Clinically proven natural products, vitamins and mineral in boosting up immunity: A comprehensive review

Abstract

Background

and Purposes: The terminology “immune boost-up” was the talk of the topic in this Covid-19 pandemic. A significant number of the people took initiative to increase the body's defense capacity through boosting up immunity worldwide. Considering this, the study was designed to explain the natural products, vitamins and mineral that were proved by clinical trail as immunity enhancer.

Methods

Information was retrieved from SciVerse Scopus ® (Elsevier Properties S. A, USA), Web of Science® (Thomson Reuters, USA), and PubMed based on immunity, nutrients, natural products in boosting up immunity, minerals and vitamins in boosting up immunity, and immune booster agents.

Result

A well-defined immune cells response provide a-well functioning defense system for the human physiological system. Cells of the immune system must require adequate stimulation so that these cells can prepare themselves competent enough to fight against any unintended onslaught. Several pharmacologically active medicinal plants and plants derived probiotics or micronutrients have played a pivotal role in enhancing the immune boost-up process. Their role has been well established from the previous study. Immune stimulating cells, especially cells of acquired immunity are closely associated with the immune-boosting up process because all the immunological reactions and mechanisms are mediated through these cells.

Conclusion

This article highlighted the mechanism of action of different natural products, vitamins and mineral in boosting up the immunity of the human body and strengthening the body's defense system. Therefore, it is recommended that until the specific immune-boosting drugs are available in pharma markets, anyone can consider the mentioned products as dietary supplements to boost up the immunity.

Highlights

• •There are a few clinically proven natural products, vitamins, and mineral as immunity-boosting agents.
• •These products can be considered as an alternative treatment option against certain types of immunologic and inflammatory diseases.
• •The Drug Design and Development authority can consider these products in developing new and relevant drugs.

1. Introduction

The immune system can be defined as a sophisticated association of varied immune cells and molecules that may provide adequate protection against infections or foreign intruders. The immune system may be categorized into two subsystems; the first is called a non-specific or innate system, and the other is called a specific or acquired system [1]. Both of the subsystems are meticulously interlinked with each other to combat inauspicious pathogens. According to Kumar H et al., the innate immune system identifies the pathogen's molecular structural pattern through pattern recognition receptors (PRRs) [2]. PRRs are receptor-type proteins that stimulate innate immune cells, e.g., epithelial cells, neutrophils, macrophages, monocytes, and dendritic cells [3,4]. The main target of PRRs is to make out both pathogen-derived pathogen-associated molecular patterns (PAMPs) and host-derived damage-associated molecular patterns (DAMPs) [5]. Natural killer cells, basophils, mast cells, eosinophils, and innate lymphoid cells are also responsible for an innate immune response [5]. Again, hematopoietic stem cell or bone marrow-derived B cells and T cells may comprise the adaptive or specific immunity [6]. The primary function of B-cells is to generate antibodies where T-cells are involved in striking force for pathogenic microorganisms. The people of the 21st century is now fighting against from non-infectious disease like cancer [[7], [8], [9]] to infectious diseases like an exterminatory COVID-19 [10,11] whose firm target is to forage the immune system. Due to the extensive mutating competency of COVID-19, it is tough to suppress the replication process of this RNA virus. The microbiota shows a major role on the induction, training and function of the host immune system. Actually, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with highly diverse microbes [1,2,6].

Moreover, the new variant name omicron can lead to severe consequences in some world regions. As a result, no appropriate vaccine or drug can block its protein synthesis pathway. Most researchers suggest that immune boost-up is the only possible solution to address the current pandemic situation as COVID-19 attacks the immune system, especially the older one greatly suffered. Mousa et al. described formulation derived from natural products, e.g., herbals, probiotics, and trace elements, which could be a fruitful approach in strengthening the immune system that may restrain viral infections [12]. The immune-stimulating role of various natural products (e.g., yoghurt, Chyawanprash, Ginseng, whey protein, and beta glucagon) and micronutrients (e.g., Zn, vitamin C, vitamin E) have been well established in previous studies, and they are still playing a crucial role in boosting up our immune system precisely [[13], [14], [15]]. One of the most promising features of the herbal drug is that it can tremendously execute the immune-stimulating response. For that reason, the herbal drug has been considered an immune boost-up agent that can easily tackle the pandemic situation through an immune-strengthening manner [16,17]. The main purpose of this study was to explain the mechanism of action of different natural products (like - yoghurt, Chyawanprash, Ginseng, whey protein, and beta glucagon), vitamins and mineral in boosting up the immunity of the human body and strengthening the body's defense system.

2. Methodology

This review has been written based on a systematic search strategy and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [18]. For searching relevant articles or databases, we studied the articles of renowned publishers like SciVerse Scopus ® (Elsevier Properties S. A, USA), Web of Science® (Thomson Reuters, USA), and PubMed® (U.S. National Library of Medicine, USA). Search items include immunity, nutrients, natural products in boosting up immunity, minerals and vitamins in boosting up immunity, and immune booster agents. A total of 300 non-duplicate articles have been identified in the initial phase. After careful scrutinization, 200 relevant articles have been selected after initial screening. Finally, after 33 exclusions, only 167 more relevant articles have been selected. Non-English articles have been kept out of search. Only clinical and relevant scientific articles were considered as inclusion criteria for this study. The relevant articles' full manuscripts, including title, abstract and concluding remarks, have been thoroughly read to verify the expedience criterion. For checking data extraction accuracy and discrepancies, a second and third author has been involved when required (Fig. 1).

Fig. 1.

Overview of the search strategy and article exclusion.

3. Natural products as immunity boosting agents

3.1. Yoghurt

The term probiotics may be coined as an enduring non-wholesome microorganism that pretends a definitive outcome on the host biological system when taken orally [19]. Due to yoghurt's unambiguous positive response, Guarner et al. [20] enumerated it as an ideal probiotic. Meydani and Ha et al. [21] cited that yoghurt is susceptible to triggering an immune response and building up resistance against the pathogens of intestinal flora. The way yoghurt boosts up the immune system is not fully understood yet; however, most researchers thought that the bacterial constituents present in the yoghurt might be responsible for this phenomenon. According to the belief of Guarner et al. [20] and Van de water et al. [22], the lactic acid present in the yoghurt plays an influential role in enhancing the immune response against various diseases causing pathogens. Further, it has been speculated that gut-related lymphoid tissue and the physiological system's immune activity may be activated in the intestinal mucosa due to the mobility of active lactic acid bacteria (LAB) constituents. The immunomodulatory response of LAB is observed when there is great intimacy between lymphoid tissue and intestinal lumen [23,24]. The cell wall of gram-positive LAB comprises mainly peptidoglycan (30–70% of the total cell wall), polysaccharide, and teichoic acid. These constituents can produce an immunostimulatory effect against intestinal pathogens [25]. Peptidoglycan, also called glycopeptides, are secreted from the cell wall of LAB by using the lysosome enzyme. This lysosome enzyme originated from the intestinal Paneth cell [24], which then stimulates to produce peptidoglycan and muramyl dipeptide (MDP). To activate the immunological function of T-lymphocytes, MDP plays a crucial role in triggering the macrophages to produce both IL-1 and IFN-γ [[26], [27], [28]]. Moreover, Tufano et al. cited that MDP releases immunomodulatory cytokines like IL-1, IL-6, TNFα by monocytes and IFN-γ and IL-4 by lymphocyte respectively [29]. Another positive result of LAB cell wall has been seen in the case of enzymatic digestion, which then aids in increasing the non-specific defense system of L. monocytogenes in mice model [30], Klebsiella infection [31], and tumor cell [32], enhance the secretion of cytokine by using peripheral blood mononuclear cells and pancreatic polypeptide cells [25]. Teichoic acid, the second most crucial constituent of the LAB cell wall, plays a significant role in the secretion of IL-1, TNFα, and IL-6 [[33], [34], [35], [36]]. The gel-like cytoplasmic space in the LAB membrane may also exaggerate the number of pancreatic polypeptide cells. It has been reported that LAB present in the yoghurt showed an inhibitory response in the gastrointestinal tract (GI) due to the existence of organic acid (lactic acid fermentation) and bacteriocin [37,38]. Yoghurt that derived from the B. longum species may generate an antibody response that was detected in the cytoplasm [25]. (Fig. 2).

Fig. 2.

Schematic presentation of yoghurt and immune cells mechanism. Lactic acid derived from yogurt comprises mainly peptidoglycan (30–70%), teichoic acid and cytoplasmic space. The immune-modulatory role of yoghurt is to increase the MDP (IL-1, IL-4, IL-6, TNF-α, and IFN-γ) level and PPP numbers.

3.2. Chyawanprash (CP)

The word Chyawanprash (CP) is derived from two lexes; the first one is “Chyawan”, which denotes degenerative changes, and the other one is “Prasha”, which represents a drug or foodstuff. CP is a well-established Ayurvedic preparation containing a mixer of medicinal herbs, plant extracts, and minerals. In 2006 Parle M. and Bansal, N. et al. [39] cited that CP had been used as an effective anti-aging agent for a long time before revealing vitamins, minerals, and antioxidants. More than 50 medicinal herbs and species have been employed after synergistic blending [40]. Due to the immune-boosting competency of CP, Sastry K et al. speculated it as a powerful immune booster, vitalizer, and a prohibitor for common viral infections and allergies [41]. One of the most spectacular properties of CP formulation is that it can resist the apparent environmental insipidus phenomenon, which may vary from season to season [39]. The immune-boosting safety profile of CP has already been seen in several preclinical and clinical studies [[42], [43], [44], [45], [46]]. Furthermore, it has been precisely reported that CP can alleviate anti-allergic reactions, enhance the activity of natural killer cells (NK) and phagocytic cells and accelerate the activity of interleukin-1-b (IL-1-b) macrophage inflammatory protein (MIP-1) [43,[47], [48], [49]]. The recommended dose concentration of CP is 20 μg/ml – 500 μg/ml, which affix the NK cell activity by 1.8–10.3 fold, TNF-α, IL- 1-β and MIP-1- α by 1.3–3.2 fold and phagocytic activity by 28.9%–65.2% [39,44]. It has been found that CP showed good therapeutic activity due to its phenolic contents [41]. Others thought that CP contains honey that acts as a carrier for medicinal herbs and aid in absorption so that it can easily penetrate to the deep tissues, and finally, it helps to retain youth, charm, vigor, and longevity [39]. To improve the pharmacological activity of antitubercular drugs, CP has been suggested as an adjuvant therapy to avoid unwanted side effects [[50], [51], [52]]. In terms of respiratory infection, the role of CP is phenomenal as it may be able to secure the trachea–bronchial tree, alleviate bronchospasm, heal asthma and provide protection against seasonal or nonseasonal respiratory symptoms. Similar roles have been observed in the vascular system because CP can easily maintain good heart rhythm by regenerating the blood flow towards the musculature. A recent study has identified that gallic acid, catechin, and epicatechin-containing CP possess vital antioxidant ingredients that help to exaggerate the neuroprotective and cytoprotective activities [53,54]. Even more, Bansal et al. suggested CP as a procholenergic and antiamnesic agents [46]. Again, the cardioprotective and anti-obese potential of CP has been well established in several studies [55]. People who have been suffered from infertility problem may get potential benefit after taking CP as it ameliorates both semen quality and menstrual cycle in male and female respectively [[56], [57], [58]]. According to the clinical study of Sastry et al. CP is such a powerful immune boosting agent that can tune the activity of C3, C4 markers and IgE, suppress the level of cortisol and improve overall life quality [43]. Therefore, CP purifies the blood constituents by removing harmful disease-causing pathogen where it behaves like a natural detoxifying agent [59] and boost up the immune system praiseworthy (Fig. 3).

Fig. 3.

Schematic presentation of CP and immune cells mechanism. Ayurvedic CP plays an essential role in alleviating allergic reactions and activating NK cells, phagocytes, IL-1b, MIP-1, C3, C4 markers, and IgE.

3.3. Beta glucagon

Beta glucagon may be defined as a heterogeneous natural polysaccharide comprising mainly d-glucose monomers coupled with a beta glycosidic bond. The polysaccharides are considered an essential constituent of prokaryotes’ (e.g., bacteria and fungi) cell walls, acting as energy tankage. Usually, beta glucagon is found in oats, barley, mushroom and yeast. The (1,3)-β, (1,4)-β, or (1,6)-β glycosidic bonds are very common in the glucose submit of beta glucagon. In 1941 Pillemer L et al. was the first man who observed the immune-modulatory action of beta glucagon in the hydrophobic fraction yeast [60]. Then in 1955, it was reported that the immunological activity of such formulation was elicited from β-(1,3)-D-glucans [61]. Beta glucagon derives from fungi and yeast showed its immunological action through different mechanisms. The first mechanism involves the activation of macrophages which provide adequate stimulation to B-lymphocytes, natural killer cells, and suppressor T-cell [[62], [63], [64]]. In this case, the beta-glucan act as an effective immune stimulator. The second mechanism (in vitro) annexes with the indirect stimulation of cytokines, IL-1 or TNF; as a result, the microbiocidal effect of human neutrophils and macrophages increase significantly and protect the body from disease-causing pathogens [[65], [66], [67], [68], [69]], and the third proposed mechanism of beta glucagon is relevant to the promptness of dectin-1 pattern recognition receptor (PRR), an essential immune-stimulating receptor that plays a crucial role on blood peripheral mononuclear cells [70,71]. In phagocytosis, only insoluble beta glucagon can mediate apoptosis by binding with dectin-1 [72]. However, the soluble beta glucagon combines with complement receptor 3 (CR3) involved in complement-mediated immune processes provided by particular antibodies [72]. The human body, in general, cannot able to produce beta glucagon. To make it convenient, the human immune system initially receives beta-glucan as a stranger. Then, using pattern recognition receptors (PRR), the innate immune system makes it competent to combat against harmful pathogens. Here, the most important immune-stimulating role is played by PRR as it recognizes the action of pathogen-associated molecular pattern molecules (PAMPs) and therefore, beta glucan is marked as one of the efficient agonists of PAMPs [73,74] and other immune cells as well.

3.4. Ginseng

Ginseng is derived from the root of Panax ginseng, and Araliaceae family belonging medicinal herb employed as a herbal remedy for 3000 years ago, recognized by the traditional Chinese practitioners [75]. In general, two prominent types of ginseng is used for treatment purposes, the first one is named white ginseng, which is also known as naturally dried ginseng, and the second one is named red ginseng, which is made by applying steam before the drying process so that it can easily retain its safety profile, efficacy, and conservancy [76]. The presence of several bioactive constituents like ginsenosides (tetracyclic triterpenoid saponins), polyacetylenes, acidic polysaccharides, and polyphenolic compounds make it a unique biological plant for treatment purposes [77]. Based on chemical makeup, ginsenosides can further divide into three subtypes: subtype A) protopanaxadiol include Rb1, Rb2, Rb3, Rc, and Rd sub-type B) protopanaxatriol includes Re, Rf, Rg1, and Rg2 and sub-type C) oleanane includes Ro [77,78]. Ginseng is an influential immune stimulator as it stimulates both innate and acquired immune systems [[79], [80], [81], [82]]. The innate immune system demonstrates its effect through macrophages, dendritic cells, and natural killer cells. In 2002, Shin JY et al. ascertained that ginseng extract formulation exaggerates the phagocytosis cycle through stimulation of macrophages [83]. Further, red ginseng acidic polysaccharides (RGAPs) or ginseng treated macrophages can generate nitric oxide (NO), which acts as troops for killing phagocytized microbes [84]. According to the study of Choi HS et al., the production of IL-1β, TNF-α, and NO reaches the peak point when macrophages have been treated with RGAPs and IFN-γ [84]. An analogous activity has been found in murine J774A.1 macrophage cells and ginseng extract, which augment the secretion of interleukin-12 [85]. Dendritic cells, another vital part of the innate immune system, matured as a steroidal saponins end product (e.g., M1 and M4) provoke the expression of MHC class II, CD 80, CD 83, and CD 86 so-called dendritic cells markers [86]. In addition, ginseng extract and ginsenoside Rg-1 are responsible for promoting the activity of natural killer cells [80,87]. In contrast, the acquired immunity system consists of the humoral immune response, cell-mediated immune response, and cytokine release factors. Liou CJ et al. reported that oral or intraperitoneally administered ginseng extract could incite the production of IgM, IgG, and IgA antibody responses successfully [88,89]. Moreover, subcutaneous administration of ginsenoside Rg1 and ginsenoside reproduces antibodies against Toxoplasma gondii and improves serum-specific antibodies e.g., Ig, IgG_1, IgG_2a, IgG_2b against H₃N₂ influenza virus, respectively [90,91] in the cell-mediated immune system. Therefore, Kim KH et al. claimed that in vitro cultured of ginseng and spleen cells may increase the secretion of many cytokines like IL-1α, IL-2, granulocyte-macrophage colony-stimulating factor (GMCSF) production and IFN-γ [92] (Fig. 4).

Fig. 4.

Schematic presentation of Ginseng and immune cells mechanism. Ginseng is closely associated with both innate and acquired immune responses. Its innate immune function is mediated through macrophages, dendritic cells and NK cells, where the acquired immune response is facilitated through various humoral, cell-mediated and cytokine release factors.

3.5. Whey protein

The term whey protein may be demarked as a combination of proteins that have been segregated from whey and are commonly derived from the end-product of cheese. The constituents of whey protein include α-lactalbumin (α-LA, 25%), β-lactoglobulin (β-LG, 65%), serum albumin (8%) and immunoglobulins (2%) [93,94]. They may also contain protease-peptone, obtained from caseins [95], where the percentage of whey protein may vary from mammal to mammal. The highest percentage of whey protein has been found in human milk (approximately 60%), where cow's milk contains only 20% [96]. The most important thing about whey protein is that it contains 20 amino acids (including sulfur-containing cysteine) and provides adequate stimulation to glutathione to function as an antioxidant [97]. The cysteine found in whey protein is 3–4 times more bioactive and gets involved in the metabolism of all bodily protein and glutathione biosynthesis [98,99]. W.J. Harper reported that products that emerged or were made from whey protein took part in host immune response [100]. Also, whey peptides boost the immune response by enhancing the secretion of glutathione, which improves gut health and wound healing by triggering the activity of IgF-I and IgF-II growth factors [101]. The immune-boosting ability of α-lactalbumin (α-LA) is more specific than β-lactoglobulin (β-LG), lactoferrin (LF), and casein [102]. Another study claimed that α-LA could easily attach with trace elements (e.g., calcium, copper, iron, magnesium, manganese, phosphorus, and zinc) through enzymatic hydroxylation [103]. Neutrophil-dependent lactoferrin (LF) can enhance the functions of the humoral immune response, macrophages, and lymphocytes, thereby producing antigen-specific antibodies [104]. Further, A. Mercier narrated that it is possible to prepare immune-stimulating products from isolated whey protein peptides [105]. M.M. Mullally reported that α-Lactorphin, α-LA f [43,58,59], and β-LG f [[106], [107], [108], [109]], β-lactorphin are present in whey protein and may function like an angiotensin-converting enzyme [110]. According to the human clinical trial observational, Fe-LF mixture played a significant role in iron regulation and metabolism without producing any side effects [111]. Therefore, the whey derived peptides could be a promising alternative to fulfill the protein-energy malnutrition (PEM) deficiency in the upcoming decade (Fig. 5). Enhancing immunity by natural products supplementation against body abnormal condition have been shortened in Table 1.

Fig. 5.

Schematic presentation of Whey protein and immune cells mechanism. Both alpha and beta whey protein enhance the immune response through GSH, IgF-I and IgF-II involvement.

Table 1.

A Summery of the mechanisms of natural products in enhancing immunity.

Name of natural products	Immune boosting power	Possible mechanism	Ref
Yoghurt	Yes	↑Immune activity	[22]
		↑Immune response against various diseases
		↑Peptidoglycan	[24]
		↑Lysosome enzyme secretion
		↑Muramyl dipeptide
		↑Muramyl dipeptide	[29]
		↑IL-1, IL-6, IL-4, IFN-γ,TNFα
		↑Non-specific defense system	[25,[30], [31], [32]]
		↓ Klebsiella infection and tumor cell surveillance.
		↑Cytokine and pancreatic polypeptide secretion
		↑IL-1, TNFα, and IL-6	[[33], [34], [35], [36]]
Chyawanprash	Yes	↑ Act as a powerful immune booster, vitalizer, and a prohibitor for common viral infections and allergies	[41]
		↑Activity of natural killer (NK) and phagocytic cells	[43,[47], [48], [49]]
		↑Activity of interleukin-1-b (IL-1-b), macrophage inflammatory protein (MIP-1)
		↓Bronchospasm, heal asthma	[53,54]
		↑Seasonal or nonseasonal respiratory symptoms
		↑Antioxidant ingredients
		↑ C3, C4 markers and IgE serum level	[43]
		↓ Level of cortisol
Beta glucagon	Yes	↑Activation of macrophages, B-lymphocytes, natural killer cell.	[[62], [63], [64]]
		↑Cytokines secretion, including IL-1 or TNF	[[65], [66], [67], [68], [69]]
		↑Microbicidal effect of human neutrophils and macrophages
		↑Dectin-1 pattern recognition receptor (PRR)	[70,71]
Ginseng	Yes	↑Stimulates both innate and acquired immune systems	[[79], [80], [81], [82]]
		↑Phagocytosis	[83,84]
		↑IL-1β, TNF-α NO, RGAPs and IFN-γ production	[84]
		↑Natural killer cells activity	[80,87]
		↑IgM, IgG, and IgA antibody responses	[88,89]
		↑IL-1α, IL-2, GMCSF, and IFN-γ production	[92]
Whey protein	Yes	↑Secretion of glutathione	[101]
		↑Activity of IgF-I and IgF-II growth factors
		↑Increased the activity of α-lactalbumin (α-LA), ↑β-lactoglobulin (β-LG), lactoferrin (LF) and casein	[102]

4. Vitamins as immunity boosting agents

4.1. Vitamin C

Vitamin C or ascorbic acid is an essential hydrophilic micronutrient that has played a vital role in fostering the function of immune cells more than a jubilee [112,113]. It is involved in various synthetic processes and acts as a cofactor in several biological reactions like hydroxylation of collagen, biosynthesis of norepinephrine and carnitine, and regulation of hypoxia-inducible factor (HIF), metabolism of tyrosine, demethylation of histone and peptide hormone amidation [114]. Scottish physician James Lind in 1757, first observed that scurvy-affected patients got healed soon after they had taken fresh citrus fruits. Later, fresh citrus fruits and lemon juice were obligatory for British navy sailors [115]. Then, in 1907 Axel Holst and Alfred Frohlich claimed the existence of a particular substance in fresh citrus fruits and lemon juice [115]. Five years later (1912), Casimir Funk named the particular substance vitamin C [116] and cited that this vital substance had kept the body from diseases. After that, in 1928, scientist Albert Szent-Györgyi was able to isolate vitamin C, and finally, in1933, scientists were capable of synthesizing vitamin C [117]. Vitamin C has played a pivotal role in enhancing the activity of the immune system. It's functioning on neutrophils, chemotaxis, and phagocytes is well established [118]. Wilson et al. reported that vitamin C directly activates the lymphocytic cell through activation of SVCT (sodium-dependent vitamin C transporters) and GLUT (sodium-independent glucose transporters) [119]. Due to the activation of SVCT and GLUT, the intracellular plasma concentration of vitamin C increases about 10–100-fold than in normal conditions [120,121], which exaggerates T-cell, B-cell, and natural killer cells. In vitro study of Huijskens, M. J et al. narrated that vitamin C plays a key in the early maturation of T-cell as it removes the hindrance of the T-cell maturation process [122].

Further, daily intaking of 100 mg/kg/day vitamin C supplementation in two months may take up the activities of CD28 cells and cytokine factors [123]. In 2018, Van Gorkom GN et al. [124] cited in their review that vitamin C is responsible for the differentiation of helper T cell −1(Th-1) with the expenditure of helper T-cell polarization (Th-2). Another in vitro study on mice models reported that Vitamin C helps to generate CD8⁺ memory T cells by stimulating cytokines derived from dendritic cells [125]. In addition, vitamin C is requisite for the proper functioning of regulatory T -cell (Treg) through activation of Foxp3, the so-called master transcription factor in the epigenetic system [126,127]. In terms of B-cell, Prinz et al. found that vitamin C supplementation had enhanced the I_G concentration when guinea pigs had been immunized with red blood cells of sheep and serum albumin of bovine, respectively [128,129]. In the case of natural killer cells (NK), the role of vitamin C is somehow controversial; however, according to the in vitro report of cytokine-stimulated cell culture study, vitamin C is involved in the maturation and proliferation of natural killer cells that derive from peripheral blood mononuclear cells [130] (Fig. 6).

Fig. 6.

Schematic presentation of Vitamin C and immune cells mechanism. The activity of specific lymphocytic cells (e.g., T cell, B cell and NK cell) is boosted by ascorbic acid. Ascorbic acid helps to regulate the activity of Th1, CD8⁺, Foxp3, Treg and Ig levels.

4.2. Vitamin E

Lipid or fat-soluble vitamin E is composed of mainly four tocopherols (α, β, γ, and δ) and four tocotrienols (α, β, γ, and δ) and all of these forms are available in different food sources. Although all of these isoforms are associated with antioxidant properties, α-tocopherol is the only one that may fulfill the human nutritional requirements [131]. Vegetable oils contribute to the significant sources of vitamin E supplementation. More than 50 mg vitamin E/100 g oil has been found in wheat germ oils, cottonseed, corn, soybean, sunflower, walnut, and palm. Sheppard et al. reported that nuts contain a good amount of vitamin E [132]. The primary role of vitamin E is to scavenge the harmful peroxyl radicals and mitigate the oxidation of fatty acids, particularly the chain reactions of poly-unsaturated fatty acids; therefore, vitamin E protects the essential immune cells precisely. The various studies indicate that vitamin E is closely associated with crucial immune cell functions, e.g., macrophages, dendritic cells, B-cells, and natural killer cells. The immune-modulating activity of vitamin E on macrophages is triggered by the downregulation of prostaglandin E_2, which promotes the immune response of T-cells related to the aging process [133]. Wu et al. cited that in vivo vitamin E supplementation in aged mice model could vanquish the synthesis of prostaglandin E₂ and cyclooxygenase −2 remarkably generated from macrophages [134]. A similar type of activity has been observed by Beharka et al., where his investigation reported that vitamin E suppressed the activity of cyclooxygenase-2 in macrophages through scavenging the activity of peroxynitrite [135].

Further, taking 1500 IU d-α-tocopheryl acetate/day supplementation in 16 weeks inhibits the expression of macrophage nuclear factor erythroid 2-related factor 2 (NRF-2) and protects against allergies and asthmas [136]. In the case of NK cells, Adachi et al. reported that 100 mg/d vitamin E supplementation in an eight-week protocol could regain CD16⁺ CD56⁺ and NK cells [137]. To find out the correlation between NK cell cytotoxicity and vitamin E, Ravaglia et al. conducted an observational study on 37 female individuals (aged 90–106) who had been treated with vitamin E supplementation. At the end of the study, the author cited that the cytotoxic activity of NK cells largely depends on vitamin E supplementation [138]. According to the description of Buendía et al. [139], vitamin E supplementation may enhance the activity of protein Klotho by inhibiting the activity of dendritic cell-based nuclear factor-beta (NF-ҡB). Klotho is one kind of membrane protein that may regulate the transport of intracellular calcium control the signaling pathway of p53/p21, cAMP (cyclic adenosine monophosphate), PKC (protein kinase C), and NF-ҡB (nuclear factor-beta) [139]. Vitamin E supplementation shows its immune-stimulating effect on T-cells by augmenting the cell division and interleukin-2 secretion, as Adolfsson et al. [140] reported. Further, from the observational study on an old animal model, Marko et al. noted that vitamin E mediated T-cells may generate efficient immune synapse and help to mitigate the defect of the aging process [141,142]. In addition, vitamin E plays a significant role in balancing the activity of helper T cell-1(Th1) and helper T cell-2(Th2) [132]. On the other hand, a few clinical studies claimed that vitamin E is associated with antibody production of B-cell mediated humoral responses, although some investigators suggested further clinical trials [143,144] (Fig. 7). The Role of vitamin in support of the immune response against disease progression have been summarized in Table 2.

Fig. 7.

Schematic presentation of Vitamin E and immune cells mechanism. The immunomodulatory function of Vitamin E is to downregulate PGE2, COX-2 and NRF-2 and upregulate the activities of CD16⁺, CD56⁺, Klotho protein, IL-2, Th1/Th2 and antibody production.

Table 2.

The Role of vitamins in support of the immune response against disease progression.

Natural vitamin	Immune boosting power	Possible mechanism	Reference
Vitamin C	Yes	↑ Neutrophils, chemotaxis, and phagocytes	[118]
		↑Lymphocytic activation	[120,121]
		↑SVCT and GLUT activity
		↑T-cell, B-cell, and natural killer cells
		↑Maturation of T-cell	[122].
		↑Differentiation of helper T cell −1(Th-1) and polarization of helper T-cell-2 (Th-2).	[124]
		↑Generate CD8+ memory T cells	[125]
		↑Stimulating cytokines
Vitamin E	Yes	↑Activity of macrophages, dendritic cells, B-cells, and natural killer cells	[133]
		↑T-cells activation
		↓Prostaglandin E2 secretion
		↓Prostaglandin E2 and cyclooxygenase −2 synthesis	[134]
		↑CD16+ CD56+ and NK cells activity	[137]
		↑Protein Klotho and NF-ҡB activity	[138]
		↑T-cells activity, interleukin-2	[140]
		↑The activity of helper T cell-1(Th1) and helper T cell-2(Th2)	[132]

5. Mineral

5.1. Zinc

Zinc is one of the most influential and vital trace elements mandatory for the accrual and anabolism of all living organisms [[145], [146], [147], [148]]. Raulin was the first researcher who revealed that zinc is necessary for amplifying Aspergillus nigar in 1869 [145]. Then Todd WR et al. (1934) conducted a study on the rat model where they found that zinc played a pivotal role in growth and development [146]. For proper functioning of enzymes, transcription, and replication factors, this trace element zinc acts as a co-factor to exaggerate their activity [149,150]. The zinc concentration in human plasma is in a very minute amount, 12–16 μmol/L, but due to mobility characteristics in the circulatory system, its immunological action is phenomenal [151,152]. Again, Scott, B. J. et al. noted that in serum, zinc could quickly form a bond with serum protein molecules [153] and alter the immunological functions. From previous studies, it is clear that zinc is essential for maintaining normal immune function, and lack or deficiency of zinc may suppress the activities of human innate and acquired immunity [154]. Any depletion in zinc concentration directly interferes with the action of neutrophil granulocytes and chemotaxis of the innate immune system in vitro [155]. Hujanen et al. reported that zinc at the concentration of 500 μmol/L might provide adequate stimulation to carry out the chemotactic activity in polymorphonuclear leukocytes, noteworthy [156]. In vivo study of Allen et al. narrated that due to insufficient zinc level in the body, the phagocytic activity of macrophages, neutrophils, natural killer cells, and oxidative burst were greatly suffered and lost their immune-modulating activities [157,158]. The same phenomenon has been seen in granulocytes, as zinc deficiency proportionally decreases the number of granulocytes [106]. Further, the immune-modulating activity of specific immune cells (B and Tell) is closely associated with zinc supplementation. From previously reported studies, it is clear that zinc's influence on T cells and more specific than B-cell [107,108]. It has been thought that the generation of B-cell precursors is obliged to induce apoptosis due to the unavailability of zinc supplementation [109]. Minigari et al. speculated that zinc might affect the activities of both NK cell-mediated killing mission and cytotoxic T-cell [159]. The immune-modulating activity of T -cell precursors CD8+and CD73⁺ do not show their physiological effect if there is a zinc deficiency in the body [160]. Mention that, CD73⁺ is crucial for recognizing or proliferating the specific antigen and also provides a trigger to accelerate the cytolytic process [161]. Thymic atrophy is a very common phenomenon of T-cell-related zinc deficiency [162]. Thymulin hormone is generated from the thymus gland and secreted from epithelial cells of the thymic membrane with the help of zinc cofactor [163,164]. Zinc co-factor help the T-cell mediated physiological function by various mechanistic way. Firstly, zinc aid in the differentiation and development of both immature and mature T-cell that are located in the thymus and periphery respectively. After that, zinc stimulates the cytokine release factors with the help of peripheral blood mononuclear cells (PBMC) which then animate both CD8⁺ T cells and interleukin-2 and therefore disclose the high affinity receptor for interleukin-2 of mature T-cell [[165], [166], [167]]. In order to address the problem of zinc deficiency on thymus and peripheral cells, zinc supplementation could be an excellent solution to meet the desired vacant immune requirements [162] (Fig. 8). The overall summary of immune bosting capacity of zinc tabulated in Table 3.

Fig. 8.

Schematic presentation of Zinc and immune cells mechanism. Zinc supplementation is responsible for providing adequate immune stimulation of innate immune cells like macrophages, neutrophils, NK cells, and specific immune cells like-cell and B-cell precisely.

Table 3.

The overall summary of the immune-boosting capacity of zinc in the human body.

Name of mineral	Immune boosting power	Possible mechanism	Ref
Zinc	Yes	↑Phagocytic activity of macrophages, neutrophils, natural killer cells	[157,158]
		↑Immune-modulating activity B and Tell	[107,108]
		↑Activities of both NK and cytotoxic T-cell	[159]
		↑CD8+and CD73+ activities	[160,161]
		↑Differentiation and development of both immature and mature T-cell	[[165], [166], [167]]
		↑Cytokine release
		↑Peripheral blood mononuclear cells (PBMC)
		↑CD8+ T cells and interleukin-2

6. Future perspectives and recommendations

The future of human surveillance on the earth will be a challenging issue. The spreading of the virus-derived COVID-19 situation has given us a message that a newer pandemic will arise with its devastating power in the upcoming days. Modern allopathic drug designers have failed to find a panacea to cure the recent pandemic. Researchers are now emphasizing the immunity boost through food supplementation that yields from different natural sources. Natural products have been employed as therapeutic agents from the very beginning of human civilization. Until today and tomorrow, different immune-boosting drug formulations will be the most promising therapeutic alternative to fight against upcoming statewide critical consequences. With the help of new technology, it is possible to screen out the active constituents from natural products, and then it will accelerate the formulation of a new drug development process. So, it is high time to twig about the importance of plants or herbs-derived drug discovery projects that will precisely build up immunity. Countries should spend more time and money on immune-boosting projects than other everyday phenomena because the world has already experienced the pestilential effect of a deadly pandemic and put the nation's economy to its knees. Furthermore, more studies, including increased bioavailability, pharmacokinetics, and toxicity studies, are essential for determining better therapeutics advantages. One more recommendation is that until the specific immune-boosting drugs are available in pharma markets, authors suggest to the reader to include these clinically proven natural products, vitamins, and minerals as a dietary supplement to boost the immune system.

7. Concluding remarks

In the context of the 21st century, maintaining a healthy and disease-free life is quite challenging. The most obvious concern issue of today's perspective is immunity because dysfunction of this system is linked to the development of several chronic diseases. By advanced technological instrumentation, modern health science is now held at a peak point in treating outrageous diseases like cancer; however, at the same time, issues of immune boost up by natural products are always put in behind the scenes. As a result, 2021 has already observed millions of death cases, and now people suffer a lot due to the immunity identity crisis. Moreover, antibiotic resistance has come out due to indiscriminate drug practices, developing new viral or bacterial strains against antibiotics. To avoid such health interruptions, natural products derived from nutritional supplementation are the best way to strengthen the immune system, as most medical practitioners and nutritional scientists now suggest.

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability statement

Data included in article/supp. Material/referenced in article.

9. Declaration of interest's statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.