Abstract : Zinc is an indispensable trace element required for several critical functions of the human body. Deficiencies of micronutrients can impair immune function and increase susceptibility to infectious disease. It is noteworthy that higher susceptibility to the SARS-CoV-2 viral infection is seen in individuals with micronutrient deficiencies and poorer overall nutrition. Research in the last two decades suggests that one-third of the global population may be deficient in zinc, which affects the health and well-being of individuals of all ages and gender. Zinc deficiency is now considered one of the factors associated with susceptibility to infection and the detrimental progression of COVID-19. The trace element is essential for immunocompetence and antiviral activity, rendering zinc supplements highly popular and widely consumed. Zinc supplements are required in small doses daily, and their absorption is affected by food rich in fiber and phytase. The organic forms of zinc such as picolinate, citrate, acetate, gluconate, and the monomethionine complexes are better absorbed and have biological effects at lower doses than inorganic salts. Considering the present global scenario, choosing the right zinc supplement is essential for maintaining good health. In the present review, we reexamine the role of zinc in immunity and antiviral activity and a comparative account of different forms of zinc supplements.
Comparative bioavailability and efficacy of zinc supplements : Zinc is supplemented in humans as sulfate, acetate, gluconate, picolinate, histidine and methionine salts. Very few studies involve a direct comparison of the bioavailability of different forms of zinc in humans. The important fact is that the form of zinc needs to become dissociated into zinc ions, which then bind to ligands (proteins) for transport. The organic sources of zinc such as Zn methionine, Zn glycinate and Zn complexed to other amino acids have been reported to meet the requirement at lower doses and have a better effect than inorganic salts.
Conclusions : The current pandemic of SARS-CoV-2 infection has prompted researchers to look for essential nutrient supplements with antiviral properties and induce an effective immune response. Although randomized controlled studies on the effect of zinc supplements on SARS-CoV2 infection are minimal, several trials are being planned and few are ongoing. Evidence from literature, strongly suggests that zinc supplementation may be highly beneficial in reducing the severity and morbidity associated with the infection. Zinc supplements are cost effective and are simple options to respond to oxidative stress, uncontrolled inflammation and infection caused by the virus. Choosing the right supplement for the population at risk may be highly helpful for tackling the pandemic more effectively.
Keywords: Zinc; SARS-CoV-2; Zinc deficiency; Antiviral immunity; Supplements
Zinc Supplements in COVID-19 Pathogenesis-Current Perspectives, Majeed M, Chavez M, Nagabhushanam K and Mundkur L, Austin Journal of Nutrition / Metabolism, May 03, 2021

1. The concentration-dependent scavenging abilities of zinc DL-methionine, zinc sulfate, zinc gluconate, zinc picolinate and selected free radical scavengers, including superoxide dismutase (SOD), catalase, mannitol, allopurinol and DL-methionine, were examined against biochemically generated superoxide anion, hydroxyl radical and hypochlorite radical plus hypochlorous acid, by chemiluminescence and cytochrome c reduction.
2. Zinc methionine was the most effective of the zinc compounds that were tested. Following incubations with superoxide anion, hydroxyl radical, and hypochlorite radical-generating systems, in the presence of 50 μ,M zinc DL-methionine approximately 38%, 4 7% and 28% inhibition in reactive oxygen species generation was observed, respectively, compared to control groups.
3. The protective abilities of various zinc salts, as well as selected free radical scavengers and antioxidants were also assessed on phorbol ester (TP A)-induced lactate dehydrogenase (LDH) release from cultured PC-12 cells. Preincubation showed better protection than coincubation. Approximately 45% and 50% inhibition in TP A-induced LDH leakage was observed following preincubation with 50 μ,M zinc DL-methionine and 50 μ,M vitamin E succinate, respectively. Zinc DL-methionine exhibited better protection against LDH leakage than any other zinc salt tested.
4. The results indicate that zinc DL-methionine can attenuate the biochemical consequences of oxygen free radicals, and is comparable to other well-known antioxidants and free radical scavengers in the in vitro system that was employed.
In summary, zinc methionine was found to be the most potent free radical scavenger compared to all other zinc salts that were tested. The results indicate that zinc DL-methionine provided excellent chemoprotection against oxygen free radicals and TPA-induced LDH leakage from cultured neuroactive PC-12 cells, and was comparable to vitamin E succinate with respect to these effects. The methionine moiety may be primarily responsible for these observed effects.
KEY WORDS. Biochemically generated oxygen free radicals, cultured PC-12 cells, TPA, zinc salts, vitamin E, 􀂴-carotene, vitamin C, methionine, chemiluminescence, cytochrome c reduction, LDH leakage
Comparative In Vitro Oxygen Radical Scavenging Ability of Zinc Methionine and Selected Zinc Salts and Antioxidants - D. Bagchi, M. Bagchi and S. ]. Stohs - Gen. Pharmac. Vol. 28, No. 1, pp. 85-91, 1997

It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. Research has begun to clarify the molecular mechanisms underlying the action of zinc on the immune function. It is clear that this trace element has a broad impact on key immunity mediators, such as enzymes, thymic peptides and cytokines, explaining the paramount importance of zinc’s status on the regulation of lymphoid cell activation, proliferation and apoptosis. Ongoing and future studies regarding the immunological status of zinc deficiency ‘at risk’ groups could lead to public health interventions with nutritional doses of zinc supplements to prevent alteration of the immune system and improve resistance to infections.
Marginal zinc deficiency and suboptimal zinc status have been observed in several ‘at risk’ population groups, such as the elderly, in both developing and industrialized countries. Adequate zinc supplementation administered to vulnerable individuals could prevent the impairment of the immune system and substantially improve the host’s resistance to infections in these populations.
Keywords: zinc intake; immune system; zinc deficiency; zinc supplementation; zinc excess
Zinc and immune function - M Dardenne - European Journal of Clinical Nutrition (2002) 56, Suppl 3, S20–S23

Abstract : Zinc is essential for multiple cellular functions including immunity. Many investigators have used zinc supplementation in an attempt to affect the outcome of various diseases. These efforts were aimed at either supporting immunity by zinc administration or correcting the zinc dependent immune functions in zinc deficient individuals.
Recent findings : in this review, recent findings of zinc supplementation in various diseases have been presented. Beneficial therapeutic response of zinc supplementation has been observed in the diarrhea of children, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory tract infection, common cold, and leishmaniasis. Zinc supplementation was effective in decreasing incidences of infections in the elderly, in patients with sickle cell disease (SCD) and decreasing incidences of respiratory tract infections in children. Zinc supplementation has prevented blindness in 25% of the elderly individuals with dry type of AMD. Zinc supplementation was effective in decreasing oxidative stress and generation of inflammatory cytokines such as TNF-a and IL-1b in elderly individuals and patients with SCD.
Summary : Zinc supplementation has been successfully used as a therapeutic and preventive agent for many conditions. Zinc functions as an intracellular signal molecule for immune cells.
Conclusion : Zinc is an intracellular signaling molecule and it plays an important role in cell-mediated immune functions and oxidative stress. Zinc is also an anti-inflammatory agent. These unique properties of zinc may have significant therapeutic benefits in several diseases in humans. In many diseases concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress and increase the generation of inflammatory cytokines. It is currently believed that oxidative stress and chronic inflammation may play important causative roles in many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, and autoimmune diseases. It is therefore, important that the status of zinc is assessed and zinc deficiency corrected in these chronic diseases. A controlled clinical trial of zinc supplementation in these disorders in order to document the preventive and therapeutic effects of zinc is warranted.
Keyword : anti-inflammatory agent, antioxidant, immune function, zinc
Zinc: role in immunity, oxidative stress and chronic inflammation - Ananda S. Prasad - Current Opinion in Clinical Nutrition and Metabolic Care 2009, 12:646–652 - Curr Opin Clin Nutr Metab Care 12:646–652

Although the essentiality of zinc for plants and animals has been known for many decades, the essentiality of zinc for humans was recognized only 40 years ago in the Middle East. The zinc-deficient patients had severe immune dysfunctions, inasmuch as they died of intercurrent infections by the time they were 25 years of age. In our studies in an experimental human model of zinc deficiency, we documented decreased serum testosterone level, oligospermia, severe immune dysfunctions mainly affecting T helper cells, hyperammonemia, neurosensory disorders, and decreased lean body mass. It appears that zinc deficiency is prevalent in the developing world and as many as two billion subjects may be growth retarded due to zinc deficiency. Besides growth retardation and immune dysfunctions, cognitive impairment due to zinc deficiency also has been reported recently.
Our studies in the cell culture models showed that the activation of many zinc-dependent enzymes and transcription factors were adversely affected due to zinc deficiency. In HUT-78 (T helper 0 [Th0] cell line), we showed that a decrease in gene expression of interleukin-2 (IL-2) and IL-2 receptor α (IL-2Rα) were due to decreased activation of nuclear factor-κB (NF-κB) in zinc deficient cells. Decreased NF-κB activation in HUT-78 due to zinc deficiency was due to decreased binding of NF-κB to DNA, decreased level of NF-κB p105 (the precursor of NF-κB p50) mRNA, decreased κB inhibitory protein (IκB) phosphorylation, and decreased Iκκ. These effects of zinc were cell specific. Zinc also is an antioxidant and has anti-inflammatory actions. The therapeutic roles of zinc in acute infantile diarrhea, acrodermatitis enteropathica, prevention of blindness in patients with age-related macular degeneration, and treatment of common cold with zinc have been reported. In HL-60 cells (promyelocytic leukemia cell line), zinc enhances the upregulation of A20 mRNA, which, via TRAF pathway, decreases NF-κB activation, leading to decreased gene expression and generation of tumor necrosis factor-α (TNF-α), IL-1β, and IL-8. We have reported recently that in both young adults and elderly subjects, zinc supplementation decreased oxidative stress markers and generation of inflammatory cytokines.
Zinc in Human Health: Effect of Zinc on Immune Cells - Ananda S Prasad

Abstract : Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in immunemodulation has arisen. This reviewaims at describing themechanisms involved in the regulation of Zn homeostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators.When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adaptive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T helper cell subsets are particularly susceptible to changes in Zn status.While acute Zn deficiency causes a decrease ininnate and adaptive immunity, chronic deficiency increases inflammation.During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory diseases, including rheumatoid arthritis.
Conclusion : The nutritional importance of Zn is well known. Zn requires daily intake, and to achieve a steady-state level, the homeostasis of Zn inside the cells is tightly regulated by different transporters and regulators. Zn functions as a key structural or catalytic component of more than 300 enzymes and it is implicated at all levels of cellular signal transduction.
In this way, Zn regulates also cell–cell communication, cell proliferation, differentiation and survival. Furthermore, Zn involvement in the regulation of immune cells and inflammation contributes to pathologies in which both Zn deficiency and inflammation are observed.
However, several mechanisms about Zn action on the immune system are still unclear. Further studies on the expression and regulation of transporters or on the interactions of Zn with other ions will also help to better understand the pathogenesis of Zn-related diseases, such as RA, leading to potential newand innovative therapeutic avenues in the immunological field.
Key word : Zinc, Metallothioneins, Inflammation, Cytokines, Immune diseases, Rheumatoid arthritis
Zinc and its role in immunity and inflammation - Paola Bonaventura, Giulia Benedetti, Francis Albarede, Pierre Miossec - Autoimmunity Reviews - AUTREV-01647; No of Pages 9

Zinc supplementation can modulate immunity through inhibition of NF-KB, a transcription factor that controls many immune response genes. Thus, we sought to examine the mechanism by which zinc supplementation tempers the response to a common allergen and determine its effect on allergic airway inflammation.
Methods : Mice were injected with zinc gluconate prior to German cockroach (GC) feces (frass) exposure and airway inflammation was assessed. Primary bone marrow-derived neutrophils and DMSO-differentiated HL-60 cells were used to assess the role of zinc gluconate on tumor necrosis factor (TNF)a expression. NF-KB:DNA binding and IKK activity were assessed by EMSA and in vitro kinase assay. Protein levels of A20, RIP1 and TRAF6 were assessed by Western blot analysis. Establishment of allergic airway inflammation with GC frass was followed by administration of zinc gluconate. Airway hyperresponsiveness, serum IgE levels, eosinophilia and Th2 cytokine production were assessed.
Results : Administration of zinc gluconate prior to allergen exposure resulted in significantly decreased neutrophil infiltration and TNFa cytokine release into the airways. This correlated with decreased NF-KB activity in the whole lung. Treatment with zinc gluconate significantly decreased GC frass-mediated TNFa production from bonemarrow derived neutrophils and HL-60 cells. We confirmed zinc-mediated decreases in NF-KB:DNA binding and IKK activity in HL-60 cells. A20, a natural inhibitor of NF-KB and a zinc-fingered protein, is a potential target of zinc. Zinc treatment did not alter A20 levels in the short term, but resulted in the degradation of RIP1, an important upstream activator of IKK. TRAF6 protein levels were unaffected. To determine the application for zinc as a therapeutic for asthma, we administered zinc following the establishment of allergic airway inflammation in a murine model. Zinc supplementation decreased airway hyperresponsiveness and serum IgE levels, but had no effect on Th2 cytokine expression.
Conclusion : This report suggests that the mechanism by which zinc supplementation alters NF-KB activity is via the alteration of A20 activity. In addition, this study provides evidence that supplementation of zinc to asthmatics may alter airway reactivity and serum IgE levels, suggesting zinc supplementation as a potential treatment for asthmatics.
Zinc supplementation alters airway inflammation and airway hyperresponsiveness to a common allergen - Carrie I Morgan, John R Ledford, Ping Zhou and Kristen Page - Morgan et al. Journal of Inflammation 2011, 8:36

Zinc is an essential trace element for the immune system, and zinc deficiency compromises the function of primarily T cells but also of several other immune cells. Recently, zinc homeostasis has been demonstrated to affect dendritic cells, in particular the involvement of zinc transport proteins during lipopolysaccharide-induced upregulation of major histocompatibility complex proteins and co-stimulatory molecules. This adds to our understanding of the immunomodulatory potential of zinc and highlights its significance for immune function.
The recent advances in understanding the role of zinc homeostasis in immunity are certainly only the tip of the iceberg, but there are already so many aspects that all of them cannot be discussed in detail here, for example, the effects of zinc on glucocorticoids or apoptosis [24]. These all form an interesting immunomodulatory network with zinc in its center. The latest addition by Kitamura et al. – the suppression of DC functions by zinc – might have severe implications during zinc deficiency, when it could lead to increased cell-surface expression of MHC and co-stimulatory molecules. Simultaneously, a shift in the cytokine profile could occur, potentially resulting in unwanted T-cell activation and T-cell-mediated autoimmunity. This agrees with the observation that zinc deficiency is frequently observed during autoimmune diseases [2], and indicates that modulating zinc homeostasis could be a promising approach to counteract inflammation and autoimmunity.
Zinc homeostasis and immunity - Lothar Rink and Hajo Haase - TRENDS in Immunology Vol.28 No.1

Abstract : Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised.
The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency.
Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.
Keyword :  Zinc, zinc deficiency, immunity, infection, micronutrients, ontogeny, apoptosis
Zinc and immune function: the biological basis of altered resistance to infection - Anuraj H Shankar and Ananda S Prasad - Am J Clin Nutr 1998; 68(suppl):447S–63S

Abstract : Management of prediabetes is a critical step to prevent type-2 diabetes. Curcumin and zinc have been studied as an antioxidant, anti-inflammatory, and antidiabetic agents. In this clinical trial, 84 subjects were randomized into curcumin (500 mg), zinc (30 mg), zinc and curcumin, and placebo groups for 90 days. At the baseline and the end of the study, the outcomes (fasting plasma glucose (FPG), 2-hour postprandial glucose (2hpp), HbA1 C, insulin, insulin sensitivity (IS), insulin resistance (IR), beta-cell function (BCF), weight, body mass index (BMI), dietary intake, and physical activity (PA)) were measured. A hypocaloric diet and PA were recommended for all subjects. In total, 82 subjects completed the study. After the intervention, dietary intake, PA, weight, and BCF% did not show a significant difference among the groups. However, subjects taking only zinc and zinc and curcumin groups experienced decreased BMI compared to the placebo (p = .01 and .007, respectively). The three treated groups had improved FPG (p = .01), 2hpp (p = .003), HbA1C (p = .004), insulin (p = .001), IS% (p = .001), and IR (p max .001) compared to the placebo. Based on these results, zinc and curcumin supplementation exerted a beneficial effect on several key glycemic parameters.
Keywords: blood glucose; curcumin; insulin resistance; insulin sensitivity; prediabetes; zinc.
The effect of curcumin and zinc co-supplementation on glycemic parameters in overweight or obese prediabetic subjects: A phase 2 randomized, placebocontrolled trial with a multi-arm, parallel-group design, Majid Karandish , Hassan Mozaffari-Khosravi , Seyed Mohammad Mohammadi , Bahman Cheraghian , Maryam Azhdari, Phytother Res. 2021 Apr 23