARS-CoV-2 pneumonia: a systematic review. Adv Respir Med 2022; 90(4): 362–375.

17.

Mohapatra

Kumar

Farooq

, et al. COVID 19 pandemic challenges and their management: a review of medicines, vaccines, patents and clinical trials with emphasis on psychological health issues. Saudi Pharm J 2022.

18.

Kulkarni

Nair

Kadam

, et al. Probable treatment options for Covid-19: a brief review. IP International Journal of Comprehensive and Advanced Pharmacology 2022; 7(1): 17–26.

19.

Baker

Parrella

, et al. Consumer acceptance toward functional foods: a scoping review. Int J Environ Res Publ Health 2022; 19(3): 1217.

20.

Moscatelli

Sessa

Valenzano

, et al. COVID-19: role of nutrition and supplementation. Nutrients 2021; 13(3): 976.

21.

Yang

Zhang

Tariq

, et al. Food as medicine: a possible preventive measure against coronavirus disease (COVID-19). Phytother Res 2020; 34: 3124–3136. DOI: 10.1002/ptr.6770.

22.

Yahfoufi

Alsadi

Jambi

, et al. The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients 2018; 10: 1618. DOI: 10.3390/nu10111618.

23.

Singh

. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr 2020; 87(4): 281–286.

24.

Damián

Cortes-Perez

Quintana

, et al. Functional foods, nutraceuticals and probiotics: a focus on human health. Microorganisms 2022; 10(5): 1065.

25.

Pahwa

Sharan

. Food and nutrition as modifiers of the immune system: a mechanistic overview. Trends Food Sci Technol 2022; 123: 393.

26.

Khalid

Arshad

Jabeen

, et al. Fiber‐enriched botanicals: a therapeutic tool against certain metabolic ailments. Food Sci Nutr 2022; 10: 3203.

27.

Hamid

Thakur

, et al. Pomegranate and its wild genotypes: nutraceutical opportunities and challenges. Ann Phytomed 2020; 9(1): 32–43. DOI: 10.21276/ap.2020.9.1.5.

28.

Alkhatib

Tuomilehto

. Lifestyle diabetes prevention. In: Huhtaniemi

Martini

(eds) Encyclopaedia of endocrine diseases. Amsterdam, The Netherlands: Elsevier, 2019, pp. 148–159.

29.

Dehghani-Samani

Kamali

Hoseinzadeh-Chahkandak

. The role of vitamins on the prevention and/or treatment of COVID-19 infection: a systematic review. Model Care J 2020; 17(3): 104740. DOI: 10.5812/modernc.104740.

30.

Mahalanabis

Lahiri

Paul

, et al. Randomized, double-blind, placebocontrolled clinical trial of the efficacy of treatment with zinc or vitamin A in infants and young children with severe acute lower respiratory infection. Am J Clin Nutr 2004; 79(3): 430–436. DOI: 10.1093/ajcn/79.3.430.

31.

Tanumihardjo

Russell

Stephensen

, et al. Biomarkers of nutrition for development (BOND)-vitamin A review. J Nutr 2016; 146(9): 1816S–1848. DOI: 10.3945/jn.115.229708.

32.

Meydani

Ribaya-Mercado

Russell

, et al. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults. Am J Clin Nutr 1991; 53(5): 1275–1280. DOI: 10.1093/ajcn/53.5.1275.

33.

Saeed

FNM

Nadeem

Ahmed

, et al. Studying the impact of nutritional immunology underlying the modulation of immune responses by nutritional compounds: a review. Food Agric Immunol 2016; 27: 205–229. DOI: 10.1080/09540105.2015.1079600.

34.

Budi

HTS

Wintergerst

Maggini

. Multivitamin supplementation supports immune function and ameliorates conditions triggered by reduced air quality. Vitamins and Minerals 2015; 4(2): 1–15.

35.

Maggini

SBS

Sorbara

Senatore

. Feeding the immune system: the role of micronutrients in restoring resistance to infections. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources 2018; 3: 1–21.

36.

Carr

Maggini

. Vitamin C and immune function. Nutrients 2017; 9(11): 1211. DOI: 10.3390/nu9111211.

37.

Monacelli

Acquarone

Giannotti

, et al. Vitamin C, aging and Alzheimer’s disease. Nutrients 2017; 9: 670. DOI: 10.3390/nu9070670.

38.

Mousavi

Bereswill

Heimesaat

. Immunomodulatory and antimicrobial effects of vitamin C. Eur J Microbiol Immunol 2019; 9(3): 73–79. DOI: 10.1556/1886.2019.00016.

39.

Medrano

Carrillo-Cruz

Montero

, et al. Vitamin D: effect on haematopoiesis and immune system and clinical applications. Int J Mol Sci 2018; 19: 2663. DOI: 10.3390/ijms19092663.

40.

Hemila

. Vitamin E administration may decrease the incidence of pneumonia in elderly males. Clin Interv Aging 2016; 11: 1379–1385. DOI: 10.2147/CIA.S114515.

41.

Lee

Han

. The role of vitamin E in immunity. Nutrients 2018; 10(11): 1614. DOI: 10.3390/nu10111614.

42.

Huang

Liu

, et al. Role of vitamin A in the immune system. J Clin Med 2018; 7(9): 258.

43.

Calder

Carr

Gombart

, et al. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients 2020; 12: 1181.

44.

Fath

Naderi

Hamzavi

, et al. Molecular Mechanisms and therapeutic effects of different vitamins and minerals in COVID-19 patients. J Trace Elem Med Biol 2022; 73: 127044.

45.

Pisoschi

Pop

Iordache

, et al. Antioxidant, anti-inflammatory and immunomodulatory roles of vitamins in COVID-19 therapy. Eur J Med Chem 2022; 232: 114175.

46.

Mikkelsen

Stojanovska

Prakash

, et al. The effects of vitamin B on the immune/cytokine network and their involvement in depression. Maturitas 2017; 96: 58–71. DOI: 10.1016/j.maturitas.2016.11.012.

47.

Chandra

Sudhakaran

. Regulation of immune responses by vitamin B6. Ann N Y Acad Sci 1990; 585: 404–423. DOI: 10.1111/j.1749-6632.1990.tb28073.x.

48.

Shakoor

Feehan

Mikkelsen

, et al. Be well: a potential role for vitamin B in COVID-19. Maturitas 2021; 144: 108–111. DOI: 10.1016/j.maturitas.2020.08.007.

49.

Meisel

Efros

Bleier

, et al. Folate levels in patients hospitalized with coronavirus disease 2019. Nutrients 2021; 13: 812. DOI: 10.3390/nu13030812.

50.

Santos

LMJD

. Can vitamin B12 be an adjuvant to COVID-19 treatment? GSC Biological and Pharmaceutical Sciences 2020; 11(3): 1–5.

51.

Abobaker

Alzwi

Alraied

AHA

. Overview of the possible role of vitamin C in management of COVID-19. Pharmacol Rep 2020; 72: 1517–1528.

52.

Milani

Macchi

Guz-Mark

. Vitamin C in the treatment of COVID-19. Nutrients 2021; 13(4): 1172.

53.

Anywar

Kakudidi

Byamukama

, et al. Indigenous traditional knowledge of medicinal plants used by herbalists in treating opportunistic infections among people living with HIV/AIDS in Uganda. J Ethnopharmacol 2020; 246: 112205–112213.

54.

Moriguchi

Muraga

. Vitamin E and immunity. Vitam Horm 2000; 59: 305–336.

55.

Gombart

Pierre

Maggini

. A review of micronutrients and the immune system working in harmony to reduce the risk of infection. Nutrients 2020; 12: 236.

56.

Junaid

Ejaz

Abdalla

, et al. Effective immune functions of micronutrients against SARS-CoV-2. Nutrients 2020; 12(10): 2992.

57.

Berretta

Quagliariello

Bignucolo

, et al. The multiple effects of vitamin D against chronic diseases: from reduction of lipid peroxidation to updated evidence from clinical studies. Antioxidants 2022; 11(6): 1090.

58.

Mitra

Paul

Roy

, et al. Exploring the immune-boosting functions of vitamins and minerals as nutritional food bioactive compounds: a comprehensive review. Molecules 2022; 27(2): 555.

59.

Bonaventura

Benedetti

Albarede

, et al. Zinc and its role in immunity and inflammation. Autoimmun Rev 2015; 14(4): 277–285. DOI: 10.1016/j.autrev.2014.11.008.

60.

Maares

Haase

. Zinc and immunity: an essential interrelation. Arch Biochem Biophys 2016; 611: 58–65. DOI: 10.1016/j.abb.2016.03.022.

61.

Zhang

Liu

. Potential interventions for novel coronavirus in China: a systematic review. J Med Virol 2020; 92(5): 479–490.

62.

Lewis

Pae

, et al. Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance. Front Immunol 2018; 9: 3160.

63.

Prasad

. Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care 2009; 12: 646–652.

64.

Upadhyay

Dhawan

Garg

, et al. Immunomodulatory effects of neem (Azadirachta indica) oil. Int J Immunopharm 1992; 14: 1187–1193.

65.

Kuttan

. Use of Withania somnifera Dunal as an adjuvant during radiation therapy. Indian J Exp Biol 1996; 34: 854–856.

66.

Bhatt

Azmat

Subhan

, et al. Role of micronutrients (vitamins and minerals) in COVID-19. JNB (J Nutr Biochem) 2020; 6(1): 430–443.

67.

Lungu

Babarus

Oniciuc

, et al. A review of essential microelements in the immune system. Int J Immunol 2022; 10(1): 1–4.

68.

Kumar

Choudhry

. Iron deficiency and infection. Indian J Pediatr 2010; 77(7): 789–793.

69.

Dhok

Butola

Anjankar

, et al. Role of vitamins and minerals to improve immunity during COVID-19 pandemic: a review. J Evol Med Dent Sci 2020; 9(32): 2296–2300. DOI: 10.14260/jemds/2020/497.

70.

Perricone

Bartoloni

Bursi

, et al. COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy. Immunol Res 2020; 68: 213–224. DOI: 10.1007/s12026-020-09145-5.

71.

Alpert

. The role of vitamins and minerals on the immune system. Home Health Care Manag Pract 2017; 29(3): 199–202.

72.

Liu

Zhang

Nekhai

, et al. Depriving iron supply to the virus represents a promising adjuvant therapeutic against viral survival. Curr Clin Microbiol Rep 2020; 7: 1–7.

73.

Bae

Kim

. Mini-review on the roles of vitamin C, vitamin D, and selenium in the immune system against COVID-19. Molecules 2020; 25: 5346. DOI: 10.3390/molecules25225346.

74.

Kieliszek

Lipinski

. Selenium supplementation in the prevention of coronavirus infections (COVID-19). Med Hypotheses 2020; 143: 109878. DOI: 10.1016/j.mehy.2020.109878.

75.

Moghaddam

Heller

Sun

, et al. Selenium deficiency is associated with mortality risk from COVID-19. Nutrients 2020; 12: 2098. DOI: 10.3390/nu12072098.

76.

Raha

Mallick

Basak

, et al.

Is copper beneficial for COVID-19 patients?

Med Hypotheses 2020; 142: 109814. DOI: 10.1016/j.mehy.2020.109814.

77.

Cortes

Zuniga

. The use of copper to help prevent transmission of SARS-coronavirus and influenza viruses. A general review. Diagn Microbiol Infect Dis 2020; 98(4): 115176. DOI: 10.1016/j.diagmicrobio.2020.115176.

78.

Quiros-Sauceda

Palafox-Carlos

Sayago-Ayerdi

, et al. Dietary fiber and phenolic compounds as functional ingredients: interaction and possible effect after ingestion. Food Funct 2014; 5: 1063–1072.

79.

Sferrazzo

Palmeri

Restuccia

, et al. Mangifera indica L. Leaves as a potential food source of phenolic compounds with biological activity. Antioxidants 2022; 11(7): 1313.

80.

Wan-Fei

Chik

Dong-Ying

, et al. Plant phenolic compounds as potential lead compounds in functional foods for antiviral drug discovery. Curr Org Chem 2017; 21: 1847–1860.

81.

Bettuzzi

Gabba

Cataldo

. Efficacy of a polyphenolic, standardized green tea extract for the treatment of COVID-19 syndrome: a proof-of-principle study. Covid 2021; 1(1): 2–12.

82.

Chia

Kok

Chew

, et al.

Can algae contribute to the war with COVID-19?

Bioengineered 2021; 12(12): 1226–1237.

83.

Khazeei Tabari

Iranpanah

Bahramsoltani

, et al. Flavonoids as promising antiviral agents against SARS-CoV-2 infection: a mechanistic review. Molecules 2021; 26: 3900.

84.

Mehany

Khalifa

Barakat

, et al. Polyphenols as promising biologically active substances for preventing SARS-CoV-2: a review with research evidence and underlying mechanisms. Food Biosci 2021; 40: 100891.

85.

Gligorijevic

Radomirovic

Nedic

, et al. Molecular mechanisms of possible action of phenolic compounds in COVID-19 protection and prevention. Int J Mol Sci 2021; 22(22): 12385.

86.

Pérez de la Lastra

Andrés-Juan

Plou

, et al. Impact of zinc, glutathione, and polyphenols as antioxidants in the immune response against SARS-CoV-2. Processes 2021; 9: 506.

87.

Oliviero

Scanu

Zamudio-Cuevas

, et al. Anti-inflammatory effects of polyphenols in arthritis. J Sci Food Agric 2018; 98: 1653–1659.

88.

Godfrey

Kennedy

Suda

, et al. Pillars article: a developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 1993. 150: 4244-4252. J Immunol 2012; 189: 4203–4211.

89.

Hamid

TNS

Kumar

Thakur

. Development of syrup from mulberry (Morus alba L.) and its quality evaluation under ambient and refrigerated storage conditions. Int J Biodivers Sci Manag 2017; 8(1): 116–121.

90.

Islam

Sarkar

El-Kersh

, et al. Natural products and their derivatives against coronavirus: a review of the non-clinical and pre-clinical data. Phytother Res 2020; 34(10): 2471–2492. DOI: 10.1002/ptr.6700.

91.

Sayed

Khattab

AboulMagd

, et al. Nature as a treasure trove of potential anti SARS-CoV drug leads: a structural/mechanistic rationale. RSC Adv 2020; 10: 19790–19802. DOI: 10.1039/D0RA04199H.

92.

Manjunath

Thimmulappa

. Antiviral, immunomodulatory, and anticoagulant effects of quercetin and its derivatives: potential role in prevention and management of COVID-19. J Pharm Anal 2021; 12(1): 29–34.

93.

Fakhar

Faramarzi

Pacifico

, et al. Anthocyanin derivatives as potent inhibitors of SARS-CoV-2 main protease: an in-silico perspective of therapeutic targets against COVID-19 pandemic. J Biomol Struct Dyn 2021; 39(16): 6171–6183.

94.

Levy

Delvin

Marcil

, et al.

Can phytotherapy with polyphenols serve as a powerful approach for the prevention and therapy tool of novel coronavirus disease 2019 (COVID-19)?

Am J Physiol Endocrinol Metab 2020; 319: E689–708. DOI: 10.1152/ajpendo.00298.2020.

95.

Wahedi

Ahmad

Abbasi

. Stilbene-based natural compounds as promising drug candidates against COVID-19. J Biomol Struct Dyn 2020; 12: 1–10. DOI: 10.1080/07391102.2020.1762743.

96.

Gianchecchi

Fierabracci

. Insights on the effects of resveratrol and some of its derivatives in cancer and autoimmunity: a molecule with a dual activity. Antioxidants 2020; 9: 91.