Metals/Minerals (Nutrients)
A good overview of the nutritional requirements and biological activity of metals and minerals is available on Wikipedia. Brief descriptions of each are provided below.
Click on each heading to disclose a detailed description
-
Important for healthy bones and teeth; helps muscles relax and contract; important in nerve functioning, blood clotting, blood pressure regulation, immune system health
-
Needed for proper fluid balance, stomach acid
-
Works closely with insulin to regulate blood sugar (glucose) levels
-
Copper is an essential trace element with a daily dietary requirement of 900 µgfor adults [220]. Copper has been well-established as involved in immune protective functionalities, supported by a large body of experimental evidence [3]. Copper plays a pivotal role as an important cofactor in redox reactions, regulating a wide range of physiological activities, including neurotransmission, energy production, connective tissue development, and iron metabolism [221]. Although a major portion of copper exists in the cupric (Cu2+) form, copper can readily donate and accept electrons, playing important roles in redox reactions and free radical scavenging [221]. The majority of copper in living organisms is closely connected to ceruloplasmin, rendering it inactive in Fenton-like processes. Free copper stimulates the production of free radicals when combined with biological reducing agents, according to some researchers. Inorganic copper in dietary supplements may raise free copper levels in the body, which may increase the risk of the production of reactive oxygen species, henceforth showing oxidative stress (referred to as prooxidant activity) [222]. Copper’s potential to act as a catalyst for the production of free radicals is well documented. Many in vitro studies have shown that copper (Cu2+)has been found to be a significantly more redox-active metal than iron (Fe3+) in various applications [223]. Mild to severe copper deficiencies result in reduced IL-2 production and decreased T cell proliferation, resulting in lymphopenia, making copper an essential component for the maintenance of a healthy immune system [212]. Neutrophils in the peripheral blood decrease in cases of severe copper insufficiency, reducing the capacity to produce superoxide anions and destroy ingested bacteria [3].In cattle, a copper deficit results in disrupted plasma cells, reducing antibody generation and decreasing the production of IFN-γ and TNF-α by the mucosal immune system. Increased copper administration is associated with a decreased proliferative response to concanavalin A in mice. Ex vivo studies indicated that increased copper levels in the blood are associated with lymphocyte inhibition and mitogen suppression, resulting in reduced immune function (Figure 2) [212]. Listed in Table 2 are key immunomodulatory roles played by minerals.
-
The daily iodine allowance for males and non-pregnant women is 150 µg. For pregnant women, a daily dosage of 220 to 250 micrograms is suggested, whereas daily intake of 250to 290 micrograms is recommended for breastfeeding mothers. Iodine contributes to the regulation of the immune system by fighting infection. It may improve immune function by assisting in the removal of both chemical and biological toxins. It also suppresses autoimmune responses, improving immunity control [211].In vitro, iodine kills bacteria through interactions with myeloperoxidase in phagocytic cells and promotes IgG production by human B lymphocytes (Figure 2). Iodine deficiency is associated with an increased risk of immunodeficiency and cancer development due to disruptions in the antioxidant mechanism. Excessive iodine consumption is associated with both hypothyroidism and hyperthyroidism, which are characterized by decreased NK cell activity. In rats, increasing iodine concentrations increases macrophage antigen presentation activity, suggesting that iodine serves as an initiating factor in thyroid autoimmunity [212]. Thyroid autoimmunity is caused by excessive iodine intake, which causes an imbalance in cytokine production [213].
-
The average daily allowance of iron is 13.7–15.1 mg for children, 16.3 mg for teenagers, 19.3–20.5 mg for men and 17.0–18.9 mg for women above 19. Iron is essentially required by all living organisms and is involved in a variety of biological processes. However, large amounts of free iron may be cytotoxic, when found in high amounts as it can stimulate the development of oxidative radicals that disrupt proteins, lipids, and nucleic acids. As a result, both iron deficiency and overabundance may confer detrimental impact on a wide range of cells, tissues, and organ functions; however, it has been challenging to relate such functional abnormalities to changes in particular iron-dependent biochemical pathways in general [194].
Heme is a vital component that can be found in abundance throughout our bodies’ tissues. The heme protein complex, which is made up of a variety of proteins, plays crucial roles in cellular physiology and metabolism [195]. Once free heme is liberated from cells and hemeproteins, it produces oxidative damage and inflammation, serving as a template for damage-associated molecular patterns in the body. This is because free heme is an important component of the pathogenic process of sterile and infectious hemolytic disorders such as malaria, hemolytic anemia, ischemia-reperfusion, and hemorrhage [196]. The mechanism through which heme produces ROS, activates innate immune cells, and triggers cell death is not well known [197]. In addition to increasing the formation of reactive oxygen species and inflammation-inducing mediators directly via its iron atom, heme may also activate certain signaling pathways and so indirectly enhance lipid peroxidation as well [197]. Heme stimulates innate immune cells such as macrophages and neutrophils by activating innate immune receptors on the surface of these cells [198].
Many of the proteins and genes involved in iron homeostasis also perform crucial roles in the regulation of iron flux, preventing bacteria from utilizing iron for growth.
The average daily allowance of iron is 13.7–15.1 mg for children, 16.3 mg for teenag-
In addition, cells in the innate immune system, such as monocytes and macrophages,ers, 19.3–20.5 mg for men and 17.0–18.9 mg for women above 19. Iron is essentially re-respond to bacterial infections by carefully regulating iron flux, mediated by hepcidin and quired by all living organisms and is involved in a variety of biological processes. How-ferroportin, which are expressed in microglia and lymphocytes. Several effector molecules, ever, large amounts of free iron may be cytotoxic, when found in high amounts as it can including TLRs, NF-κB, hypoxia-inducible factor-1 (HIF-1), and heme oxygenase (HO), stimulate the development of oxidative radicals that disrupt proteins, lipids, and nucleic regulate the inflammatory response by mobilizing various cytokines and neurotrophic acids. As a result, both iron deficiency and overabundance may confer detrimental impact factors [199].
The effects of iron on Tregs are much more nebulous and may be characterized as both direct and indirect effects. FOXP3, the master transcription factor in Tregs, appears to be inhibited by iron chelation, and iron chelation also reduces CD25 and signal transducer and activator of transcription 5 (STAT5) phosphorylation levels [200-203]. Iron also affects NF-kB activation. Normal to high iron levels induce the increased generation of ROS, which activate NF-kB and lead to the increased expression and release of cytokines. Under conditions of iron deficiency, ROS formation decreases, reducing the activation of NF-κB and cytokine release [204]. By contrast, iron chelation in macrophagesincreases the production of antimicrobial NO, which may help prevent infections. Total white blood cell counts, the proportion of CD4+ or CD8+lymphocytes in the blood, theCD4+/CD8+ratio, in vitro IL-2 production, CD8+cytotoxicity, and delayed-type hypersensitivity responses are downregulated under conditions of iron overload (Figure 2) [204].
-
Part of many enzymes
-
Magnesium is a trace element with a daily dietary requirement of 400–420 mg for men and 310–320 mg for women [214]. The protective effects of magnesium in inflammatory reactions are among the many functions associated with this vital mineral, which deserves special attention due to its importance. Magnesium deficiency increases the ability of macrophages to produce inflammatory cytokines, especially TNF-α, IL-1, and IL-6, resulting in the development of low-grade inflammation [215]. Pro-inflammatory cytokines areupregulated in HUVECs grown under low-magnesium conditions [216]. Magnesium also reduces the generation of TNF-α and IL-6 by LPS-stimulated cord blood mononuclear cells in vitro [217]. Mesenchymal stem cells (MSCs) have immunomodulatory properties that are modulated by magnesium, and magnesium inhibits the formation of IL-1 and IL-6while increasing the production of IL-10 and PGE2 and inhibits the pNF-κB/NF-κB ratio while increasing the pSTAT-3/STAT-3 ratio [218]. Magnesium deficiency in rats causes cardiac dysfunction and inflammation, increasing the production of TNF-α, IL-1, and IL-6. When NF-κB is activated, magnesium regulates the production of cytokines, promoting disease development (Figure 2) [219].
-
Important for healthy bones and teeth; found in every cell; part of the system that maintains acid-base balance
-
Needed for proper fluid balance, nerve transmission, and muscle contraction
-
The recommended dietary allowance (RDA) of selenium for adults aged 19 and above is 55 µg per day. Pregnant and breastfeeding women need between 60 and 70 micrograms per day, respectively. Selenium is an essential component of selenoproteins, which are necessary for NK cell, macrophage, neutrophil, and T lymphocyte functions [205]. Increased vivo selenium levels significantly influence the proliferation and differentiation CD4+ Th cells into CD25+FOXP3+ Tregs [206,207]. Increased dietary selenium consumption results in the enhanced production of IFN-γ in response to T cell receptor (TCR) stimulation and the TCR-induced differentiation of CD4+ T cells, whereas reduced dietary selenium intake results in increased IL-4 production (Figure 2). Selenium levels influence B-cell-dependent antibody production in a pathogen-dependent manner, although these effects are less consistent than the effects observed on T cell immunity, according to the literature. Bcell activation and differentiation are controlled by the oxidatively sensitive NF-κB and stimulate the production of leukotrienes, which may be influenced by selenium intake [207]. Inflammatory cytokine gene expression is regulated by NF-κB, and recent research suggests that decreased serum selenium levels contribute to NF-κB-mediated inflammation [208]. Selenium supplementation is commonly immunostimulatory, resulting in T cell proliferation, innate immune cell activation, NK cell activity, and a variety of other indicators [207]. Selenium supplementation also regulates the inflammatory response in patients with respiratory distress syndrome through the restoration of lung antioxidant activity, which lowers IL-1 and IL-6 levels, reducing the inflammatory response and considerably improving respiratory mechanics [209]. Selenium is an essential component of antioxidative enzymes, including thioredoxin reductase and glutathione peroxidase, and selenium deficiencies increase ROS generation in neutrophils and macrophages [210].
-
Needed for proper fluid balance, nerve transmission, and muscle contraction
-
The recommended daily amount of zinc is 8 mg for women and 11 mg for adult men.Zinc plays a key role in the immunological response, and zinc-deficient individuals aremore susceptible to a range of infections including malaria, tuberculosis, HIV, pneumonia,and measles. Zinc deficiency increases the vulnerability to infections via immunologicprocesses that have been studied for decades. Zinc appears to have a wide range of effectson the immune system, including effects on the physical skin barrier and gene regulation inlymphocytes. Zinc is also required for neutrophil and NK cell development and function,which are involved in the nonspecific innate immune system. In this regard, zinc deficiencyimpairs the development of adaptive immunity by inhibiting T lymphocyte expansion andthe activation of Th1 cells, which produce cytokines and assist B lymphocytes [188,189].Zinc deficiency also has an adverse effect on antibody production and B lymphocytedevelopment, especially IgG synthesis. Macrophages, which play vital roles in manyimmunologic processes, are negatively influenced by zinc deficiency, resulting in thedysregulation of intracellular cell death, cytokine generation, and phagocytosis, amongother functions. Zinc plays various roles in multiple fundamental cellular processes,including cell activation, cell division, DNA replication, and RNA transcription, and itseffects on these important immunologic mediators are well understood [190].Research findings revealed that zinc promotes the development of tolerogenic phenotypes in bone-marrow-derived DCs, inhibiting MHC-II production, increasing the expression of the programmed death-ligand (PD-L) 1 and 2, and upregulating tryptophandegradation and kynurenine production, resulting in an imbalance between Th17 and Tcells, which favors the proliferation of Tregs (Figure 2) [191]. Furthermore, zinc plays apivotal role in the regulation of phosphatases (PTPs) and protein tyrosine kinases (PTKs).Several experimental studies have reported that zinc exerts an inhibitory effect on multiplePTPs, even at the very low amounts observed intracellularly [192]. Thymus involution,reduced Th1 cell numbers, and impaired immune functions, including lymphocyte proliferation, IL-2 production, delayed-type hypersensitivity responses, antibody responses, NKcell activity, macrophage phagocytosis, and specific neutrophil functions, are all impactednegatively by zinc deficiency [193].