Next Article in Journal
Functional Activity of Four Autochthonous Strains L. paraplantarum AB362736.1, L. plantarum MF369875.1, W. paramesenteroides CP023501.1, and E. faecalis HQ802261.1 in a Probiotic Grape Marmalade during Storage
Previous Article in Journal
Timing of Treatment with the Flavonoid 7,8-DHF Critically Impacts on Its Effects on Learning and Memory in the Ts65Dn Mouse
Open AccessReview

Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications

Department of Oncology, School of Medicine, Wayne State University and Karmanos Cancer Center, Detroit, MI 48201, USA
Author to whom correspondence should be addressed.
Antioxidants 2019, 8(6), 164;
Received: 25 March 2019 / Revised: 21 May 2019 / Accepted: 27 May 2019 / Published: 6 June 2019


The essentiality of zinc as a trace mineral in human health has been recognized for over five decades. Zinc deficiency, caused by diet, genetic defects, or diseases, can cause growth retardation, delayed sexual maturation, depressed immune response, and abnormal cognitive functions in humans. Zinc supplementation in zinc-deficient individuals can overcome or attenuate these abnormalities, suggesting zinc is an essential micro-nutrient in the body. A large number of in vitro and in vivo experimental studies indicate that zinc deficiency also causes apoptosis, cellular dysfunction, deoxyribonucleic acid (DNA) damage, and depressed immune response. Oxidative stress, due to the imbalance of reactive oxygen species (ROS) production and detoxification in the anti-oxidant defense system of the body, along with subsequent chronic inflammation, is believed to be associated with many chronic degenerative diseases such as diabetes, heart diseases, cancers, alcohol-related disease, macular degenerative disease, and neuro-pathogenesis. A large number of experimental studies including cell culture, animal, and human clinical studies have provided supportive evidence showing that zinc acts as an anti-oxidative stress agent by inhibition of oxidation of macro-molecules such as (DNA)/ribonucleic acid (RNA) and proteins as well as inhibition of inflammatory response, eventually resulting in the down-regulation of (ROS) production and the improvement of human health. In this article, we will discuss the molecular mechanisms of zinc as an anti-oxidative stress agent or mediator in the body. We will also discuss the applications of zinc supplementation as an anti-oxidative stress agent or mediator in human health and disease.
Keywords: zinc; MT; NF-κB; A20; HNF-4α; ROS zinc; MT; NF-κB; A20; HNF-4α; ROS

1. Introduction

The earliest clinical cases of human zinc deficiency, as manifested by dwarfism, sexual development delay in males, depressed immune response, and cognitive dysfunction, were observed by Dr. Prasad and his team in the Middle East in the 1960s [1]. There were no reports on zinc deficiency at that time. Iron treatment was initially given to those patients to correct the symptoms of anemia. However, iron supplementation only corrected the anemia and did not correct other symptoms [1]. Growth retardation, hypogonadism in males, and immune dysfunction were able to be corrected by zinc supplementation [1]. Zinc deficiency in the Middle East is caused by diets rich in organic phosphate compounds (phytates) which decrease the availability of zinc. Nutritional zinc deficiency is very common in developing countries. One recent study showed that there was zinc deficiency in around 43% of children aged 3–5 years in South Africa [2]. Another recent study showed that there was zinc deficiency in about 20% of children aged between 6 months and 12 years in Iran [3]. Moreover, conditioned zinc deficiency is also commonly found associated with some medical conditions such as chronic renal disease, diabetes, gastrointestinal diseases, sickle cell anemia, and cancers [4] Furthermore, zinc deficiency is widely prevalent in the elderly population worldwide, in part due to changes in lifestyle, diet, and health conditions. It has been estimated that 30–40% of elderly subjects have mild/marginal to modest zinc deficiency in the United States [5,6]. Zinc supplementation in elderly subjects improves their zinc and health status, for example through decreased incidence of infections [5,6,7].
Increased number of human studies shows that zinc deficiency is highly associated with increased levels of oxidative stress biomarkers such as lipid peroxidation products and DNA oxidation products in humans. Zinc supplementation suppresses or attenuates these adverse effects [5,6,7]. These findings suggest that zinc might have a protective role as a pro-antioxidant agent or mediator by the down-regulation of ROS production and accumulation. In the following paragraphs, we will summarize the biological functions of zinc as a ROS/oxidative suppressor or pro-antioxidant agent through several molecular mechanisms including anti-inflammatory effects and zinc-binding proteins such as nuclear factor κB (NF-κB), zinc containing transcription factor (A20), peroxisome proliferator-activated receptor (PPAR), tristetraprolin (TTP), hepatocyte nuclear factor-4α (HNF-4α), nuclear factor erythroid 2-related factor 2 (Nrf2), Kruppel-associated box domain (KRAB), and metallothionein (MT)/metal regulatory transcription factor 1 (MTF-1) in human health and diseases.

2. Physiological and Biological Functions of Zinc

Since human zinc deficiency was first reported by Dr. Prasad there has been no doubt as to the role of zinc as an essential micronutrient for human health [1]. Tremendous evidence shows that zinc plays very important roles in a variety of biological and physiological functions in humans [4,8]. For example, it is known that zinc participates in the activation of more than 300 enzymes that mediate the regulation of macromolecule biosynthesis in DNA, RNA, and proteins, as well as cell growth and proliferation and other types of metabolism [9]. The evidence also shows that zinc is required to stabilize the tertiary structures of more than 300 proteins (for example zinc finger proteins) and many transcription factors. These Cys2–His2 (C2H2)-enriched zinc finger domain proteins are reported to be involved in the control of gene expression of a wide variety of growth factors, steroid receptors, and immune response mediators by binding DNA, RNA, and proteins [10,11,12]. Inadequate zinc condition in the cells affects the structures of zinc-dependent proteins, subsequently leading to aberrations in protein activities, suggesting the important role of zinc as an essential micro-nutrient in humans.

3. Immunological Functions of Zinc

Immunological response is a very important biological process by which the body’s defense system recognizes and defends itself against the infection of microorganisms such as bacteria, viruses, and fungi as well as other substances that are foreign and harmful to the body. It is known that zinc acts as an immune mediator to maintain normal immune response against micro-organism infections in the body. A large number of clinical observations, as well as experimental and animal studies, have provided supportive evidence showing that zinc is involved in the regulation of several immune functions of T cells, B cells, and natural killer (NK) cells, specifically, cellular immunological function [13,14,15,16]. The evidence clearly suggests that zinc deficiency affects cellular immunological functions, for example resulting in decreased production of T helper 1 (Th1) cytokines and reduced DNA-binding activity of T-bet. T-bet is a major transcription factor for Th1 cytokine gene expression [17]. For example, zinc deficiency was found to decrease the expression and production of interleukin-2 (IL-2) and IL-2 receptors as well as interferon γ (IFN-γ) cytokines in HUT-78 cells (a type of Th0 malignant lymphomatoid cell), as compared to zinc-sufficient cells [17,18,19]. Dysfunction of cellular immune response caused by zinc deficiency in humans causes frequent severe fungal, bacterial, and viral infections, thymic atrophy, anergy, decreased proliferative response of serum lymphocytes to mitogens (a selective decreased population of T helper cells), and decreased activity of thymulin, a thymic hormone that induces the differentiation of T-cells and enhances the functions of the different T-cell subsets. Zinc supplementation reverses all of these manifestations in the body [20,21]. These findings clearly suggest that zinc could be an important immune responsive mediator.

4. ROS, Oxidative Stress, and Inflammatory Response

Chemically, in the presence of a free electron (e), the univalent reduction of oxygen generates superoxide (•O2), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH), all of which are reactive oxygen species (ROS). Superoxide has an unpaired electron, which imparts higher reactivity and renders it very unstable and short-lived [22,23,24,25]. ROS are usually produced continuously in vivo under aerobic conditions. The production of ROS and its elimination by the anti-oxidant defense system in cells is a highly modulated process for maintaining normal physiological function in the body. In eukaryotic cells, the mitochondrial respiratory chain, microsomal cytochrome p450 enzymes, flavoprotein oxidases, and peroxisomal fatty acid metabolism are the most significant intracellular sources of ROS [26,27,28,29]. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are a group of plasma membrane-associated enzymes which catalyze the production of superoxide •O2 from oxygen by using NADPH as the electron donor [30]. Broadly speaking, ROS cover reactive nitrogen species (RNS) including radicals such as nitric oxide (NO•) and nitric dioxide (NO2), as well as non-radicals such as nitrous acid (HNO2) and dinitrogen tetroxide (N2O4). ROS, including reactive nitrogen species (RNS), are considered as second messengers for important molecular signaling transductions [31]. Similar to second messengers, the production of ROS is highly triggered by extra-cellular stimuli such as hypoxia, growth factors, and inflammatory cytokines. Reduction-oxygenation (redox) signaling involves at least one reaction with oxidation of a signaling molecule by ROS, which is reversible [32].
The homeostasis of ROS has been implicated in a variety of biological responses from transcriptional activation to cell proliferation. Under pathological conditions, a disequilibrium between ROS production and elimination by the antioxidant defense system results in increased bio-availability of ROS, leading to a state of oxidative stress, a deleterious process [29,33]. The pathogenic outcomes of oxidative stress involve oxidative damage of cells or tissues [23], a major cause of DNA damage. The failure of the repair of this ROS-induced DNA damage by the DNA repair system in the body leads to genomic instability or mutations, subsequently contributing to the development of many chronic degenerative diseases such as cancers and diabetes.
The inflammatory response is a complex and critical immunological process resulting from the host defense mechanisms against trauma, micro-organism infection, and other adverse environmental stresses or complex combinations of many biological insults by the involvement of several different immune cells such as lymphocytes, macrophages, NK cells, dendritic cells, and other cells, as well as many different cytokines/molecules [34,35,36,37,38]. Such inflammatory processes, especially sustained chronic conditions of inflammation, along with inflammation-induced oxidative stress from dead or injured cells, could lead to irreversible cellular or tissue damage with the passage of time, which further contributes to the development of chronic degenerative diseases.
As discussed in Section 6.1, ROS are a potent stimulus for the activation of NF-κB, a major transcription factor that regulates the expression of many inflammatory genes. The over-production of ROS, namely oxidative stress, results in the chronic, sustained constitutive activation of the NF-κB signaling pathway, eventually leading to the up-regulation of inflammatory cytokines. Thus, oxidative stress, along with sustained, chronic inflammatory responses acts as a deleterious contributor for the development of many chronic degenerative diseases such as atherosclerosis, rheumatoid arthritis, and diabetes mellitus in humans, mediated through the oxidation of macro-molecules such as DNA, lipids, and proteins and ROS-induced inflammatory response processes [39,40,41].

5. Zinc as an Anti-Oxidative Stress and Anti-Inflammatory Agent

From a chemical perspective, zinc is a redox-inert ion which cannot oxidize nor reduce other substances in the body, and is not a direct anti-oxidant agent itself [42]. Zinc can bind to the sulfur (thiolate) donor of cysteine to form zinc thiolate, which turns zinc redox-active. Oxidants can interact with thiolate and release zinc in a free state. Such oxidative releases of zinc from thiolate donors of cysteine residues generate a zinc signal that triggers an anti-oxidant response against ROS/oxidative stress. Physiological or adequate levels of zinc have a pro-antioxidant effect or protective effect against ROS/oxidative stress in biology. Extreme zinc levels such as severe deficiencies and toxicological or excess levels of zinc in the body exert pro-oxidant effects, causing oxidative stress, as reviewed recently [42,43]. Zinc has been proposed to act as a pro-antioxidant agent or a co-factor by three mechanisms: (1) protection of free sulfhydryl group in proteins; (2) outcompeting redox-active metals; and (3) specific induction of antioxidant system response [42,43]. A large number of early experimental studies revealed that physiological or adequate levels of zinc exert an anti-oxidant effect in a site-specific pattern in the body by the regulation of the highly cysteine-rich and heavy metal-binding protein metallothionein (MT) [42,44]. The evidence shows that zinc directly increases the expression and activity of MT, which is also known as a zinc binding protein and is highly rich in cysteine, thus being an excellent scavenger of ˙OH from the zinc thiolate of cysteine residues [45,46], as discussed further in Section 6.8.
A large number of clinical and experimental studies have indicated that zinc deficiency is highly associated with increased levels of oxidative stress biomarkers, DNA damage, and inflammatory cytokines/molecules in humans. Zinc supplementation reverses these adverse effects. For example, it has been reported that zinc-deficient human lung fibroblast cells in cultured conditions not only increase oxidative stress and DNA damage but also decrease DNA repair capacity [47,48]. The evidence shows that zinc deficiency decreased the DNA binding activities of p53, NF-κB, and activator protein 1 (AP-1), also causing an increase in the generation of oxidative stress and the expression of DNA repair proteins [47,49]. It is noted that after tumor nectosis factor-α (TNF-α) treatment, zinc-deficient porcine vascular endothelial cells showed increased levels of oxidative stress and inflammatory cytokine IL-6 as well as activation of NF-κB and AP-1 [50]. One animal study showed that zinc-deficient rats had higher concentrations of thiobarbituric acid-reactive substances (TBARS, well-known lipid peroxidation biomarkers) in the liver, brain, and testes [51]. These findings clearly suggest that zinc might have an important role in the maintaining ROS homeostasis in the body.
Our early cell culture models and clinical trials from normal healthy individuals, elderly subjects, and sickle cell anemia subjects demonstrate that zinc decreased nitric oxide (NO) production, lipid peroxidation products, DNA oxidation products, inflammatory cytokines/molecules, and inducible NO synthase (iNOS) in human subjects, and also inhibited the activations of TNF-α-, oxidized low density lipoprotein (LDL-), or lipopolysaccharide (LPS)-induced NF-κB DNA binding in human promyelocytic leukemia cells (HL-60), human monocytic leukemia cells (THP-1), human aortic endothelial cells (HAECs), or human isolated peripheral blood mononuclear cells (PMNC) [6,7,12]. Similar results have been reported by other investigators [52,53,54,55,56]. These findings strongly suggest that zinc reduces oxidative stress and ROS-mediated inflammatory responses, and that zinc acts as a potent agent by inhibition of ROS production and inflammation.

6. Molecular Mechanisms of Zinc as an Anti-Oxidative Stress Agent

A large number of experimental studied have provided valuable evidence to support zinc as an anti-oxidative stress agent by targeting several zinc-associated or zinc finger proteins such as NF-κB, A20, TTP, PPARs, Nrf2, HNF-4α, KRAB-containing proteins, and MT/MTF-1 in the body, as discussed in Section 6.1, Section 6.2, Section 6.3, Section 6.4, Section 6.5, Section 6.6, Section 6.7 and Section 6.8.

6.1. NF-κB

Nuclear factor κB (NF-κB) is a widely studied major transcription factor which regulates many different gene expressions involved in immune, inflammatory response, and other biological processes [57]. Alterations in the NF-κB signaling pathway activity are strongly related to the development and progression of age-related chronic diseases, for example, atherosclerosis, rheumatoid arthritis, diabetes, malignant tumors, and other diseases. NF-κB is highly activated by different intrinsic and extrinsic stimuli such as inflammatory cytokines/molecules, ROS, protein kinase C (PKC) activators, UV light/ionizing radiation, and other stresses [58,59]. NF-κB activation and its signaling pathway regulate the expressions of many different inflammatory cytokines/molecules, transforming growth factor, adhesion molecules (such as intracellular adhesion molecule (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin), receptors (IL-2 receptor-α), oxidant molecules/enzymes (inducible NO synthase and inducible cyclooxygenases), and other immune molecules/mediators, leading to the mediation of several immune responses including innate and adaptive immune response, stress response, and cell survival and proliferation in the body. Inflammatory cytokines such as TNF-α and interleukin 1β (IL-1β) not only activate the NF-κB signaling pathway but also are induced by the activation of the NF-κB signaling pathway [58,59], which results in a positive feedback-loop of amplification with sustained chronic activation of the NF-κB signaling pathway in many different cells such as immune cells and cancer cells, eventually leading to pathological processes. NF-κB proteins consisting of five different isoforms such as p65 (RelA), RelB, c-Rel, p105/p50 (NF-κB1), and p100/p52 (NF-κB2), rather than acting alone, can usually co-operate with other transcription factor proteins such as activator protein 1 (AP-1), specific protein 1 (SP-1), and CCAAT enhancer binding protein (C/EBP) (NF-κB–bZip interactions), to enhance the expressions of many different genes with a variety of molecular and cellular functions in a cell type-dependent pattern [60,61].
If no stimulation or exposure to stress occur, NF-κB proteins in the cytoplasm are not activated by binding to inhibitory proteins of NF-κB (IκB) such as IκB-α, IκB-β, and IκB-γ subunits [58,59,60]. The activation of NF-κB is mediated through its dissociation from the binding of IκB proteins to NF-κB proteins. Thus, cytosolic NF-κB proteins become an active form for translocation into the nucleus only when IκB proteins are released from the NF-κB proteins in the cytoplasm. Many stimuli such as cytokines, PKC activation, oxidants, UV light, and radiation can induce the activation of NF-κB via phosphorylation of IκB proteins mediated through the action of IκB kinases (IKK), which finally results in ubiquitination and subsequent degradation of IκB proteins by the proteolytic enzyme-enriched proteasome complex in the cells [58,59,60]. Dissociations of IκB proteins from NF-κB proteins cause their rapid nuclear translocation for the activation of NF-κB targeted genes. Aberrations of NF-κB activation cause alternations in the expression of many different NF-κB-targeted genes, which contribute to the regulation of many different molecular and cellular functions such as cell growth, proliferation, differentiation, apoptosis, and immune response in the body.
The data from several early experimental studies have provided solid evidence to support the concept that zinc plays a critical role in the modulation of NF-κB signaling pathway activity, and that the regulation of NF-κB activation by zinc appears to be cell lineage-dependent [62,63]. For example, the evidence from early in vitro studies has shown that zinc is required for the activity of NF-κB and its protein-DNA binding in either purified NF-κB proteins, recombinant NF-κB p50, or Th0 cell line (HUT-78)-derived nuclear protein extracts, although one early report has revealed that there is no zinc-binding site in the structures of NF-κB proteins [18,64,65]. One early animal study showed that rats undergoing a short period (14 days) of diet-induced zinc deficiency had lower levels of NF-κB DNA binding activity in testes, along with increased levels of oxidative stress, suggesting that the reduction of NF-κB binding reflects an early response to zinc deficiency-induced oxidative stress [66]. However, many other experimental studies in cell culture models have revealed that zinc can suppress LPS-, ROS-, or TNF-α-induced NF-κB activation in endothelial cells, pancreatic cancer cells, embryonic fibroblast cells, and PMNCs, consistent with a decrease in the expression/production of inflammatory cytokines and oxidative stress [7,47,48,49,67,68,69,70,71,72,73]. These findings clearly suggest that the regulation of the NF-κB signaling pathway activity by zinc is cell type-specific. More studies on the specificity of zinc on NF-κB activation in different types of cells are required for further investigation.

6.2. A20

A20 has been widely recognized as an endogenous inhibitor of NF-κB activation, and is different from IκB protein. A20 (also known as TNF-α-induced protein 3, TNFAIP3) is a cytoplasmic zinc finger transactivating factor that plays an important role in the inhibitory regulation of inflammatory response via the inhibition of IL-1β- and TNF-α-induced NF-κB signaling pathway activity [74,75,76]. The expression of A20 is mainly induced for the inhibitory regulation of NF-κB signaling pathway activity in many different types of cells in response to a number of stimuli such as TNF-α, IL-1β, LPS, phorbol myristate acetate (PMA), and ROS as well as other stimuli [76]. A20 was originally identified to protect cells from TNF-α-induced cytotoxicity by the suppression of the activity of the NF-κB signaling pathway, which leads to a decrease in TNF-α and IL-1β signaling pathways in endothelial cells and other cells [76]. It has been shown that the genetic A20 null (A20−/−) mice can develop severe inflammation and cachexia, and are highly sensitive to both LPS and TNF treatments, with death in the early stage after birth [77]. A20 knockout (A20-deficient) cells cannot suppress TNF-induced NF-κB responses. Early evidence also revealed that A20 inhibited the TNF-α- and IL-1β-activated NF-κB signaling pathway by mediating TNF-receptor associated factor (TRAF) pathways in endothelial cells [74,75,78]. More evidence shows that A20 contains two ubiquitin-editing domains for de-ubiquitinating proteins to inhibit NF-κB signaling pathway activity by inhibition of the ubiquitination of IκB proteins [79,80]. All of these findings clearly support the concept of A20 as an endogenous anti-inflammatory molecule by the inhibition of NF-κB activation via TRAF pathways. The inhibitory effects of zinc on NF-κB-mediated inflammation and oxidative stress have been considered to be associated with the expression of A20 protein in non-T cells [70]. Our previous experimental studies have shown that zinc sufficiency increases A20 expression and A20–TRAF1 complex binding, and decreases the generation of inflammatory cytokines and oxidative stress in non-T lymphocyte cells such as (HL-60) human promyelocytic leukemia cell line, (TPH-1) the human monocytic leukemia cell line, and (HUVEC) the human umbilical vein endothelial cells, as compared to zinc deficiency in those cells [7,69,70]. The under-expression of A20 by its anti-sense mRNA increases the generation of inflammatory cytokines such as TNF-α and IL-1β in zinc-sufficient cells [70]. These findings clearly suggest that zinc suppresses the generation of inflammatory cytokines and ROS via the regulation of A20 signaling pathway, as a result of deregulation of NF-κB activity. One recent in vitro study showed that zinc could suppress LPS-induced NF-κB activation by induction of A20 expression in RAW 264.7 macrophage cells [81]. More evidence from a recent animal study revealed that zinc treatment could inhibit NF-κB activation via the induction of A20 expression in rats [81]. Therefore, zinc may act as an anti-inflammatory and anti-oxidative stress agent, partially being associated with the modulation of A20 expression.

6.3. TTP

Tristetraprolin (TTP; also known as Nup475, TIS11, or Zfp36), another known zinc finger protein, is one of three family members of CCCH tandem zinc finger proteins in mammals, characteristic of two CCCH zinc finger domains and three tetraprolin motifs [82,83,84]. TTP is known to bind class II AU-rich elements of mRNAs, specifically encoding TNF-α and granulocyte/macrophage colony-stimulating factor. Such RNA–protein binding results in the destabilization of these mRNAs by removal of poly A tail of these mRNAs, decreased translation, and depressed secretion of these cytokines/molecules [82,83,84]. TNF-α is a strong inflammatory cytokine which can induce/activate the NF-κB signaling pathway [83,85]. Early animal studies indicate that TTP deficiency causes chronic inflammatory syndromes which are similar to human rheumatoid arthritis and gastrointestinal inflammatory syndromes by the increased stabilization of TNF-α mRNA, and consequent over-production of this cytokine in mice [86,87,88,89,90]. Recently, one animal study showed that TTP-null (TTP-deficient) mice had increased levels of reactive oxygen and nitrogen species, along with the activation of NADPH oxidase 2 (NOX2), which contributes to chronic inflammatory syndromes in the TNF-α-independent manner [89], suggesting a potential role of TTP in the regulation of ROS homeostasis. The early experimental study in several types of cultured cells and mice indicates that a zinc-sufficient condition (100 μM) up-regulates the gene expression of TTP [91]. These findings suggest that TTP may have a protective role against oxidative stress mediated through the inhibition of TNF-α by zinc.

6.4. PPAR

Peroxisome proliferator-activated receptors (PPARs) α and γ in nuclear receptors have widely been known as potent mediators for lipoprotein metabolism, inflammation, and glucose homeostasis in the body for decades and shown to play an important protective role in the development and progression of several age-related degenerative diseases such as atherosclerosis, diabetes, and cancer [92,93,94]. PPAR-α and γ are extensively expressed in many different tissues such as the liver and pancreas, and are abundantly present in the vascular vessels where they may exert anti-inflammatory effects [95,96]. Increasing evidence has shown that PPAR proteins have anti-inflammatory properties [97,98,99,100]. Clinically, several PPAR agonists have been used for the treatment of cardiovascular disease (CVD) or patients with high risk for CVD such as those with diabetes [101], in part associated with its inhibition of inflammatory response. Although the mechanisms of PPAR-α and γ agonist drugs against these degenerative diseases have not been fully elucidated, increasing evidence shows that one of the mechanisms may be due to its anti-inflammatory and anti-oxidant effects through the inhibition of oxidant-sensitive NF-κB activation via a negative cross-talk at the nuclear DNA binding level [102]. The evidence also reveals that the activation of PPAR-α and γ leading to the inhibition of inflammatory cytokines/molecules in cells is believed to be zinc-dependent [103].
One early experimental study revealed that after the zinc depletion induced by TPEN (N,N,NN′-tetrakis (2-pyridylmethyl) ethylenediamine), a zinc-specific chelator, in porcine pulmonary arterial endothelial cells, the PPAR-α or PPAR-γ agonist-pre-treated cells lost the potency to inhibit TNF-α-induced NF-κB and AP-1 DNA binding activities. However, when zinc was added back into the zinc-depleted cells, PPAR agonists significantly inhibited these inflammatory parameters [104]. Another experimental study revealed that zinc deficiency induced inflammatory cytokines/molecules associated with NF-κB and PPAR signaling pathways [94]. In our previous experimental study, human aortic endothelial cells (HAECs) cultured in zinc-deficient conditions (1 μM of zinc) resulted in a decrease in the expression of PPAR-α protein after oxidized LDL stimulation, as compared to those cells cultured in zinc-sufficient conditions (15 μM of zinc) [7], suggesting that zinc increases the expression of PPAR-α, which may contribute to the inhibition of NF-κB-mediated inflammatory cytokines/molecules. Therefore, the protective role of zinc as an anti-inflammatory and anti-oxidative stress agent may be partially associated with zinc-dependent PPAR signaling pathways.

6.5. Nrf2

Nuclear factor erythroid 2-related factor 2 (Nrf2), another known zinc finger protein, is a family member of Cap’n’Collar/basic leucine zipper (CNC-bZIP) proteins, and is known as a critical transcription factor that regulates the gene expressions of anti-oxidant proteins and enzymes such as glutathione (GSH) and superoxide dismutase (SOD). It also detoxifies enzymes such as glutathione S-transferase-1 (GSTA1) and heme oxygenase-1 (HO-1), by binding to anti-oxidant responsive elements (ARE) in the DNA promoter regions of these target genes [105,106]. It is known that these anti-oxidant molecules/enzymes and phase II detoxifying enzymes have a protective role in anti-oxidant defense system against electrophilic stressors and oxidative stress in cells [106]. The data from a large number of experiments have provided clear evidence supporting the concept that Nrf2 plays an important cytoprotective role in the regulation of oxidative stress-induced cellular damage in the body [107,108]. It has been revealed that in aged rats there is an approximately 50% reduction of Nrf2 activity and ARE binding activity in the liver, associated with a low level of HO-1 [106]. Therefore, Nrf2 has been considered as an anti-oxidant mediator in the anti-oxidant defense system through the regulation of these anti-oxidant proteins and enzymes in the body. Deregulation of Nrf2 expression has been shown to be associated with the development of age-related degenerative diseases including cancers and diabetes [107,109,110,111].
The evidence from several recent experimental studies suggests that zinc may have an important role in the regulation of Nrf2 expression. One experimental study revealed that zinc depletion induced by administration of TPEN (a known zinc-specific chelator) to mice increased oxidative stress and decreased Nrf2 activity [112]. A high dose of zinc increased non-protein thiol levels, HO-1 expression, and nuclear Nrf2 protein in human colon cancer HCT-116 cells [113]. It has also been documented that zinc can prevent H2O2-induced endothelial cell damage via Nrf2-dependent stimulation of glutathione biosynthesis, and zinc depletion has a reverse effect on ROS and Nrf2 [114]. Moreover, dietary zinc supplementation can restore bacterial clearance in the lung, along with an increase in nuclear Nrf2 binding activity in alveolar macrophages, and decrease oxidative stress in alcohol-fed rats [108]. These findings clearly suggest that zinc up-regulates Nrf2 activity and inhibits the generation of oxidative stress. Thus, the regulation of Nrf2 by zinc may be one of the molecular mechanisms of zinc as an anti-oxidative stress agent in the body. More studies are required to investigate the protective role of Nrf2 in inflammation and oxidative stress by zinc.

6.6. HNF-4α

Hepatocyte nuclear factor-4α (HNF-4α) is a zinc finger transcription factor and is mostly expressed in the liver in the body. This zinc finger transcription factor regulates the expression of a large number of genes which are involved in several aspects of hepatocyte functions such as cell proliferation and apoptosis [115,116]. Increasing evidence has shown that HNF-4α has an important protective role against alcohol-induced and TNF-α-induced cellular damage in the liver [117,118,119]. Moreover, one recent animal study indicates that HNF-4α null (HNF-4α-deficient) mice significantly had significantly impaired expression of transferrin, resulting in hypoferremia, a state of abnormal metabolism of Fe, which may cause oxidative stress in liver cells [120]. These findings suggest that HNF-4α regulates the homeostasis of Fe metabolism, which is associated with the ROS signaling pathway.
Several experimental studies show that zinc supplementation increased the expression of HNF-4α in liver and has a protective role in alcohol-induced liver disease in animals. Specifically, one animal study demonstrated that zinc supplementation reversed alcoholic liver disease by the re-activation of HNF-4α and PPAR-α in mice. Zinc depletion significantly down-regulated HNF-4α and PPRA-α downstream target proteins in liver cells [118]. Other experimental studies indicate that zinc deficiency decreased cell proliferation and related proteins such as hepatocyte growth factor (HGF), insulin like growth factor I (IGF), IGF binding protein 1 (IGFBP-1), MT, and cyclin D1, along with HNF-4α protein. The functional loss of HNF-4α by its small interfering ribonucleic acid (siRNA) has similar effect to zinc deficiency [118,121]. These findings suggest zinc-mediated HNF-4α might have an important protective role against oxidative stress by several molecular signaling pathways.

6.7. KRAB Proteins

Kruppel-associated box domain (KRAB) proteins are a large family of zinc finger transcription factors, which were discovered in 1991 [122]. They are also called as KRAB-containing zinc finger proteins. There are nearly 800 different KRAB-containing proteins in tetrapod vertebrates. However, only one third (around 300) of KRAB-containing proteins have been found in the human genome, although they represent the most of the zinc finger proteins in humans. KRAB-containing proteins are characterized by the presence of a DNA-binding domain consisting of 4–30 zinc finger motifs and a KRAB domain, which is located near the amino terminal of the proteins [123].
KRAB domain has been identified to act as a transcription repressor domain by binding to co-repressor proteins, whereas the C2H2 zinc finger motifs of these proteins binds to DNA elements of the target genes. The functions of these KRAB-containing proteins currently proposed are the transcriptional repression of RNA polymerase I, II, and III promoters as well as binding and splicing of RNA. The members of the KRAB-containing protein family are considered to involve in the maintenance of the nucleus, cell differentiation, growth, proliferation, cell apoptosis, and neoplastic transformation [122].
Recent experimental studies have demonstrated that several KRAB-containing proteins such as zinc finger protein 552 (ZNF552) (407 amino acids at length with one KRAB domain at the amino terminal and seven C2H2 zinc finger motifs at the carboxyl terminal), ZNF328 (792 amino acids at length with a N-terminal KRAB domain and classic C-terminal C2H2 zinc finger motifs), and ZNF649 (505 amino acids of protein with N-terminal KRAB domain and C-terminal C2H2 zinc finger motifs) significantly inhibited serum response element (SRE) and AP-1 activities in COS-7 kidney fibroblast cells [124,125,126]. AP-1 is one key transcription factor for redox signaling pathway. Zinc deficiency has been found to induce ROS and AP-1 in 3T3 mouse embryonic fibroblast cells [73]. Thus, the regulation of KRAB-containing protein homeostasis by zinc would regulate AP-1-mediated redox signaling pathway.

6.8. MT and MTF-1

Metallothionein (MT) is another well-known zinc binding protein, which has been widely studied for several decades, and is a group of metal binding proteins characteristic of low molecular weight (ranging from 500 to 1400 Da) with a single peptide chain [45]. One third of its amino acids are cysteines distributed in two domains α and β clusters, contributing to high binding affinity to seven ions of divalent metals such as zinc, iron (Fe), copper (Cu), selenium (Se), and cadmium (Cd) through the thiol group (SH) in cysteine residues in the body [45]. To date, four isoforms of MT proteins, namely, MT-I, II, III, and IV, have been identified. MT-I and MT-II are predominantly expressed in many different tissues such as liver, kidney, intestine, and brain in humans [127].
The key function of MT is to mediate the homeostasis, storage, and transport of essential trace elements such as zinc and Cu as well as detoxification in the body [44,128,129]. Other metal elements including heavy metals such as Cd in the body can also bind to MT through its thiol group. Due to the presence of multiple thiol groups of its cysteine residues, MT has been considered as an anti-oxidant molecule in the cellular defense antioxidant system in the body by acting as a free radical scavenger [44,127,130,131,132]. The evidence shows MT has an anti-inflammatory effect by the modulation of the expression of several pro- and anti-inflammatory cytokines [127,133,134], contributing its anti-oxidant effect in the body. Many animal studies show that MT clearly have a protective role against oxidative stress-induced damage in many different tissues as reviewed recently [127]. The regulation of MT gene expression is zinc-sensitive. A variety of stimuli such as metal exposure, ROS/oxidative stress, and steroids also induce the gene expression of MT. Many experimental studies show that zinc supplementation induces MT gene expression [135,136]. One animal study shows that zinc supplementation induced the concentration of tissue MT and antioxidant enzymes and decreased the levels of tissue Cu and Fe as well as Cu- and Fe-associated free radicals in rats [137], suggesting that the induction of MT synthesis by zinc contributes to the reduction of free radicals generated by Cu and Fe.
Metal response element (MRE) binding transcription factor 1 (MTF-1) was identified as a zinc finger protein in the 1990s [138]. This protein has six zinc finger motifs in the Cys2–His2 family. Increasing evidence shows that MTF-1 is involved in zinc homeostasis and cellular responses to heavy metals, hypoxia, ROS/oxidative stress, and ionizing radiation by the regulation of metal-dependent (especially zinc-dependent) induction of targeted genes containing the MRE DNA sequence in the promoter region [139]. Upon the binding of zinc to its zinc finger motifs due to the change in intracellular free zinc concentration, MTF-1 induces the transcription activation by its binding to MRE site in the promoter region of targeted genes encoding MT1, MT2, zinc transporter1 (Znt1, a zinc efflux transporter protein), and the glutamate–cysteine ligase heavy chain (an oxidative stress-related protein) [136,139,140,141]. This is why MTF-1 is known as a zinc sensor in the cells. The exact molecular mechanism and function of MTF-1 activation is not fully understood. Besides high sensitivity to zinc, ROS, specifically H2O2, can induce MTF-1 activation, resulting in the increased expression of MT proteins [44,139]. Experimental studies show that zinc supplementation increased MTF-1 DNA binding activity and MT-1 in vitro and in vivo [142,143,144]. This suggests that zinc has protective effect against ROS/oxidative stress, partially via the activation of the MTF-1/MT signal pathway. However, further studies are required to elucidate how zinc act as a pro-antioxidant agent or ROS/oxidative stress suppressor, in part by modulation of the MTF-1/MT signal pathway.

7. Applications of Zinc Supplement as a Pro-Antioxidant Mediator in Human Health

Zinc has been widely considered not only as an immune mediator, but also as a pro-antioxidant mediator in human health and disease. Therefore, the supplementation of zinc as a pro-antioxidant mediator against oxidative stress would have beneficial effects in different groups, for example the elderly and patients with age-related macular degenerative disease, sickle cell anemia, diabetes mellitus, (especially type 2), and alcohol-related liver disease, as discussed in Section 7.1, Section 7.2, Section 7.3, Section 7.4, Section 7.5 and Section 7.6.

7.1. Normal Adult Subjects

We at first reported the supplementation of zinc as a pro-antioxidant mediator in human adult subjects [69]. In our earlier human subject study in healthy adults, we found that oral zinc supplementation (45 mg zinc as gluconate per day for eight weeks) in normal healthy volunteers resulted in the significant decrease in the blood lipid peroxidation products malonyl dialdehyde (MDA) and 4-hydroxyalkenals (HAE), and DNA oxidation products (8-OHdG), compared to the placebo group of normal healthy subjects. Zinc supplementation attenuated TNF-α-induced NF-κB activation from isolated mononuclear cells (MNCs), compared to the MNCs isolated from the placebo group of healthy subjects who did not receive zinc supplementation. Zinc supplementation also decreased the mRNA levels of TNF-α and IL-1β in LPS-stimulated MNCs [69]. In our other clinical trial studies, we found that zinc treatment can significantly decreased the duration and severity of common colds in association with a decrease in inflammatory cytokines/molecules in normal healthy subjects [145,146]. These findings suggest that zinc may act as an anti-oxidative stress and anti-inflammatory mediator in human health.

7.2. Elderly Subjects

It is clear that aging is associated with oxidative stress, leading to macro-molecule damage and consequently chronic inflammation in the body. Due to changes in the dietary habits, lifestyle, and health conditions, zinc deficiency is very common in the elderly population. It has been estimated that 30–40% of elderly subjects have mild to moderate zinc deficiency in the United States [5]. A large number of experimental studies support the fact that zinc plays very important roles in the human health, especially in elderly subjects [147,148,149,150]. Zinc supplementation for the elderly would provide beneficial health effects [150,151]. For example, in our earlier studies, we found that so-called healthy elderly subjects had increased levels of blood lipid peroxidation products (MDA and HAE) and DNA oxidation intermittent products (8-OHdG) as well as inflammatory cytokines/molecules as compared to young healthy subjects [6,7,152]. We administered oral zinc supplementation (45 mg zinc for 6 months) to healthy elderly subjects. After 6 months of follow-up, zinc supplementation resulted in increased blood zinc levels and anti-oxidant power as well as ex vivo production of interleukin-2 (IL-2) and interferon γ (IFN-γ) and decreased blood levels of inflammatory cytokines/molecules such as high-sensitivity C-reactive protein (hsCRP), IL-6, macrophage chemoattractant-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule (ICAM), and secretary phospholipase A2 [6,7,152], as well as ROS biomarkers such as MDA and HAE, as compared to the placebo group of healthy elderly subjects [6,7,152]. Zinc supplementation also decreased the incidence of infection in these elderly subjects [6,7,152]. Another clinical trial study in elderly subjects also provides solid evidence showing that zinc supplementation enhanced anti-oxidant defense system of peripheral blood lymphocytes by the up-regulation of activities of protein maintenance systems responsible for the elimination of oxidized protein in elderly subjects [153]. All of these findings confirmed that zinc may have anti-oxidant and anti-inflammatory effects, which could be useful for maintaining normal health conditions in elderly population who are vulnerable to infections and many other chronic degenerative diseases.

7.3. Age-Related Macular Degeneration Disease

Age-related macular degeneration (AMD) disease is one of the leading causes of permanent, irreversible, and central vision loss (blindness) in individuals aged over 50 worldwide [154]. It has been estimated that approximately 2 million individuals in the United States and 50 million elderly persons worldwide suffer from AMD [154]. AMD is a complicated chronic neurodegenerative and progressive disease. Its etiology is complicated and is not fully understood. Multiple factors are involved in the pathogenesis of AMD. It has been known that aging and genetics play a critical role in the development of AMD. However, other environmental factors such as cigarette smoking, heart disease, hypertension, dyslipidemia, obesity/diabetes, and phototoxic exposure that are associated with oxidative stress also play an important role in the development of AMD [155].
It has been documented that excessive production of ROS with oxidative stress play a key role in the pathogenesis of AMD [156,157,158]. The increased levels of ROS and suppressed cellular antioxidant defense system can result in oxidative stress and the consequent damage to photoreceptors, retinal pigment epithelial cells, and choriocapillaris, as reviewed recently [159]. Thus, the supplementation of dietary anti-oxidant agents or mediators to elderly subjects would provide a protective effect on AMD.
One large multi-center study supported by the national Institute of Health/the National Eye Institute, namely the Age-Related Eye Disease Study (AREDS) in the United States, enrolled 4700 participants aged 55 years or older, reporting that the supplementation of antioxidants including zinc provided a protective role in the development of AMD. Specifically, a long period (more than five years) of either the supplementation of 80 mg zinc as zinc oxide and 2 mg copper as cupric oxide or the supplementation of antioxidants (vitamin C, vitamin E, and beta-carotene) plus zinc significantly reduced the risk of developing advanced AMD [160]. A high dose (greater than 45 mg) of zinc supplementation or intake may impact copper absorption and cause copper deficiency due to its competition to copper binding protein or transporter in the body. Copper supplementation was administered to prevent copper deficiency caused by a high dose of zinc intake. The report showed that zinc alone decreased the odds of developing advanced dry type of neovascular form of AMD and prevented blindness in AMD subjects. It was also reported that only zinc showed a 27% decrease in mortality of AMD subjects, due to decreased incidence of adverse cardiovascular events [161,162]. Another report from the Rotterdam Study showed that high dietary intake of zinc reduced the hazard ratio of early AMD from 2.25 to 1.27 [163]. A recent systematically report supports that high level of zinc intake has a beneficial effect on progression of dry-type AMD in the elderly subjects [164], suggesting that anti-oxidants or its mediators including zinc have a beneficial effect on the development of AMD in elderly subjects.

7.4. Sickle Cell Anemia

Sickle cell anemia (SCD) is an inherited disease, a condition in which there are not enough healthy red blood cells to carry adequate oxygen throughout the body. The disease is caused by a mutation in the gene encoding iron-rich hemoglobin. Hemoglobin allows red blood cells to carry oxygen from the lungs to all parts of the body. In sickle cell anemia, abnormal hemoglobin causes red blood cells to become rigid, sticky, and misshapen. In sickle cell disease, a single amino acid substitution in β-chain at the sixth position takes place (Val replaces Glu). The sickle cell gene is passed from generation to generation in a pattern of inheritance called autosomal recessive inheritance. This disease is commonly seen in the African American population in the United States.
It has been documented that zinc deficiency is very common in adult SCD subjects [165,166,167,168,169,170]. We previously reported that approximately 60–70% of adult SCD subjects had zinc deficiency based on the plasma zinc level in our medical center [165,166,167,168,169]. These SCD patients with the lower levels of zinc had growth retardation, hypogonadism in male subjects, abnormal dark adaptation, hyperammonemia, and cell-mediated immunological abnormality. The clinical trials showed that zinc supplementation to those SCD patients who had zinc deficiency increased growth and gonadal development in male subjects, improved dark adaptation, decreased plasma ammonia levels, corrected anergy, and increased cell-mediated immunological function [165,166,167,168,169,170,171].
Increasing evidence shows that SCD patients also have an aberration of ROS homeostasis in body, which can worsen the progress of SCD. Thus, zinc supplementation would improve the status of ROS in SCD patients, attenuating the development and progression of SCD. Our clinical trial demonstrated that zinc supplementation (25 mg zinc for 3 months) decreased the incidence of infection, compared to the placebo subjects who did not receive zinc supplementation in SCD patients. After 3 months of follow-up, red blood cells, hemoglobin, hematocrit, plasma zinc, and anti-oxidant power significantly increased; plasma levels of nitrite and nitrate, lipid peroxidation products measured by MDA and HAE, and DNA oxidation intermediate products (8-OHdG), soluble VCAM-1 decreased in zinc-supplemented SCD patients, as compared to the placebo group. Three months of zinc supplementation to those SCD patients also showed significant decreases in LPS-stimulated mRNA levels of TNF-α and IL-1β as well as TNF-α-stimulated activation of NF-κB-DNA binding in MNC cells, compared to the placebo group [67]. These findings clearly suggest the beneficial effects of zinc as an anti-inflammatory and pro-antioxidant mediator in SCD patients.

7.5. Diabetes Mellitus

Diabetes mellitus (DM), in particular type II, is a major metabolic disease, which is widely prevalent worldwide, especially in developed countries. Accumulating evidence from experimental and clinical studies indicates that oxidative stress plays a very important role in the pathogenesis of both types of DM [172]. It is known that significant amounts of free radicals are generated in diabetes by glucose oxidation and non-enzymatic glycation of proteins, resulting in oxidative degradation of glycated proteins. Such aberration of free radical production and its decreased detoxification by anti-oxidant defense mechanisms in the body can cause cellular and molecular damage, including the development of insulin resistance. These consequences of oxidative stress eventually enhance the development of complications of DM. It has been documented that in DM, especially type II, there are decreased levels of zinc in the body [173,174,175,176]. More evidence shows that zinc deficiency is involved in the development and progression of diabetes and that zinc supplementation improves the status of DM, as previously reviewed [176]. Therefore, zinc supplementation might have beneficial effects in DM via several molecular mechanisms including the suppression of ROS generation.
The earlier clinical trial in the patients with DM type I demonstrated that after three months of follow-up, zinc supplementation (30 mg zinc as gluconate daily) decreased lipid peroxidation as measured by blood thiobarbituric acid (a lipid peroxidation biomarker) and increased antioxidant power as measured by blood and erythrocyte glutathione peroxidase [177]. Another earlier clinical trial in patients with DM type II demonstrated that zinc supplementation (30 mg zinc as gluconate daily for 3 months) decreased the blood level of lipid peroxidation as measured by thiobarbituric acid reactive substances (TBARS) compared to the placebo group of the patients [178]. A similar result was found in 56 of the patients with DM type II who received 6 months of zinc supplementation [53].
One meta-analysis study of zinc supplementation on both types of DM has provided supportive evidence showing that zinc supplementation decreases lipid peroxidation and promote glycemic control in DM patients [179]. Another recent more comprehensive meta-analysis study including 111 original research articles of in vitro, in vivo, and clinical trials showed that zinc has an important role in antioxidant defense system against lipid peroxidation, β-cell function, insulin action, glucose homeostasis, and pathogenesis of diabetes and its complications [180]. A more recent clinical trial indicates that six months of 30 mg zinc supplementation can improve glucose metabolism for example in terms of fasting blood glucose, β-cell function, and insulin sensitivity in pre-diabetic subjects [181]. These findings clearly suggest beneficial effects of zinc through several molecular mechanisms including its role in anti-oxidant defense system in DM patients. However, more clinical trials of zinc supplementation in a large sample sizes of DM patients will be required to provide more conclusive evidence for the improvement of DM status.

7.6. Alcohol-Related Liver Disease

Alcohol-related liver disease (ALD) is one of the major causes of chronic liver disease worldwide, due to chronic and high consumption of alcohol or alcohol-containing beverages. This leads to fibrosis, the generation and proliferation of smooth muscle α-actin-positive myofibroblasts of periportal and perisinusoidal areas that results in hepatic cirrhosis [182,183].
Aberrant production and accumulation of ROS or oxidative stress molecules and inflammation have been documented to be associated with the pathogenesis of alcohol-related liver disease [93,183,184]. It is known that acetaldehyde, one major intermediate alcohol metabolite in the body, is a highly reactive oxygen species and is highly toxic to several types of cells such as hepatocytes and cardiocytes. Acetaldehyde can deplete endogenous antioxidant compounds such as glutathione and increase lipid peroxidation, DNA oxidation, and protein oxidation as well as mitochondrial damage, resulting in oxidative stress. Alcohol-derived ROS can also directly trigger the inflammatory response via the activation of oxidant-sensitive NF-κB, which up-regulates the expression and production of inflammatory cytokines/molecules such as TNF-α, IL-6, and other cytokines [93,182,185,186]. Thus, alcohol-induced oxidative stress and the consequent inflammatory response can lead to hepatocyte damage.
It has been documented that zinc deficiency is associated with ALD since alcohol consumption increases zinc excretion in the urine and decreases zinc absorption from the intestine [187,188]. Zinc deficiency enhances the development and progression of ALD. As described above, zinc is a potent pro-antioxidant and anti-inflammatory agent. Therefore, zinc supplementation would have beneficial effects on ALD [121,189]. Animal studies show that zinc supplementation can prevent chronic alcohol-induced liver damage in mice through the inhibition of oxidative stress [190]. One in vitro study indicated that 30 μM of zinc treatment attenuated alcohol-induced cell damage in rat hepatic stellate cells by inhibition of mitogen activated protein kinase (MAPK), stress-activated protein kinase (JNK), NF-κB, transforming growth factor (TGF-β), and tumor necrosis factor (TNF-α), and ROS production [191]. Another animal study revealed that the protective role of zinc in ALD might contribute to the activation of the HNF-4α and PPAR signaling pathways by zinc [118]. Therefore, zinc has a protective role against alcohol toxicity-caused liver cell damage by the inhibition of ROS production and accumulation through the regulation of several molecular signaling pathways.

8. Conclusions and Perspectives

In this article, we have discussed the role of zinc as an anti-inflammatory and anti-oxidative stress agent or mediator in human health and diseases. In summary, the evidence shows that zinc is essential for normal physiological function in humans for maintaining immunity and function as an pro-antioxidant and anti-inflammatory mediator via the role of its co-factor. Zinc is involved in regulation of several molecular signaling pathways of zinc associated proteins/zinc finger proteins such as NF-κB, A20, PPAR, TTP, HNF-4α, Nrf2, KRAB, and MT/MTF-1. Zinc supplementation may be useful for the improvement and/or treatment of human health and diseases in different populations with zinc-deficient conditions due to its physiological and biological functions of immunity, anti-inflammation, and suppression of oxidative stress. Further studies are needed to fully understand the molecular mechanisms of zinc. Well-designed clinical trials are needed in order to fully appreciate the benefits of zinc as an anti-oxidative and anti-inflammatory agent for human health.


This research was funded by the National Institute of Nursing Research, (SBIR-1306012102)

Conflicts of Interest

The authors declare no conflict of interest.


  1. Prasad, A.S.; Miale, A., Jr.; Farid, Z.; Sandstead, H.H.; Schulert, A.R. Zinc Metabolism in Patients with the Syndrome of Iron Deficiency Anemia, Hepatosplenomegaly, Dwarfism, and Hypognadism. J. Lab. Clin. Med. 1963, 61, 537–549. [Google Scholar] [PubMed]
  2. Motadi, S.A.; Mbhenyane, X.G.; Mbhatsani, H.V.; Mabapa, N.S.; Mamabolo, R.L. Prevalence of Iron and Zinc Deficiencies Among Preschool Children Ages 3 to 5 y in Vhembe District, Limpopo Province, South Africa. Nutrition 2015, 31, 452–458. [Google Scholar] [CrossRef] [PubMed]
  3. Rahmati, M.; Safdarian, F.; Zakeri, M.; Zare, S. The Prevalence of Zinc Deficiency in 6-Month to 12-Year Old Children in Bandar Abbas in 2013. Electron. Physician 2017, 9, 5088–5091. [Google Scholar] [CrossRef] [PubMed]
  4. Prasad, A.S.; Beck, F.W.; Snell, D.C.; Kucuk, O. Zinc in Cancer Prevention. Nutr. Cancer 2009, 61, 879–887. [Google Scholar] [CrossRef] [PubMed]
  5. Prasad, A.S.; Fitzgerald, J.T.; Hess, J.W.; Kaplan, J.; Pelen, F.; Dardenne, M. Zinc Deficiency in Elderly Patients. Nutrition 1993, 9, 218–224. [Google Scholar]
  6. Prasad, A.S.; Beck, F.W.; Bao, B.; Fitzgerald, J.T.; Snell, D.C.; Steinberg, J.D.; Cardozo, L.J. Zinc Supplementation Decreases Incidence of Infections in the Elderly: Effect of Zinc on Generation of Cytokines and Oxidative Stress. Am. J. Clin. Nutr. 2007, 85, 837–844. [Google Scholar] [CrossRef] [PubMed]
  7. Bao, B.; Prasad, A.S.; Beck, F.W.; Fitzgerald, J.T.; Snell, D.; Bao, G.W.; Singh, T.; Cardozo, L.J. Zinc Decreases C-Reactive Protein, Lipid Peroxidation, and Inflammatory Cytokines in Elderly Subjects: A Potential Implication of Zinc As an Atheroprotective Agent. Am. J. Clin. Nutr. 2010, 91, 1634–1641. [Google Scholar] [CrossRef]
  8. Prasad, A.S. Zinc in Growth and Development and Spectrum of Human Zinc Deficiency. J. Am. Coll. Nutr. 1988, 7, 377–384. [Google Scholar] [CrossRef]
  9. Prasad, A.S. Impact of the Discovery of Human Zinc Deficiency on Health. J. Am. Coll. Nutr. 2009, 28, 257–265. [Google Scholar] [CrossRef]
  10. Ahmad, W.M.; Bdul Hamid, F.S.; Boul-Khair, M.R. Zinc in Human Health and Disease. Ric. Clin. Lab. 1988, 18, 9–16. [Google Scholar]
  11. Kelleher, S.L.; Seo, Y.A.; Lopez, V. Mammary Gland Zinc Metabolism: Regulation and Dysregulation. Genes Nutr. 2009, 4, 83–94. [Google Scholar] [CrossRef] [PubMed]
  12. Kloubert, V.; Rink, L. Zinc As a Micronutrient and Its Preventive Role of Oxidative Damage in Cells. Food Funct. 2015, 6, 3195–3204. [Google Scholar] [CrossRef] [PubMed]
  13. Antoniou, L.D.; Shalhoub, R.J.; Schechter, G.P. The Effect of Zinc on Cellular Immunity in Chronic Uremia. Am. J. Clin. Nutr. 1981, 34, 1912–1917. [Google Scholar] [CrossRef] [PubMed]
  14. Fraker, P.J.; Gershwin, M.E.; Good, R.A.; Prasad, A. Interrelationships between Zinc and Immune Function. Fed. Proc. 1986, 45, 1474–1479. [Google Scholar] [PubMed]
  15. Prasad, A.S.; Dardenne, M.; Abdallah, J.; Meftah, S.; Brewer, G.J.; Bach, J.F. Serum Thymulin and Zinc Deficiency in Humans. Trans. Assoc. Am. Physicians 1987, 100, 222–231. [Google Scholar] [CrossRef]
  16. Prasad, A.S.; Meftah, S.; Abdallah, J.; Kaplan, J.; Brewer, G.J.; Bach, J.F.; Dardenne, M. Serum Thymulin in Human Zinc Deficiency. J. Clin. Investig. 1988, 82, 1202–1210. [Google Scholar] [CrossRef]
  17. Bao, B.; Prasad, A.S.; Beck, F.W.; Bao, G.W.; Singh, T.; Ali, S.; Sarkar, F.H. Intracellular Free Zinc Up-Regulates IFN-Gamma and T-Bet Essential for Th1 Differentiation in Con-A Stimulated HUT-78 Cells. Biochem. Biophys. Res. Commun. 2011, 407, 703–707. [Google Scholar] [CrossRef]
  18. Prasad, A.S.; Bao, B.; Beck, F.W.; Sarkar, F.H. Zinc Activates NF-KappaB in HUT-78 Cells. J. Lab. Clin. Med. 2001, 138, 250–256. [Google Scholar] [CrossRef]
  19. Prasad, A.S.; Bao, B.; Beck, F.W.; Sarkar, F.H. Zinc Enhances the Expression of Interleukin-2 and Interleukin-2 Receptors in HUT-78 Cells by Way of NF-KappaB Activation. J. Lab. Clin. Med. 2002, 140, 272–289. [Google Scholar] [CrossRef]
  20. Falchuk, K.H. The Molecular Basis for the Role of Zinc in Developmental Biology. In Molecular and Cellular Effects of Nutrition on Disease Processes; Springer: Boston, MA, USA, 1998; pp. 41–48. [Google Scholar]
  21. Wellinghausen, N.; Rink, L. The Significance of Zinc for Leukocyte Biology. J. Leukoc. Biol. 1998, 64, 571–577. [Google Scholar] [CrossRef]
  22. Han, D.; Antunes, F.; Canali, R.; Rettori, D.; Cadenas, E. Voltage-Dependent Anion Channels Control the Release of the Superoxide Anion from Mitochondria to Cytosol. J. Biol. Chem. 2003, 278, 5557–5563. [Google Scholar] [CrossRef] [PubMed]
  23. Schafer, F.Q.; Buettner, G.R. Redox Environment of the Cell As Viewed Through the Redox State of the Glutathione Disulfide/Glutathione Couple. Free Radic. Biol. Med. 2001, 30, 1191–1212. [Google Scholar] [CrossRef]
  24. Lushchak, V.I. Free Radicals, Reactive Oxygen Species, Oxidative Stress and Its Classification. Chem. Biol. Interact. 2014, 224, 164–175. [Google Scholar] [CrossRef] [PubMed]
  25. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free Radicals and Antioxidants in Normal Physiological Functions and Human Disease. Int. J. Biochem. Cell Biol. 2007, 39, 44–84. [Google Scholar] [CrossRef] [PubMed]
  26. Castro, L.; Alvarez, M.N.; Radi, R. Modulatory Role of Nitric Oxide on Superoxide-Dependent Luminol Chemiluminescence. Arch. Biochem. Biophys. 1996, 333, 179–188. [Google Scholar] [CrossRef] [PubMed]
  27. Castro, L.; Freeman, B.A. Reactive Oxygen Species in Human Health and Disease. Nutrition 2001, 2, 161–165. [Google Scholar] [CrossRef]
  28. Lachance, P.A.; Nakat, Z.; Jeong, W.S. Antioxidants: An Integrative Approach. Nutrition 2001, 17, 835–838. [Google Scholar] [CrossRef]
  29. Landmesser, U.; Harrison, D.G. Oxidative Stress and Vascular Damage in Hypertension. Coron. Artery Dis. 2001, 12, 455–461. [Google Scholar] [CrossRef] [PubMed]
  30. DeCoursey, T.E.; Morgan, D.; Cherny, V.V. The Voltage Dependence of NADPH Oxidase Reveals Why Phagocytes Need Proton Channels. Nature 2003, 422, 531–534. [Google Scholar] [CrossRef]
  31. Touyz, R.M. Reactive Oxygen Species and Angiotensin II Signaling in Vascular Cells—Implications in Cardiovascular Disease. Braz. J. Med. Biol. Res. 2004, 37, 1263–1273. [Google Scholar] [CrossRef]
  32. Forman, H.J.; Torres, M. Reactive Oxygen Species and Cell Signaling: Respiratory Burst in Macrophage Signaling. Am. J. Respir. Crit. Care Med. 2002, 166, S4–S8. [Google Scholar] [CrossRef] [PubMed]
  33. Zalba, G.; San, J.G.; Moreno, M.U.; Fortuno, M.A.; Fortuno, A.; Beaumont, F.J.; Diez, J. Oxidative Stress in Arterial Hypertension: Role of NAD(P)H Oxidase. Hypertension 2001, 38, 1395–1399. [Google Scholar] [CrossRef] [PubMed]
  34. Grivennikov, S.I.; Karin, M. Inflammation and Oncogenesis: A Vicious Connection. Curr. Opin. Genet. Dev. 2010, 20, 65–71. [Google Scholar] [CrossRef] [PubMed]
  35. Hansson, G.K. Inflammation, Atherosclerosis, and Coronary Artery Disease. N. Engl. J. Med. 2005, 352, 1685–1695. [Google Scholar] [CrossRef] [PubMed]
  36. Khatami, M. Inflammation, Aging, and Cancer: Tumoricidal Versus Tumorigenesis of Immunity: A Common Denominator Mapping Chronic Diseases. Cell Biochem. Biophys. 2009, 55, 55–79. [Google Scholar] [CrossRef] [PubMed]
  37. Koh, K.K.; Han, S.H.; Quon, M.J. Inflammatory Markers and the Metabolic Syndrome: Insights from Therapeutic Interventions. J. Am. Coll. Cardiol. 2005, 46, 1978–1985. [Google Scholar] [CrossRef] [PubMed]
  38. Sutcliffe, S.; Platz, E.A. Inflammation in the Etiology of Prostate Cancer: An Epidemiologic Perspective. Urol. Oncol. 2007, 25, 242–249. [Google Scholar] [CrossRef]
  39. Fleshner, N.E.; Klotz, L.H. Diet, Androgens, Oxidative Stress and Prostate Cancer Susceptibility. Cancer Metastasis Rev. 1998, 17, 325–330. [Google Scholar] [CrossRef]
  40. Minelli, A.; Bellezza, I.; Conte, C.; Culig, Z. Oxidative Stress-Related Aging: A Role for Prostate Cancer? Biochim. Biophys. Acta 2009, 1795, 83–91. [Google Scholar] [CrossRef]
  41. Khandrika, L.; Kumar, B.; Koul, S.; Maroni, P.; Koul, H.K. Oxidative Stress in Prostate Cancer. Cancer Lett. 2009, 282, 125–136. [Google Scholar] [CrossRef]
  42. Maret, W. The Redox Biology of Redox-Inert Zinc Ions. Free Radic. Biol. Med. 2019, 134, 311–326. [Google Scholar] [CrossRef]
  43. Lee, S.R. Critical Role of Zinc As Either an Antioxidant or a Prooxidant in Cellular Systems. Oxid. Med. Cell. Longev. 2018, 2018, 9156285. [Google Scholar] [CrossRef]
  44. Andrews, G.K. Regulation of Metallothionein Gene Expression by Oxidative Stress and Metal Ions. Biochem. Pharmacol. 2000, 59, 95–104. [Google Scholar] [CrossRef]
  45. Kagi, J.H.; Schaffer, A. Biochemistry of Metallothionein. Biochemistry 1988, 27, 8509–8515. [Google Scholar] [CrossRef]
  46. Prasad, A.S. Clinical, Immunological, Anti-Inflammatory and Antioxidant Roles of Zinc. Exp. Gerontol. 2008, 43, 370–377. [Google Scholar] [CrossRef]
  47. Ho, E.; Ames, B.N. Low Intracellular Zinc Induces Oxidative DNA Damage, Disrupts P53, NFkappa B, and AP1 DNA Binding, and Affects DNA Repair in a Rat Glioma Cell Line. Proc. Natl. Acad. Sci. USA 2002, 99, 16770–16775. [Google Scholar] [CrossRef]
  48. Ho, E.; Courtemanche, C.; Ames, B.N. Zinc Deficiency Induces Oxidative DNA Damage and Increases P53 Expression in Human Lung Fibroblasts. J. Nutr. 2003, 133, 2543–2548. [Google Scholar] [CrossRef]
  49. Ho, E.; Quan, N.; Tsai, Y.H.; Lai, W.; Bray, T.M. Dietary Zinc Supplementation Inhibits NFkappaB Activation and Protects Against Chemically Induced Diabetes in CD1 Mice. Exp. Biol. Med. 2001, 226, 103–111. [Google Scholar] [CrossRef]
  50. Hennig, B.; Meerarani, P.; Toborek, M.; McClain, C.J. Antioxidant-Like Properties of Zinc in Activated Endothelial Cells. J. Am. Coll. Nutr. 1999, 18, 152–158. [Google Scholar] [CrossRef]
  51. Yousef, M.I.; El-Hendy, H.A.; El-Demerdash, F.M.; Elagamy, E.I. Dietary Zinc Deficiency Induced-Changes in the Activity of Enzymes and the Levels of Free Radicals, Lipids and Protein Electrophoretic Behavior in Growing Rats. Toxicology 2002, 175, 223–234. [Google Scholar] [CrossRef]
  52. Candan, F.; Gultekin, F.; Candan, F. Effect of Vitamin C and Zinc on Osmotic Fragility and Lipid Peroxidation in Zinc-Deficient Haemodialysis Patients. Cell Biochem. Funct. 2002, 20, 95–98. [Google Scholar] [CrossRef]
  53. Roussel, A.M.; Kerkeni, A.; Zouari, N.; Mahjoub, S.; Matheau, J.M.; Anderson, R.A. Antioxidant Effects of Zinc Supplementation in Tunisians with Type 2 Diabetes Mellitus. J. Am. Coll. Nutr. 2003, 22, 316–321. [Google Scholar] [CrossRef]
  54. Hopkins, M.H.; Fedirko, V.; Jones, D.P.; Terry, P.D.; Bostick, R.M. Antioxidant Micronutrients and Biomarkers of Oxidative Stress and Inflammation in Colorectal Adenoma Patients: Results from a Randomized, Controlled Clinical Trial. Cancer Epidemiol. Biomark. Prev. 2010, 19, 850–858. [Google Scholar] [CrossRef]
  55. Dimitrova, A.A.; Strashimirov, D.S.; Russeva, A.L.; Andreeva-Gateva, P.A.; Lakova, E.T.; Tzachev, K.N. Effect of Zinc on the Activity of Cu/Zn Superoxide Dismutase and Lipid Profile in Wistar Rats. Folia Med. 2005, 47, 42–46. [Google Scholar]
  56. Goel, A.; Dani, V.; Dhawan, D.K. Protective Effects of Zinc on Lipid Peroxidation, Antioxidant Enzymes and Hepatic Histoarchitecture in Chlorpyrifos-Induced Toxicity. Chem. Biol. Interact. 2005, 156, 131–140. [Google Scholar] [CrossRef]
  57. Vallabhapurapu, S.; Karin, M. Regulation and Function of NF-KappaB Transcription Factors in the Immune System. Annu. Rev. Immunol. 2009, 27, 693–733. [Google Scholar] [CrossRef]
  58. Barnes, P.J. Nuclear Factor-Kappa, B. Int. J. Biochem. Cell Biol. 1997, 29, 867–870. [Google Scholar] [CrossRef]
  59. Perkins, N.D. Achieving Transcriptional Specificity with NF-Kappa, B. Int. J. Biochem. Cell Biol. 1997, 29, 1433–1448. [Google Scholar] [CrossRef]
  60. Baldwin, A.S., Jr. The NF-Kappa B and I Kappa B Proteins: New Discoveries and Insights. Annu. Rev. Immunol. 1996, 14, 649–683. [Google Scholar] [CrossRef]
  61. Oeckinghaus, A.; Ghosh, S. The NF-KappaB Family of Transcription Factors and Its Regulation. Cold Spring Harb. Perspect. Biol. 2009, 1, a000034. [Google Scholar] [CrossRef]
  62. Prasad, A.S. Zinc Is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health. Front. Nutr. 2014, 1, 14. [Google Scholar] [CrossRef]
  63. Vasto, S.; Mocchegiani, E.; Malavolta, M.; Cuppari, I.; Listi, F.; Nuzzo, D.; Ditta, V.; Candore, G.; Caruso, C. Zinc and Inflammatory/Immune Response in Aging. Ann. N. Y. Acad. Sci. 2007, 1100, 111–122. [Google Scholar] [CrossRef]
  64. Otsuka, M.; Fujita, M.; Aoki, T.; Ishii, S.; Sugiura, Y.; Yamamoto, T.; Inoue, J. Novel Zinc Chelators with Dual Activity in the Inhibition of the Kappa B Site-Binding Proteins HIV-EP1 and NF-Kappa, B. J. Med. Chem. 1995, 38, 3264–3270. [Google Scholar] [CrossRef]
  65. Zabel, U.; Schreck, R.; Baeuerle, P.A. DNA Binding of Purified Transcription Factor NF-Kappa, B. Affinity, Specificity, Zn2+ Dependence, and Differential Half-Site Recognition. J. Biol. Chem. 1991, 266, 252–260. [Google Scholar]
  66. Oteiza, P.I.; Clegg, M.S.; Keen, C.L. Short-Term Zinc Deficiency Affects Nuclear Factor-Kappab Nuclear Binding Activity in Rat Testes. J. Nutr. 2001, 131, 21–26. [Google Scholar] [CrossRef]
  67. Bao, B.; Prasad, A.S.; Beck, F.W.; Snell, D.; Suneja, A.; Sarkar, F.H.; Doshi, N.; Fitzgerald, J.T.; Swerdlow, P. Zinc Supplementation Decreases Oxidative Stress, Incidence of Infection, and Generation of Inflammatory Cytokines in Sickle Cell Disease Patients. Transl. Res. 2008, 152, 67–80. [Google Scholar] [CrossRef]
  68. Connell, P.; Young, V.M.; Toborek, M.; Cohen, D.A.; Barve, S.; McClain, C.J.; Hennig, B. Zinc Attenuates Tumor Necrosis Factor-Mediated Activation of Transcription Factors in Endothelial Cells. J. Am. Coll. Nutr. 1997, 16, 411–417. [Google Scholar] [CrossRef]
  69. Prasad, A.S.; Bao, B.; Beck, F.W.; Kucuk, O.; Sarkar, F.H. Antioxidant Effect of Zinc in Humans. Free Radic. Biol. Med. 2004, 37, 1182–1190. [Google Scholar] [CrossRef]
  70. Prasad, A.S.; Bao, B.; Beck, F.W.; Sarkar, F.H. Zinc-Suppressed Inflammatory Cytokines by Induction of A20-Mediated Inhibition of Nuclear Factor-KappaB. Nutrition 2011, 27, 816–823. [Google Scholar] [CrossRef]
  71. Uzzo, R.G.; Leavis, P.; Hatch, W.; Gabai, V.L.; Dulin, N.; Zvartau, N.; Kolenko, V.M. Zinc Inhibits Nuclear Factor-Kappa B Activation and Sensitizes Prostate Cancer Cells to Cytotoxic Agents. Clin. Cancer Res. 2002, 8, 3579–3583. [Google Scholar]
  72. Uzzo, R.G.; Crispen, P.L.; Golovine, K.; Makhov, P.; Horwitz, E.M.; Kolenko, V.M. Diverse Effects of Zinc on NF-KappaB and AP-1 Transcription Factors: Implications for Prostate Cancer Progression. Carcinogenesis 2006, 27, 1980–1990. [Google Scholar] [CrossRef]
  73. Oteiza, P.I.; Clegg, M.S.; Zago, M.P.; Keen, C.L. Zinc Deficiency Induces Oxidative Stress and AP-1 Activation in 3T3 Cells. Free Radic. Biol. Med. 2000, 28, 1091–1099. [Google Scholar] [CrossRef]
  74. Heyninck, K.; Beyaert, R. The Cytokine-Inducible Zinc Finger Protein A20 Inhibits IL-1-Induced NF-KappaB Activation at the Level of TRAF6. FEBS Lett. 1999, 442, 147–150. [Google Scholar] [CrossRef]
  75. Jaattela, M.; Mouritzen, H.; Elling, F.; Bastholm, L. A20 Zinc Finger Protein Inhibits TNF and IL-1 Signaling. J. Immunol. 1996, 156, 1166–1173. [Google Scholar]
  76. Song, H.Y.; Rothe, M.; Goeddel, D.V. The Tumor Necrosis Factor-Inducible Zinc Finger Protein A20 Interacts with TRAF1/TRAF2 and Inhibits NF-KappaB Activation. Proc. Natl. Acad. Sci. USA 1996, 93, 6721–6725. [Google Scholar] [CrossRef]
  77. Lee, E.G.; Boone, D.L.; Chai, S.; Libby, S.L.; Chien, M.; Lodolce, J.P.; Ma, A. Failure to Regulate TNF-Induced NF-KappaB and Cell Death Responses in A20-Deficient Mice. Science 2000, 289, 2350–2354. [Google Scholar] [CrossRef]
  78. Beyaert, R.; Heyninck, K.; Van, H.S. A20 and A20-Binding Proteins As Cellular Inhibitors of Nuclear Factor-Kappa B-Dependent Gene Expression and Apoptosis. Biochem. Pharmacol. 2000, 60, 1143–1151. [Google Scholar] [CrossRef]
  79. Hymowitz, S.G.; Wertz, I.E. A20: From Ubiquitin Editing to Tumour Suppression. Nat. Rev. Cancer 2010, 10, 332–341. [Google Scholar] [CrossRef]
  80. Malynn, B.A.; Ma, A. A20 Takes on Tumors: Tumor Suppression by an Ubiquitin-Editing Enzyme. J. Exp. Med. 2009, 206, 977–980. [Google Scholar] [CrossRef]
  81. Kim, M.H.; Jeong, H.J. Zinc Oxide Nanoparticles Suppress LPS-Induced NF-KappaB Activation by Inducing A20, a Negative Regulator of NF-KappaB, in RAW 264.7 Macrophages. J. Nanosci. Nanotechnol. 2015, 15, 6509–6515. [Google Scholar] [CrossRef]
  82. Blackshear, P.J. Tristetraprolin and Other CCCH Tandem Zinc-Finger Proteins in the Regulation of MRNA Turnover. Biochem. Soc. Trans. 2002, 30, 945–952. [Google Scholar] [CrossRef]
  83. Brooks, S.A.; Blackshear, P.J. Tristetraprolin (TTP): Interactions with MRNA and Proteins, and Current Thoughts on Mechanisms of Action. Biochim. Biophys. Acta 2013, 1829, 666–679. [Google Scholar] [CrossRef]
  84. Kang, J.G.; Amar, M.J.; Remaley, A.T.; Kwon, J.; Blackshear, P.J.; Wang, P.Y.; Hwang, P.M. Zinc Finger Protein Tristetraprolin Interacts with CCL3 MRNA and Regulates Tissue Inflammation. J. Immunol. 2011, 187, 2696–2701. [Google Scholar] [CrossRef]
  85. Carrick, D.M.; Lai, W.S.; Blackshear, P.J. The Tandem CCCH Zinc Finger Protein Tristetraprolin and Its Relevance to Cytokine MRNA Turnover and Arthritis. Arthritis Res. Ther. 2004, 6, 248–264. [Google Scholar] [CrossRef]
  86. Carballo, E.; Lai, W.S.; Blackshear, P.J. Feedback Inhibition of Macrophage Tumor Necrosis Factor-Alpha Production by Tristetraprolin. Science 1998, 281, 1001–1005. [Google Scholar] [CrossRef]
  87. Carballo, E.; Gilkeson, G.S.; Blackshear, P.J. Bone Marrow Transplantation Reproduces the Tristetraprolin-Deficiency Syndrome in Recombination Activating Gene-2 (-/-) Mice. Evidence That Monocyte/Macrophage Progenitors May Be Responsible for TNFalpha Overproduction. J. Clin. Investig. 1997, 100, 986–995. [Google Scholar] [CrossRef]
  88. Taylor, G.A.; Carballo, E.; Lee, D.M.; Lai, W.S.; Thompson, M.J.; Patel, D.D.; Schenkman, D.I.; Gilkeson, G.S.; Broxmeyer, H.E.; Haynes, B.F.; et al. A Pathogenetic Role for TNF Alpha in the Syndrome of Cachexia, Arthritis, and Autoimmunity Resulting from Tristetraprolin (TTP) Deficiency. Immunity 1996, 4, 445–454. [Google Scholar] [CrossRef]
  89. Bollmann, F.; Wu, Z.; Oelze, M.; Siuda, D.; Xia, N.; Henke, J.; Daiber, A.; Li, H.; Stumpo, D.J.; Blackshear, P.J.; et al. Endothelial Dysfunction in Tristetraprolin-Deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-Alpha Expression. J. Biol. Chem. 2014, 289, 15653–15665. [Google Scholar] [CrossRef]
  90. Carballo, E.; Blackshear, P.J. Roles of Tumor Necrosis Factor-Alpha Receptor Subtypes in the Pathogenesis of the Tristetraprolin-Deficiency Syndrome. Blood 2001, 98, 2389–2395. [Google Scholar] [CrossRef]
  91. Taylor, G.A.; Blackshear, P.J. Zinc Inhibits Turnover of Labile MRNAs in Intact Cells. J. Cell Physiol. 1995, 162, 378–387. [Google Scholar] [CrossRef]
  92. Blaschke, F.; Takata, Y.; Caglayan, E.; Law, R.E.; Hsueh, W.A. Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes. Arterioscler. Thromb. Vasc. Biol. 2006, 26, 28–40. [Google Scholar] [CrossRef]
  93. Ceni, E.; Mello, T.; Galli, A. Pathogenesis of Alcoholic Liver Disease: Role of Oxidative Metabolism. World J. Gastroenterol. 2014, 20, 17756–17772. [Google Scholar] [CrossRef]
  94. Shen, H.; Oesterling, E.; Stromberg, A.; Toborek, M.; MacDonald, R.; Hennig, B. Zinc Deficiency Induces Vascular Pro-Inflammatory Parameters Associated with NF-KappaB and PPAR Signaling. J. Am. Coll. Nutr. 2008, 27, 577–587. [Google Scholar] [CrossRef]
  95. Jiang, C.; Ting, A.T.; Seed, B. PPAR-Gamma Agonists Inhibit Production of Monocyte Inflammatory Cytokines. Nature 1998, 391, 82–86. [Google Scholar] [CrossRef]
  96. Ricote, M.; Li, A.C.; Willson, T.M.; Kelly, C.J.; Glass, C.K. The Peroxisome Proliferator-Activated Receptor-Gamma Is a Negative Regulator of Macrophage Activation. Nature 1998, 391, 79–82. [Google Scholar] [CrossRef]
  97. Graham, T.L.; Mookherjee, C.; Suckling, K.E.; Palmer, C.N.; Patel, L. The PPARdelta Agonist GW0742X Reduces Atherosclerosis in LDLR(-/-) Mice. Atherosclerosis 2005, 181, 29–37. [Google Scholar] [CrossRef]
  98. Han, S.H.; Quon, M.J.; Koh, K.K. Beneficial Vascular and Metabolic Effects of Peroxisome Proliferator-Activated Receptor-Alpha Activators. Hypertension 2005, 46, 1086–1092. [Google Scholar] [CrossRef]
  99. Li, A.C.; Brown, K.K.; Silvestre, M.J.; Willson, T.M.; Palinski, W.; Glass, C.K. Peroxisome Proliferator-Activated Receptor Gamma Ligands Inhibit Development of Atherosclerosis in LDL Receptor-Deficient Mice. J. Clin. Investig. 2000, 106, 523–531. [Google Scholar] [CrossRef]
  100. Li, A.C.; Binder, C.J.; Gutierrez, A.; Brown, K.K.; Plotkin, C.R.; Pattison, J.W.; Valledor, A.F.; Davis, R.A.; Willson, T.M.; Witztum, J.L.; et al. Differential Inhibition of Macrophage Foam-Cell Formation and Atherosclerosis in Mice by PPARalpha, Beta/Delta, and Gamma. J. Clin. Investig. 2004, 114, 1564–1576. [Google Scholar] [CrossRef]
  101. Israelian-Konaraki, Z.; Reaven, P.D. Peroxisome Proliferator-Activated Receptor-Alpha and Atherosclerosis: From Basic Mechanisms to Clinical Implications. Cardiol. Rev. 2005, 13, 240–246. [Google Scholar] [CrossRef]
  102. Delerive, P.; De, B.K.; Besnard, S.; Vanden, B.W.; Peters, J.M.; Gonzalez, F.J.; Fruchart, J.C.; Tedgui, A.; Haegeman, G.; Staels, B. Peroxisome Proliferator-Activated Receptor Alpha Negatively Regulates the Vascular Inflammatory Gene Response by Negative Cross-Talk with Transcription Factors NF-KappaB and AP-1. J. Biol. Chem. 1999, 274, 32048–32054. [Google Scholar] [CrossRef]
  103. Meerarani, P.; Reiterer, G.; Toborek, M.; Hennig, B. Zinc Modulates PPARgamma Signaling and Activation of Porcine Endothelial Cells. J. Nutr. 2003, 133, 3058–3064. [Google Scholar] [CrossRef]
  104. Reiterer, G.; Toborek, M.; Hennig, B. Peroxisome Proliferator Activated Receptors Alpha and Gamma Require Zinc for Their Anti-Inflammatory Properties in Porcine Vascular Endothelial Cells. J. Nutr. 2004, 134, 1711–1715. [Google Scholar] [CrossRef]
  105. Alam, J.; Stewart, D.; Touchard, C.; Boinapally, S.; Choi, A.M.; Cook, J.L. Nrf2, a Cap’n’Collar Transcription Factor, Regulates Induction of the Heme Oxygenase-1 Gene. J. Biol. Chem. 1999, 274, 26071–26078. [Google Scholar] [CrossRef]
  106. Mastaloudis, A.; Wood, S.M. Age-Related Changes in Cellular Protection, Purification, and Inflammation-Related Gene Expression: Role of Dietary Phytonutrients. Ann. N. Y. Acad. Sci. 2012, 1259, 112–120. [Google Scholar] [CrossRef]
  107. Hybertson, B.M.; Gao, B.; Bose, S.K.; McCord, J.M. Oxidative Stress in Health and Disease: The Therapeutic Potential of Nrf2 Activation. Mol. Asp. Med. 2011, 32, 234–246. [Google Scholar] [CrossRef]
  108. Mehta, A.J.; Joshi, P.C.; Fan, X.; Brown, L.A.; Ritzenthaler, J.D.; Roman, J.; Guidot, D.M. Zinc Supplementation Restores PU.1 and Nrf2 Nuclear Binding in Alveolar Macrophages and Improves Redox Balance and Bacterial Clearance in the Lungs of Alcohol-Fed Rats. Alcohol Clin. Exp. Res. 2011, 35, 1519–1528. [Google Scholar] [CrossRef]
  109. Lee, J.H.; Khor, T.O.; Shu, L.; Su, Z.Y.; Fuentes, F.; Kong, A.N. Dietary Phytochemicals and Cancer Prevention: Nrf2 Signaling, Epigenetics, and Cell Death Mechanisms in Blocking Cancer Initiation and Progression. Pharmacol. Ther. 2013, 137, 153–171. [Google Scholar] [CrossRef]
  110. Zhou, S.; Ye, W.; Zhang, M.; Liang, J. The Effects of Nrf2 on Tumor Angiogenesis: A Review of the Possible Mechanisms of Action. Crit Rev. Eukaryot. Gene Expr. 2012, 22, 149–160. [Google Scholar] [CrossRef]
  111. Sinha, D.; Biswas, J.; Bishayee, A. Nrf2-Mediated Redox Signaling in Arsenic Carcinogenesis: A Review. Arch. Toxicol. 2013, 87, 383–396. [Google Scholar] [CrossRef]
  112. Zhao, Y.; Tan, Y.; Dai, J.; Li, B.; Guo, L.; Cui, J.; Wang, G.; Shi, X.; Zhang, X.; Mellen, N.; et al. Exacerbation of Diabetes-Induced Testicular Apoptosis by Zinc Deficiency Is Most Likely Associated with Oxidative Stress, P38 MAPK Activation, and P53 Activation in Mice. Toxicol. Lett. 2011, 200, 100–106. [Google Scholar] [CrossRef]
  113. Smith, A.F.; Loo, G. Upregulation of Haeme Oxygenase-1 by Zinc in HCT-116 Cells. Free Radic. Res. 2012, 46, 1099–1107. [Google Scholar] [CrossRef]
  114. Cortese, M.M.; Suschek, C.V.; Wetzel, W.; Kroncke, K.D.; Kolb-Bachofen, V. Zinc Protects Endothelial Cells from Hydrogen Peroxide Via Nrf2-Dependent Stimulation of Glutathione Biosynthesis. Free Radic. Biol. Med. 2008, 44, 2002–2012. [Google Scholar] [CrossRef]
  115. Schrem, H.; Klempnauer, J.; Borlak, J. Liver-Enriched Transcription Factors in Liver Function and Development. Part I: The Hepatocyte Nuclear Factor Network and Liver-Specific Gene Expression. Pharmacol. Rev. 2002, 54, 129–158. [Google Scholar] [CrossRef]
  116. Schaeffer, E.; Guillou, F.; Part, D.; Zakin, M.M. A Different Combination of Transcription Factors Modulates the Expression of the Human Transferrin Promoter in Liver and Sertoli Cells. J. Biol. Chem. 1993, 268, 23399–23408. [Google Scholar]
  117. Guo, H.; Wei, J.; Inoue, Y.; Gonzalez, F.J.; Kuo, P.C. Serine/Threonine Phosphorylation Regulates HNF-4alpha-Dependent Redox-Mediated INOS Expression in Hepatocytes. Am. J. Physiol. Cell Physiol. 2003, 284, C1090–C1099. [Google Scholar] [CrossRef]
  118. Kang, X.; Zhong, W.; Liu, J.; Song, Z.; McClain, C.J.; Kang, Y.J.; Zhou, Z. Zinc Supplementation Reverses Alcohol-Induced Steatosis in Mice Through Reactivating Hepatocyte Nuclear Factor-4alpha and Peroxisome Proliferator-Activated Receptor-Alpha. Hepatology 2009, 50, 1241–1250. [Google Scholar] [CrossRef]
  119. Zhou, Z. Zinc and Alcoholic Liver Disease. Dig. Dis. 2010, 28, 745–750. [Google Scholar] [CrossRef]
  120. Matsuo, S.; Ogawa, M.; Muckenthaler, M.U.; Mizui, Y.; Sasaki, S.; Fujimura, T.; Takizawa, M.; Ariga, N.; Ozaki, H.; Sakaguchi, M.; et al. Hepatocyte Nuclear Factor 4alpha Controls Iron Metabolism and Regulates Transferrin Receptor 2 in Mouse Liver. J. Biol. Chem. 2015, 290, 30855–30865. [Google Scholar] [CrossRef]
  121. Kang, Y.J.; Zhou, Z. Zinc Prevention and Treatment of Alcoholic Liver Disease. Mol. Asp. Med. 2005, 26, 391–404. [Google Scholar] [CrossRef]
  122. Bellefroid, E.J.; Poncelet, D.A.; Lecocq, P.J.; Revelant, O.; Martial, J.A. The Evolutionarily Conserved Kruppel-Associated Box Domain Defines a Subfamily of Eukaryotic Multifingered Proteins. Proc. Natl. Acad. Sci. USA 1991, 88, 3608–3612. [Google Scholar] [CrossRef]
  123. Urrutia, R. KRAB-Containing Zinc-Finger Repressor Proteins. Genome Biol. 2003, 4, 231–234. [Google Scholar] [CrossRef]
  124. Deng, Y.; Liu, B.; Fan, X.; Wang, Y.; Tang, M.; Mo, X.; Li, Y.; Ying, Z.; Wan, Y.; Luo, N.; et al. ZNF552, a Novel Human KRAB/C2H2 Zinc Finger Protein, Inhibits AP-1- and SRE-Mediated Transcriptional Activity. BMB Rep. 2010, 43, 193–198. [Google Scholar] [CrossRef]
  125. Yang, H.; Yuan, W.; Wang, Y.; Zhu, C.; Liu, B.; Wang, Y.; Yang, D.; Li, Y.; Wang, C.; Wu, X.; et al. ZNF649, a Novel Kruppel Type Zinc-Finger Protein, Functions As a Transcriptional Suppressor. Biochem. Biophys. Res. Commun. 2005, 333, 206–215. [Google Scholar] [CrossRef]
  126. Ou, Y.; Wang, S.; Cai, Z.; Wang, Y.; Wang, C.; Li, Y.; Li, F.; Yuan, W.; Liu, B.; Wu, X.; et al. ZNF328, a Novel Human Zinc-Finger Protein, Suppresses Transcriptional Activities of SRE and AP-1. Biochem. Biophys. Res. Commun. 2005, 333, 1034–1044. [Google Scholar] [CrossRef]
  127. Juarez-Rebollar, D.; Rios, C.; Nava-Ruiz, C.; Mendez-Armenta, M. Metallothionein in Brain Disorders. Oxid. Med. Cell Longev. 2017, 2017, 5828056. [Google Scholar] [CrossRef]
  128. Kagi, J.H. Overview of Metallothionein. Methods Enzymol. 1991, 205, 613–626. [Google Scholar]
  129. Sharma, S.; Ebadi, M. Significance of Metallothioneins in Aging Brain. Neurochem. Int. 2014, 65, 40–48. [Google Scholar] [CrossRef]
  130. Thornalley, P.J.; Vasak, M. Possible Role for Metallothionein in Protection Against Radiation-Induced Oxidative Stress. Kinetics and Mechanism of Its Reaction with Superoxide and Hydroxyl Radicals. Biochim. Biophys. Acta 1985, 827, 36–44. [Google Scholar] [CrossRef]
  131. Abel, J.; de, R.N. Inhibition of Hydroxyl-Radical-Generated DNA Degradation by Metallothionein. Toxicol. Lett. 1989, 47, 191–196. [Google Scholar] [CrossRef]
  132. Thomas, J.P.; Bachowski, G.J.; Girotti, A.W. Inhibition of Cell Membrane Lipid Peroxidation by Cadmium- and Zinc-Metallothioneins. Biochim. Biophys. Acta 1986, 884, 448–461. [Google Scholar] [CrossRef]
  133. Asmussen, J.W.; Von Sperling, M.L.; Penkowa, M. Intraneuronal Signaling Pathways of Metallothionein. J. Neurosci. Res. 2009, 87, 2926–2936. [Google Scholar] [CrossRef]
  134. Rahman, M.T.; Karim, M.M. Metallothionein: A Potential Link in the Regulation of Zinc in Nutritional Immunity. Biol. Trace Elem. Res. 2018, 182, 1–3. [Google Scholar] [CrossRef]
  135. Haase, H.; Mazzatti, D.J.; White, A.; Ibs, K.H.; Engelhardt, G.; Hebel, S.; Powell, J.R.; Rink, L. Differential Gene Expression After Zinc Supplementation and Deprivation in Human Leukocyte Subsets. Mol. Med. 2007, 13, 362–370. [Google Scholar] [CrossRef]
  136. Langmade, S.J.; Ravindra, R.; Daniels, P.J.; Andrews, G.K. The Transcription Factor MTF-1 Mediates Metal Regulation of the Mouse ZnT1 Gene. J. Biol. Chem. 2000, 275, 34803–34809. [Google Scholar] [CrossRef]
  137. Medici, V.; Santon, A.; Sturniolo, G.C.; D’Inca, R.; Giannetto, S.; Albergoni, V.; Irato, P. Metallothionein and Antioxidant Enzymes in Long-Evans Cinnamon Rats Treated with Zinc. Arch. Toxicol. 2002, 76, 509–516. [Google Scholar] [CrossRef]
  138. Radtke, F.; Heuchel, R.; Georgiev, O.; Hergersberg, M.; Gariglio, M.; Dembic, Z.; Schaffner, W. Cloned Transcription Factor MTF-1 Activates the Mouse Metallothionein I Promoter. EMBO J. 1993, 12, 1355–1362. [Google Scholar] [CrossRef]
  139. Laity, J.H.; Andrews, G.K. Understanding the Mechanisms of Zinc-Sensing by Metal-Response Element Binding Transcription Factor-1 (MTF-1). Arch. Biochem. Biophys. 2007, 463, 201–210. [Google Scholar] [CrossRef]
  140. Andrews, G.K. Cellular Zinc Sensors: MTF-1 Regulation of Gene Expression. Biometals 2001, 14, 223–237. [Google Scholar] [CrossRef]
  141. Gunes, C.; Heuchel, R.; Georgiev, O.; Muller, K.H.; Lichtlen, P.; Bluthmann, H.; Marino, S.; Aguzzi, A.; Schaffner, W. Embryonic Lethality and Liver Degeneration in Mice Lacking the Metal-Responsive Transcriptional Activator MTF-1. EMBO J. 1998, 17, 2846–2854. [Google Scholar] [CrossRef]
  142. Bittel, D.C.; Smirnova, I.V.; Andrews, G.K. Functional Heterogeneity in the Zinc Fingers of Metalloregulatory Protein Metal Response Element-Binding Transcription Factor-1. J. Biol. Chem. 2000, 275, 37194–37201. [Google Scholar] [CrossRef]
  143. Hardyman, J.E.; Tyson, J.; Jackson, K.A.; Aldridge, C.; Cockell, S.J.; Wakeling, L.A.; Valentine, R.A.; Ford, D. Zinc Sensing by Metal-Responsive Transcription Factor 1 (MTF1) Controls Metallothionein and ZnT1 Expression to Buffer the Sensitivity of the Transcriptome Response to Zinc. Metallomics 2016, 8, 337–343. [Google Scholar] [CrossRef]
  144. Jiang, H.; Daniels, P.J.; Andrews, G.K. Putative Zinc-Sensing Zinc Fingers of Metal-Response Element-Binding Transcription Factor-1 Stabilize a Metal-Dependent Chromatin Complex on the Endogenous Metallothionein-I Promoter. J. Biol. Chem. 2003, 278, 30394–30402. [Google Scholar] [CrossRef]
  145. Prasad, A.S.; Beck, F.W.; Bao, B.; Snell, D.; Fitzgerald, J.T. Duration and Severity of Symptoms and Levels of Plasma Interleukin-1 Receptor Antagonist, Soluble Tumor Necrosis Factor Receptor, and Adhesion Molecules in Patients with Common Cold Treated with Zinc Acetate. J. Infect. Dis. 2008, 197, 795–802. [Google Scholar] [CrossRef]
  146. Prasad, A.S.; Fitzgerald, J.T.; Bao, B.; Beck, F.W.; Chandrasekar, P.H. Duration of Symptoms and Plasma Cytokine Levels in Patients with the Common Cold Treated with Zinc Acetate. A Randomized, Double-Blind, Placebo-Controlled Trial. Ann. Intern. Med. 2000, 133, 245–252. [Google Scholar] [CrossRef]
  147. Hodkinson, C.F.; Kelly, M.; Coudray, C.; Gilmore, W.S.; Hannigan, B.M.; O’Connor, J.M.; Strain, J.J.; Wallace, J.M. Zinc Status and Age-Related Changes in Peripheral Blood Leukocyte Subpopulations in Healthy Men and Women Aged 55-70 Y: The ZENITH Study. Eur. J. Clin. Nutr. 2005, 59 (Suppl. 2), S63–S67. [Google Scholar] [CrossRef]
  148. Andriollo-Sanchez, M.; Hininger-Favier, I.; Meunier, N.; Toti, E.; Zaccaria, M.; Brandolini-Bunlon, M.; Polito, A.; O’Connor, J.M.; Ferry, M.; Coudray, C.; et al. Zinc Intake and Status in Middle-Aged and Older European Subjects: The ZENITH Study. Eur. J. Clin. Nutr. 2005, 59 (Suppl. 2), S37–S41. [Google Scholar] [CrossRef]
  149. Stewart-Knox, B.J.; Simpson, E.E.; Parr, H.; Rae, G.; Polito, A.; Intorre, F.; Meunier, N.; Andriollo-Sanchez, M.; O’Connor, J.M.; Coudray, C.; et al. Zinc Status and Taste Acuity in Older Europeans: The ZENITH Study. Eur. J. Clin. Nutr. 2005, 59 (Suppl. 2), S31–S36. [Google Scholar] [CrossRef]
  150. Meunier, N.; O’Connor, J.M.; Maiani, G.; Cashman, K.D.; Secker, D.L.; Ferry, M.; Roussel, A.M.; Coudray, C. Importance of Zinc in the Elderly: The ZENITH Study. Eur. J. Clin. Nutr. 2005, 59 (Suppl. 2), S1–S4. [Google Scholar] [CrossRef]
  151. Mocchegiani, E. Zinc and Ageing: Third Zincage Conference. Immun. Ageing 2007, 4, 5. [Google Scholar] [CrossRef]
  152. Prasad, A.S.; Bao, B.; Beck, F.W.; Sarkar, F.H. Correction of Interleukin-2 Gene Expression by in Vitro Zinc Addition to Mononuclear Cells from Zinc-Deficient Human Subjects: A Specific Test for Zinc Deficiency in Humans. Transl. Res. 2006, 148, 325–333. [Google Scholar] [CrossRef]
  153. Cabreiro, F.; Perichon, M.; Jatje, J.; Malavolta, M.; Mocchegiani, E.; Friguet, B.; Petropoulos, I. Zinc Supplementation in the Elderly Subjects: Effect on Oxidized Protein Degradation and Repair Systems in Peripheral Blood Lymphocytes. Exp. Gerontol. 2008, 43, 483–487. [Google Scholar] [CrossRef]
  154. Gordois, A.; Cutler, H.; Pezzullo, L.; Gordon, K.; Cruess, A.; Winyard, S.; Hamilton, W.; Chua, K. An Estimation of the Worldwide Economic and Health Burden of Visual Impairment. Glob. Public Health. 2012, 7, 465–481. [Google Scholar] [CrossRef]
  155. Nita, M.; Grzybowski, A. The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults. Oxid. Med. Cell Longev. 2016, 2016, 3164734. [Google Scholar] [CrossRef]
  156. Beatty, S.; Koh, H.; Phil, M.; Henson, D.; Boulton, M. The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration. Surv. Ophthalmol. 2000, 45, 115–134. [Google Scholar] [CrossRef]
  157. Lu, L.; Hackett, S.F.; Mincey, A.; Lai, H.; Campochiaro, P.A. Effects of Different Types of Oxidative Stress in RPE Cells. J. Cell Physiol. 2006, 206, 119–125. [Google Scholar] [CrossRef]
  158. Zarbin, M.A. Current Concepts in the Pathogenesis of Age-Related Macular Degeneration. Arch. Ophthalmol. 2004, 122, 598–614. [Google Scholar] [CrossRef]
  159. Ung, L.; Pattamatta, U.; Carnt, N.; Wilkinson-Berka, J.L.; Liew, G.; White, A.J.R. Oxidative Stress and Reactive Oxygen Species: A Review of Their Role in Ocular Disease. Clin. Sci. 2017, 131, 2865–2883. [Google Scholar] [CrossRef]
  160. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation with Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch. Ophthalmol. 2001, 119, 1417–1436. [CrossRef]
  161. Clemons, T.E.; Kurinij, N.; Sperduto, R.D. Associations of Mortality with Ocular Disorders and an Intervention of High-Dose Antioxidants and Zinc in the Age-Related Eye Disease Study: AREDS Report No. 13. Arch. Ophthalmol. 2004, 122, 716–726. [Google Scholar]
  162. Chew, E.Y.; Klein, M.L.; Clemons, T.E.; Agron, E.; Abecasis, G.R. Genetic Testing in Persons with Age-Related Macular Degeneration and the Use of the AREDS Supplements: To Test or Not to Test? Ophthalmology 2015, 122, 212–215. [Google Scholar] [CrossRef]
  163. Ho, L.; van, L.R.; Witteman, J.C.; van Duijn, C.M.; Uitterlinden, A.G.; Hofman, A.; de Jong, P.T.; Vingerling, J.R.; Klaver, C.C. Reducing the Genetic Risk of Age-Related Macular Degeneration with Dietary Antioxidants, Zinc, and Omega-3 Fatty Acids: The Rotterdam Study. Arch. Ophthalmol. 2011, 129, 758–766. [Google Scholar] [CrossRef]
  164. Evans, J.R.; Lawrenson, J.G. Antioxidant Vitamin and Mineral Supplements for Slowing the Progression of Age-Related Macular Degeneration. Cochrane. Database. Syst. Rev. 2017, 7, CD000254. [Google Scholar] [CrossRef]
  165. Prasad, A.S.; Schoomaker, E.B.; Ortega, J.; Brewer, G.J.; Oberleas, D.; Oelshlegel, F.J., Jr. Zinc Deficiency in Sickle Cell Disease. Clin. Chem. 1975, 21, 582–587. [Google Scholar]
  166. Prasad, A.S.; Cossack, Z.T. Zinc Supplementation and Growth in Sickle Cell Disease. Ann. Intern. Med. 1984, 100, 367–371. [Google Scholar] [CrossRef]
  167. Prasad, A.S.; Abbasi, A.A.; Rabbani, P.; DuMouchelle, E. Effect of Zinc Supplementation on Serum Testosterone Level in Adult Male Sickle Cell Anemia Subjects. Am. J. Hematol. 1981, 10, 119–127. [Google Scholar] [CrossRef]
  168. Warth, J.A.; Prasad, A.S.; Zwas, F.; Frank, R.N. Abnormal Dark Adaptation in Sickle Cell Anemia. J. Lab Clin. Med. 1981, 98, 189–194. [Google Scholar]
  169. Ballester, O.F.; Abdallah, J.M.; Prasad, A.S. Lymphocyte Subpopulation Abnormalities in Sickle Cell Anemia: A Distinctive Pattern from That of AIDS. Am. J. Hematol. 1986, 21, 23–27. [Google Scholar] [CrossRef]
  170. Niell, H.B.; Leach, B.E.; Kraus, A.P. Zinc Metabolism in Sickle Cell Anemia. JAMA. 1979, 242, 2686–2687. [Google Scholar] [CrossRef]
  171. Beck, F.W.; Kaplan, J.; Fine, N.; Handschu, W.; Prasad, A.S. Decreased Expression of CD73 (Ecto-5′-Nucleotidase) in the CD8+ Subset Is Associated with Zinc Deficiency in Human Patients. J. Lab. Clin. Med. 1997, 130, 147–156. [Google Scholar] [CrossRef]
  172. Maritim, A.C.; Sanders, R.A.; Watkins, J.B., III. Diabetes, Oxidative Stress, and Antioxidants: A Review. J. Biochem. Mol. Toxicol. 2003, 17, 24–38. [Google Scholar] [CrossRef]
  173. Beletate, V.; El Dib, R.P.; Atallah, A.N. Zinc Supplementation for the Prevention of Type 2 Diabetes Mellitus. Cochrane Database Syst. Rev. 2007, 28, CD005525. [Google Scholar]
  174. DiSilvestro, R.A. Zinc in Relation to Diabetes and Oxidative Disease. J. Nutr. 2000, 130, 1509S–1511S. [Google Scholar] [CrossRef]
  175. Islam, M.S.; Loots, D.T. Diabetes, Metallothionein, and Zinc Interactions: A Review. Biofactors 2007, 29, 203–212. [Google Scholar] [CrossRef]
  176. Jansen, J.; Karges, W.; Rink, L. Zinc and Diabetes--Clinical Links and Molecular Mechanisms. J. Nutr. Biochem. 2009, 20, 399–417. [Google Scholar] [CrossRef]
  177. Faure, P.; Benhamou, P.Y.; Perard, A.; Halimi, S.; Roussel, A.M. Lipid Peroxidation in Insulin-Dependent Diabetic Patients with Early Retina Degenerative Lesions: Effects of an Oral Zinc Supplementation. Eur. J. Clin. Nutr. 1995, 49, 282–288. [Google Scholar]
  178. Anderson, R.A.; Roussel, A.M.; Zouari, N.; Mahjoub, S.; Matheau, J.M.; Kerkeni, A. Potential Antioxidant Effects of Zinc and Chromium Supplementation in People with Type 2 Diabetes Mellitus. J. Am. Coll. Nutr. 2001, 20, 212–218. [Google Scholar] [CrossRef]
  179. Jayawardena, R.; Ranasinghe, P.; Galappatthy, P.; Malkanthi, R.; Constantine, G.; Katulanda, P. Effects of Zinc Supplementation on Diabetes Mellitus: A Systematic Review and Meta-Analysis. Diabetol. Metab Syndr. 2012, 19, 13–14. [Google Scholar] [CrossRef]
  180. Ranasinghe, P.; Pigera, S.; Galappatthy, P.; Katulanda, P.; Constantine, G.R. Zinc and Diabetes Mellitus: Understanding Molecular Mechanisms and Clinical Implications. DARU 2015, 23, 44. [Google Scholar] [CrossRef]
  181. Islam, M.R.; Attia, J.; Ali, L.; McEvoy, M.; Selim, S.; Sibbritt, D.; Akhter, A.; Akter, S.; Peel, R.; Faruque, O.; et al. Zinc Supplementation for Improving Glucose Handling in Pre-Diabetes: A Double Blind Randomized Placebo Controlled Pilot Study. Diabetes Res. Clin. Pract. 2016, 115, 39–46. [Google Scholar] [CrossRef]
  182. Altamirano, J.; Bataller, R. Alcoholic Liver Disease: Pathogenesis and New Targets for Therapy. Nat. Rev. Gastroenterol. Hepatol. 2011, 8, 491–501. [Google Scholar] [CrossRef]
  183. Ghorbani, Z.; Hajizadeh, M.; Hekmatdoost, A. Dietary Supplementation in Patients with Alcoholic Liver Disease: A Review on Current Evidence. Hepatobiliary. Pancreat. Dis. Int. 2016, 15, 348–360. [Google Scholar] [CrossRef]
  184. Ambade, A.; Mandrekar, P. Oxidative Stress and Inflammation: Essential Partners in Alcoholic Liver Disease. Int. J. Hepatol. 2012, 2012, 853175. [Google Scholar] [CrossRef]
  185. McClain, C.J.; Barve, S.S.; Barve, A.; Marsano, L. Alcoholic Liver Disease and Malnutrition. Alcohol Clin. Exp. Res. 2011, 35, 815–820. [Google Scholar] [CrossRef]
  186. Kaur, J.; Shalini, S.; Bansal, M.P. Influence of Vitamin E on Alcohol-Induced Changes in Antioxidant Defenses in Mice Liver. Toxicol. Mech. Methods 2010, 20, 82–89. [Google Scholar] [CrossRef]
  187. Dinsmore, W.; Callender, M.E.; McMaster, D.; Todd, S.J.; Love, A.H. Zinc Absorption in Alcoholics Using Zinc-65. Digestion 1985, 32, 238–242. [Google Scholar] [CrossRef]
  188. Valberg, L.S.; Flanagan, P.R.; Ghent, C.N.; Chamberlain, M.J. Zinc Absorption and Leukocyte Zinc in Alcoholic and Nonalcoholic Cirrhosis. Dig. Dis. Sci. 1985, 30, 329–333. [Google Scholar] [CrossRef]
  189. Mohammad, M.K.; Zhou, Z.; Cave, M.; Barve, A.; McClain, C.J. Zinc and Liver Disease. Nutr. Clin. Pract. 2012, 27, 8–20. [Google Scholar] [CrossRef]
  190. Zhou, Z.; Wang, L.; Song, Z.; Saari, J.T.; McClain, C.J.; Kang, Y.J. Zinc Supplementation Prevents Alcoholic Liver Injury in Mice Through Attenuation of Oxidative Stress. Am. J. Pathol. 2005, 166, 1681–1690. [Google Scholar] [CrossRef]
  191. Szuster-Ciesielska, A.; Plewka, K.; Daniluk, J.; Kandefer-Szerszen, M. Zinc Supplementation Attenuates Ethanol- and Acetaldehyde-Induced Liver Stellate Cell Activation by Inhibiting Reactive Oxygen Species (ROS) Production and by Influencing Intracellular Signaling. Biochem. Pharmacol. 2009, 78, 301–314. [Google Scholar] [CrossRef]
Back to TopTop