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The essential role of zinc in human health was first suggested by our studies in growth-retarded Iranian villagers in 1961. Our later studies in 1963 established conclusively that zinc was essential for human and that zinc deficiency resulted in severe growth retardation, hypogonadism in males, immune dysfunctions, and cognitive function impairment. The suggestion that zinc was an essential element for humans remained very controversial, but in 1974, the USA National Academy of Sciences declared zinc as an essential element for humans and established the recommended dietary allowances. In 1978, the FDA and other regulatory agencies made it mandatory to include zinc in total parenteral nutrition fluids, which resulted in saving many lives. During the past five decades, tremendous progress has been made in the understanding of the biochemical role of zinc, and we now know that zinc therapy has impacted significantly on human health and diseases. In this review, I plan to present a brief historical review of the discovery of zinc as an essential element for humans, the clinical manifestations of zinc deficiency, its therapeutic impact on human health and diseases, biomarkers of human zinc deficiency, and its biochemical role.

Zinc as an essential element for humans was recognized in 1963. Nutritional zinc deficiency is now known to affect more than 2 billion human subjects globally. Zinc is an intracellular signaling molecule and it plays an important role in cell-mediated immune functions and oxidative stress. Zinc is also an antiinflammatory agent. These unique properties of zinc may have significant therapeutic benefits in several diseases in humans. In many diseases, concurrent zinc deficiency may complicate the clinical features, adversely affect immunological status, increase oxidative stress, and increase the generation of inflammatory cytokines. It is currently believed that oxidative stress and chronic inflammation may have important causative roles in many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, and autoimmune diseases. It is therefore important that the status of zinc is assessed and zinc deficiency corrected in these chronic conditions. A controlled clinical trial of zinc supplementation in these disorders in order to document the preventive and therapeutic effects of zinc is recommended.

There were 3 presentations at the symposium, one by Ahmed El-Sohemy of the Department of Nutritional Sciences of the University of Toronto; one by George J. Brewer, Emeritus Professor, Department o...

Triple negative breast cancer (TNBC) is a more aggressive subtype of breast cancer and is characteristic of the absence of the expressions of estrogen receptor, progesterone receptor, and human epithelial growth factor receptor 2 in breast tumor tissues. This subtype of breast cancer has the poorest prognosis, compared to other subtypes of breast cancer. TNBC is heterogeneous by showing several different histo-pathological and molecular subtypes with different prognosis and is more commonly found in younger age of women, especially African-American and Hispanic women. Recent epidemiological data indicate that TNBC is highly associated with overweight/obesity. Due to the absence of the common tumor biomarkers of breast cancer, the current molecular target therapy is not effective. TNBC patients have a shorter survival rate and an increased tumor recurrence. The concept of cancer stem cells (CSC), also called tumor initiating cells (TIC) has been more and more accepted and considered to contribute to aggressive phenotypes of many tumors including breast cancer. Moreover, CSC/TIC has been identified in the tumor tissues of breast cancer including TNBC. These rare subpopulations of CSC/TIC cells might be one of the key contributors to the aggressive phenotypes of TNBC such as drug treatment resistance, metastasis, and tumor recurrence. Therefore, targeting these CSC/TIC cells will provide a new therapeutic strategy for the treatment of TNBC.

Triple negative breast cancer (TNBC) is a more aggressive subtype of breast cancer and is characteristic of the absence of the expressions of estrogen receptor, progesterone receptor, and human epithelial growth factor receptor 2 in breast tumor tissues. This subtype of breast cancer has the poorest prognosis, compared to other subtypes of breast cancer. TNBC is heterogeneous by showing several different histo-pathological and molecular subtypes with different prognosis and is more commonly found in younger age of women, especially African-American and Hispanic women. Recent epidemiological data indicate that TNBC is highly associated with overweight/obesity. Due to the absence of the common tumor biomarkers of breast cancer, the current molecular target therapy is not effective. TNBC patients have a shorter survival rate and an increased tumor recurrence. The concept of cancer stem cells (CSC), also called tumor initiating cells (TIC) has been more and more accepted and considered to contribute to aggressive phenotypes of many tumors including breast cancer. Moreover, CSC/TIC has been identified in the tumor tissues of breast cancer including TNBC. These rare subpopulations of CSC/TIC cells might be one of the key contributors to the aggressive phenotypes of TNBC such as drug treatment resistance, metastasis, and tumor recurrence. Therefore, targeting these CSC/TIC cells will provide a new therapeutic strategy for the treatment of TNBC.

Aims The aim of this study was to determine whether the allergy status and other characteristics of common cold patients modify the effects of zinc acetate lozenges. Methods We had available individual patient data for three randomized placebo-controlled trials in which zinc acetate lozenges were administered to common cold patients. We used both one stage and two stage meta-analysis to estimate the effects of zinc lozenges. Results The total number of common cold patients was 199, the majority being females. Eighty percent of them fell into the age range 20-50 years. One third of the patients had allergies. The one stage meta-analysis gave an overall estimate of 2.73 days (95% CI 1.8, 3.3 days) shorter colds by zinc acetate lozenge usage. The two stage meta-analysis gave an estimate of 2.94 days (95% CI 2.1, 3.8 days) reduction in common cold duration. These estimates are to be compared with the 7 day average duration of colds in the three trials. The effect of zinc lozenges was not modified by allergy status, smoking, baseline severity of the common cold, age, gender or ethnic group. Conclusion Since the effects of zinc acetate lozenges were consistent between the compared subgroups, the overall estimates for effect seemed applicable over a wide range of common cold patients. While the optimal composition of zinc lozenges and the best frequency of their administration should be further investigated, given the current evidence of efficacy, common cold patients may be encouraged to try zinc lozenges for treating their colds.

In this study we have assessed zinc status and zinc-dependent cell-mediated immune functions (interleukin-2 production by mononuclear cells, natural killer cell lytic activity, and interleukin-1β production by mononuclear cells) in adult patients with squamous cell carcinoma of the upper aerodigestive tract at diagnosis and before any therapy was instituted. Inasmuch as significant interactions between zinc, copper, and iron exist, we also assayed the plasma copper level, serum iron level, and total iron-binding capacity in our patients. We recruited 30 cancer subjects and 21 control subjects. On the basis of cellular zinc criteria, we diagnosed a mild deficiency of zinc in 53% of cancer subjects. The plasma zinc level was not decreased in our subjects. A univariate analysis was applied by use of one-way analysis of variance comparing study variables among the three study groups (controls and zinc-deficient and zinc-sufficient cancer patients) and Tukey's multiple comparison test, and we showed that interleukin-2 production and natural killer lytic activity were decreased in zinc-deficient cancer patients. Interleukin-1β production (ELISA assay) was increased in both zinc-deficient and zinc-sufficient groups. Plasma copper level was not different, but the iron utilization was decreased in both groups of cancer subjects. We conclude that zinc deficiency and zinc-dependent immunologic dysfunctions are present in more than half of the patients with head and neck cancer in the Detroit area.

Zinc deficiency in humans was recognized for the first time in 1963, and a recommended dietary allowance (RDA) for zinc was established by the US National Academy of Sciences in 1974. The present World Health Organization (WHO) estimate is that nearly 2 billion subjects living in the developing world may have zinc deficiency. This is mainly because they subsist on cereal proteins which contain high quantities of organic phosphate compounds, which combine with zinc making it unavailable for absorption. The major adverse clinical effects of zinc deficiency are growth retardation, decreased cell-mediated immunity, impairment of cognitive functions, increased oxidative stress, and upregulation of inflammatory cytokines. Our studies have shown that nearly 30% of healthy, well-to-do elderly subjects living in developed countries may also be zinc deficient due to an increased phytate to zinc molar ratio in their diet. Over 300 enzymes and 2000 transcription factors are now known to require zinc for their functions and stability of their structures, and several studies have now shown that zinc may be a molecular signal for neuronal and immune cells. Fourteen ZIP and 10 ZNT zinc transporters are known to maintain intracellular zinc homeostasis. Therapeutic impacts of zinc on human health are also being investigated. Zinc is being used for the treatment of acute diarrhea in infants and children in developing countries globally, and this has resulted in saving millions of lives. Zinc is now an approved drug for the treatment and maintenance therapy of Wilson's disease, a serious fatal genetic disorder. According to a recent Cochrane Review, zinc is the only treatment which is effective in decreasing the incidence of infections and pain crises in patients with sickle cell disease. Zinc acetate lozenges have been shown to decrease the duration of the common cold by 50%, provided the treatment is started within 24 h of the onset of symptoms, the solution chemistry of the zinc preparation is proper, and the zinc dosages are adequate. Age-related macular degeneration (AMD) accounts for a large proportion of legal blindness in elderly subjects throughout the world. The Age-Related Eye Disease Study Group (AREDS) was supported by National Eye Institute. The National Institutes of Health (NIH) has now reported the results of their 10-year zinc supplementation study in patients with AMD. Zinc was effective in decreasing the incidences of blindness and progression of AMD in elderly subjects. Most importantly, zinc-supplemented subjects showed increased longevity and this was due to a decrease in cardiovascular events. No other micronutrient has shown this dramatic effect on decreasing mortality in the elderly. Our placebo-controlled, zinc supplementation trial in the elderly has shown that zinc supplementation decreased the incidence of infections by 66% and improved cell-mediated immunity. Also, we showed that oxidative stress markers and gene expression of inflammatory cytokines were decreased in elderly subjects who received zinc supplementation. These studies suggest that zinc supplementation in the elderly may have a preventive role in atherosclerosis. Plasma zinc is widely used as a biomarker of zinc deficiency in humans. This test is, however, neither specific nor sensitive. Assays of immunological markers such as plasma active thymulin and gene expression of IL-2 in PHA-stimulated lymphocytes are very sensitive and specific for the diagnosis of human zinc deficiency. The assay of zinc in cells such as lymphocytes and granulocytes are better than plasma zinc; however, even these assays are less sensitive than immunological biomarkers.

In the developed countries nearly 30% of the elderly are zinc deficient. Many chronic diseases seen in the elderly such as atherosclerosis, diabetes, neuro-degenerative disorders, Parkinson's disease and age related macular degeneration (AMD) may be due to chronic inflammation and increased oxidative stress. Zinc in human plays an important role in cell mediated immunity and is also an antioxidant and anti-inflammatory agent. Zinc supplementation studies in the elderly have shown decreased incidence of infections, decreased oxidative stress, and decreased generation of inflammatory cytokines. Decreased incidences of blindness in patients with AMD and increased atheroprotective effect have been observed in the zinc supplemented elderly. Zinc is a molecular signal for immune cells and many transcription factors involved in gene expression of inflammatory cytokines and adhesion molecules are regulated by zinc.

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.

The essentiality of zinc in humans was established in 1963. During the past 50 y, tremendous advances in both clinical and basic sciences of zinc metabolism in humans have been observed. The major factor contributing to zinc deficiency is high phytate-containing cereal protein intake in the developing world, and nearly 2 billion subjects may be zinc deficient. Conditioned deficiency of zinc has been observed in patients with malabsorption syndrome, liver disease, chronic renal disease, sickle cell disease, and other chronic illnesses. Major clinical problems resulting from zinc deficiency in humans include growth retardation; cell-mediated immune dysfunction, and cognitive impairment. In the Middle East, zinc-deficient dwarfs did not live beyond the age of 25 y, and they died because of intercurrent infections. In 1963, we knew of only 3 enzymes that required zinc for their activities, but now we know of >300 enzymes and >1000 transcription factors that are known to require zinc for their activities. Zinc is a second messenger of immune cells, and intracellular free zinc in these cells participate in signaling events. Zinc has been very successfully used as a therapeutic modality for the management of acute diarrhea in children, Wilson’s disease, the common cold and for the prevention of blindness in patients with age-related dry type of macular degeneration and is very effective in decreasing the incidence of infection in the elderly. Zinc not only modulates cell-mediated immunity but is also an antioxidant and anti-inflammatory agent.

Background A previous meta-analysis of 3 zinc acetate lozenge trials estimated that colds were on average 40% shorter for the zinc groups. However, the duration of colds is a time outcome, and survival analysis may be a more informative approach. The objective of this individual patient data (IPD) meta-analysis was to estimate the effect of zinc acetate lozenges on the rate of recovery from colds. Methods We analyzed IPD for 3 randomized placebo-controlled trials in which 80–92 mg/day of elemental zinc were administered as zinc acetate lozenges to 199 common cold patients. We used mixed-effects Cox regression to estimate the effect of zinc. Results Patients administered zinc lozenges recovered faster by rate ratio 3.1 (95% confidence interval, 2.1–4.7). The effect was not modified by age, sex, race, allergy, smoking, or baseline common cold severity. On the 5th day, 70% of the zinc patients had recovered compared with 27% of the placebo patients. Accordingly, 2.6 times more patients were cured in the zinc group. The difference also corresponds to the number needed to treat of 2.3 on the 5th day. None of the studies observed serious adverse effects of zinc. Conclusions The 3-fold increase in the rate of recovery from the common cold is a clinically important effect. The optimal formulation of zinc lozenges and an ideal frequency of their administration should be examined. Given the evidence of efficacy, common cold patients may be instructed to try zinc acetate lozenges within 24 hours of onset of symptoms.

Objective Chronic generation of inflammatory cytokines and reactive oxygen species are implicated in atherosclerosis, aging, cancers, and other chronic diseases. We hypothesized that zinc induces A20 in premonocytic, endothelial, and cancer cells, and A20 binds to tumor necrosis factor (TNF)-receptor associated factor, and inhibits Iκ kinase-α (IKK-α)/nuclear factor-κB (NF-κB), resulting in downregulation of TNF-α and interleukin-1β (IL-1β). Methods To test this hypothesis, we used HL-60, human umbilical vein endothelial cells, and SW480 cell lines under zinc-deficient and zinc-sufficient conditions in this study. We measured oxidative stress markers, inflammatory cytokines, A20 protein and mRNA, A20–FRAF-1 complex, and IKK-α/NF-κB signaling in stimulated zinc-deficient and zinc sufficient cells. We also conducted antisense A20 and siRNA studies to investigate the regulatory role of zinc in TNF-α and IL-1β via A20. Results We found that zinc increased A20 and A20–tumor necrosis factor-receptor associated factor-1 complex, decreased the IKK-α/NF-κB signaling pathway, oxidative stress markers, and inflammatory cytokines in these cells compared with zinc-deficient cells. We confirmed that zinc-induced A20 contributes to downregulation of TNF-α and IL-1β by antisense and short interfering RNA A20 studies. Conclusion Our studies suggest that zinc suppresses generation of NF-κB–regulated inflammatory cytokines by induction of A20.

Zinc deficiency impairs cellular immunity. Up-regulation of mRNA levels of IFN-γ, IL-12Rβ2, and T-bet are essential for Th1 differentiation. We hypothesized that zinc increases Th1 differentiation via up-regulation of IFN-γ and T-bet expression. To test this hypothesis, we used zinc-deficient and zinc-sufficient HUT-78 cells (a Th0 cell line) under different condition of stimulation in this study. We also used TPEN, a zinc-specific chelator, to decrease the bioavailability of zinc in the cells. We measured intracellular free zinc, cytokines, and the mRNAs of T-bet, IFN-γ, and IL-12Rβ2. In this study, we show that in zinc-sufficient HUT-78 cells (a Th0 cell line), mRNA levels of IFN-γ, IL-12Rβ2, and T-bet in PMA/PHA-stimulated cells were increased in comparison to zinc-deficient cells. Although intracellular free zinc was increased slightly in PMA/PHA-stimulated cells, Con-A-stimulated cells in 5 μM zinc medium showed a greater sustained increase in intracellular free zinc in comparison to cells incubated in 1 μM zinc. The cells pre-incubated with TPEN showed decreased mRNA levels of IFN-γ and T-bet mRNAs in comparison to cells without TPEN incubation. We conclude that stimulation of cells by Con-A via TCR, release intracellular free zinc which functions as a signal molecule for generation of IFN-γ and T-bet, and IL-12Rbβ2 mRNAs required for Th1 cell differentiation. These results suggest that zinc increase Th1 cell differentiation by up-regulation of IFN-γ and T-bet, and IL-12Rbβ2 mRNAs.

Background: Chronic inflammation and oxidative stress are common risk factors for atherosclerosis. Zinc is an essential micronutrient that can function as an antiinflammatory and antioxidative agent, and as such, it may have atheroprotective properties. Objective: We hypothesized that zinc down-regulates the production of atherosclerosis-related cytokines/molecules in humans. Design: To examine these effects, we conducted a randomized, double-blinded, placebo trial of zinc supplementation in elderly subjects. We recruited 40 healthy elderly subjects (aged 56–83 y) and randomly assigned them to 2 groups. One group was given an oral dose of 45 mg zinc/d as a gluconate for 6 mo. The other group was given a placebo. Cell culture models were conducted to study the mechanism of zinc as an atheroprotective agent. Results: After 6 mo of supplementation, the intake of zinc, compared with intake of placebo, increased the concentrations of plasma zinc and decreased the concentrations of plasma high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, macrophage chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), secretory phospholipase A2, and malondialdehyde and hydroxyalkenals (MDA+HAE) in elderly subjects. Regression analysis showed that changes in concentrations of plasma zinc were inversely associated with changes in concentrations of plasma hsCRP, MCP-1, VCAM-1, and MDA+HAE after 6 mo of supplementation. In cell culture studies, we showed that zinc decreased the generation of tumor necrosis factor-α, IL-1β, VCAM-1, and MDA+HAE and the activation of nuclear transcription factor κB and increased antiinflammatory proteins A20 and peroxisome proliferator–activated receptor-α in human monocytic leukemia THP-1 cells and human aortic endothelial cells compared with zinc-deficient cells. Conclusion: These findings suggest that zinc may have a protective effect in atherosclerosis because of its antiinflammatory and antioxidant functions.

Epidemiologic studies suggest that zinc deficiency may be associated with increased risk of cancer. We investigated the effects of zinc picolinate supplementation on the development of leiomyomas, malondialdehyde (MDA), 8-isoprostane, 4-hydroxyalkenal (HAE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, and heat shock protein 70 (Hsp70) expression in Japanese quails. One hundred fifty quails (6 months old) were assigned to three treatment groups consisting of 50 birds in each group. Birds were fed either a basal diet or the basal diet supplemented with 30 mg or 60 mg of zinc/kg of diet. The animals were sacrificed after 350 days, and the tumors were identified. Zinc picolinate supplementation did not affect the number of leiomyomas compared to control birds (P > .05). However, the tumors in zinc-fed birds were smaller than those found in control birds (P = .01) Serum MDA, 8-isoprostane, and HAE levels were lower in the treatment groups than in the control group: MDA, 1.95 versus 0.93 micromol/L; 8-isoprostane, 108 versus 85 pg/mL; HAE, 1.55 versus 0.96 micromol/L (P = .01 for all three parameters). The concentrations of serum 8-OHdG, which is a marker of oxidative damage, in the groups were 28.5, 23.6, and 20.1 ng/mL, respectively (P = .01). Hsp70 expression was significantly decreased in zinc-treated birds (P < .01). The results indicate that dietary zinc picolinate supplementation reduces the growth of spontaneously occurring leiomyomas of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of zinc supplementation in the prevention and treatment of uterine leiomyoma in humans.

Essentiality of zinc for humans was discovered 45 yr ago. Deficiency of zinc is prevalent world wide in developing countries and may affect nearly 2 billion subjects. The major manifestations of zinc deficiency include growth retardation, hypogonadism in males, cell-mediated immune dysfunctions, and cognitive impairment. Zinc not only improves cell mediated immune functions but also functions as an antioxidant and anti-inflammatory agent. Oxidative stress and chronic inflammation have been implicated in development of many cancers. In patients with head and neck cancer, we have shown that nearly 65% of these patients were zinc deficient based on their cellular zinc concentrations. Natural killer (NK) cell activity and IL-2 generation were also affected adversely. Th2 cytokines were not affected. In our patients, zinc status was a better indicator of tumor burden and stage of disease in comparison to the overall nutritional status. Zinc status also correlated with number of hospital admissions and incidences of infections. NF-kappa B is constitutively activated in many cancer cells, and this results in activation of antiapoptotic genes, VEGF, cyclin DI, EGFR, MMP-9 and inflammatory cytokines. Zinc inhibits NF-kappa B via induction of A-20. Thus, zinc supplementation should have beneficial effects on cancer by decreasing angiogenesis and induction of inflammatory cytokines while increasing apoptosis in cancer cells. Based on the above, we recommend further studies and propose that zinc should be utilized in the management and chemoprevention of cancer.

SUMMARY A syndrome occurring in males, characterized by severe irondeficiency anemia, hypogonadism, dwarfism, hepatosplenomegaly, and geophagia, has been observed in villagers in Iran suffering from malnutrition. Eleven such patients, studied in detail, are described. Despite hepatosplenomegaly, results of the liver function tests were uniformly normal except for the serum alkaline phosphatase, which was consistently elevated. The anemia was not associated with blood loss, hookworm infestation, or intestinal malabsorption, and patients responded promptly to oral iron therapy. Although the diet contained adequate amounts of iron, it is believed that the predominantly wheat diet, with its high phosphate content, interfered with absorption because of the formation of insoluble iron complexes. Correction of the anemia resulted in marked decrease in the size of the liver and spleen. Prolonged follow-up of patients receiving a well balanced diet indicates that the endocrine abnormalities of growth and sexual development are reversible. The relationship of geophagia (which occurred in nearly all patients) to this syndrome is not clear and is discussed. The possibility of zinc deficiency is considered as an explanation of hypogonadism, dwarfism, and changes in alkaline phosphatase.

Zinc deficiency in humans decreases the activity of serum thymulin (a thymic hormone), which is required for maturation of T-helper cells. T-helper 1 (Th(1)) cytokines are decreased but T-helper 2 (Th(2)) cytokines are not affected by zinc deficiency in humans. This shift of Th(1) to Th(2) function results in cell-mediated immune dysfunction. Because IL-2 production (Th(1) cytokine) is decreased, this leads to decreased activities of natural-killer cell and T cytolytic cells, which are involved in killing viruses, bacteria, and tumor cells. In humans, zinc deficiency may decrease the generation of new CD4+ T cells from the thymus. In cell culture studies (HUT-78, a Th(0) human malignant lymphoblastoid cell line), as a result of zinc deficiency, nuclear factor-kappaB (NF-kappaB) activation, phosphorylation of IkappaB, and binding of NF-kappaB to DNA are decreased and this results in decreased Th(1) cytokine production. In another study, zinc supplementation to humans decreased the gene expression and production of pro-inflammatory cytokines and decreased oxidative stress markers. In HL-60 cells (a human pro-myelocytic leukemia cell line), zinc deficiency increased the levels of TNF-alpha, IL-1beta, and IL-8 cytokines and mRNA. In these cells, zinc induced A20, a zinc finger protein that inhibited NF-kappaB activation via tumor necrosis factor receptor associated factor pathway, and this decreased gene expression of pro-inflammatory cytokines and oxidative stress markers. We conclude that zinc has an important role in cell-mediated immune functions and also functions as antiinflammatory and antioxidant agent.

A nutritional deficiency of zinc in humans is widespread in the developing world, and a conditioned zinc deficiency is observed in many diseased states, the elderly population, and pregnant women of both developed and developing nations. It was recently reported that zinc is required for Nuclear Factor-kappaB (NF-kappaB) activation and gene expressions of both interleukin-2 (IL-2) and interleukin-2 receptor alpha (IL-2Ralpha) and beta in HUT-78, a Th0 human malignant lymphoblastoid cell line. In this study, it has been reported for the first time that zinc is also required for gene expression of IL-2 and IL-2Ralpha in primary cells. Isolated peripheral blood mononuclear cells (MNCs) from zinc-deficient elderly subjects was used for this study. NF-kappaB activation was shown to have decreased in the MNCs from zinc-deficient subjects, which was corrected by in vivo zinc supplementation. It was further shown that either in vivo zinc supplementation or the addition of zinc in vitro to MNCs from zinc-deficient subjects results in correction of the gene expression of IL-2 and IL-2Ralpha. Therefore, it was proposed that in vitro addition of zinc to MNCs for correction of gene expression of IL-2 in humans may be used as a specific test for zinc deficiency. Although currently no known specific laboratory test exists for the diagnosis of zinc deficiency in humans, the use of correction of IL-2 messenger RNA (mRNA) with in vitro zinc addition to MNCs from zinc-deficient subjects may be very useful.

Acrodermatitis enteropathica is a rare autosomal recessive disease that manifests as an inability of the affected individual to absorb intestinal zinc, and therefore patients have nutritional zinc deficiency. Without zinc therapy, this condition is fatal. Mutations in the SLC39A4 gene are responsible for acrodermatitis enteropathica. This gene encodes one member of a human zinc/iron-regulated transporter-like protein, also known as ZIP4, and consists of 12 exons and spans about 4.7 kb. We describe a novel mutation in a Tunisian family in which a chain termination codon in exon 3 yielded a truncated ZIP4 zinc transporter protein.

Zinc deficiency decreased cellular immune response. Zinc supplementation reverses this response. High concentration of zinc intake is reported to alter immune response. We hypothesize that higher concentration of zinc adversely affects T-cell immune response. In this study, we examined whether higher concentration of zinc affects expression of IL-2, IL-2Ralpha, and TNF-alpha, and NF-kappaB activation in HUT-78 (Th(0)) cells. The results show that HUT-78 cells incubated in 15, 50, and 100 microM zinc medium had significantly higher intracellular zinc contents and faster growth after 4 days of incubation, compared to the cells incubated in 1 microM zinc medium. After PMA/PHA stimulation, 1 microM zinc showed significant decreases in NF-kappaB activation, and in the levels of IL-2, IL-2Ralpha, and TNF-alpha production and mRNAs compared to 15 microM zinc. The cells incubated in higher concentrations of zinc (50 and 100 microM zinc) showed mild to moderate decreases in the levels of IL-2, IL-2Ralpha, and TNF-alpha production and mRNAs, and in NF-kappaB activation compared to those incubated in 15 microM zinc medium. These data indicate that not only low level of zinc, but also high levels of zinc decrease Th1 function.

BACKGROUND Altered zinc levels in prostate benign prostatic hyperplasia (BPH) and carcinoma is well documented. It is not known whether loss of zinc, necessary to restrain aggressive growth, results from loss of a single specific or multiple zinc transporters. METHODS Human prostate tissues from patients who underwent radical prostatectomy were screened by RT-PCR analysis for five zinc transporters. Relative cDNA expression was determined in normal, BPH, and tumor specimens and four prostate epithelial cell lines. RESULTS Surgical specimens were obtained from patients with assigned Gleason scores ranging from 5 to 9. Relative expression of hZIP-1 and hZnT-1 were prominent in most samples with relatively lesser degree of expression of hZIP-2 and no detectable expression of hZnT-3. Expression of hZnT-4 was decreased in BPH and tumor samples compared to normal tissue. CONCLUSIONS These data suggest that zinc homeostasis in normal prostate tissues results from an interplay of multiple transporters and decreased hZnT-4 expression is associated with prostate tissue abnormalities independent of total cellular zinc content. © 2003 Wiley-Liss, Inc.

The essentiality of zinc for humans was recognized in 1963. It is now evident that nutritional deficiency of zinc in human populations throughout the developing world is common. The major factor responsible for this deficiency is the consumption of mainly cereal proteins rich in phytate. The clinical manifestations of zinc deficiency include growth retardation and male hypogonadism in the adolescents, rough skin, poor appetite, mental lethargy, delayed wound healing, cell-mediated immune dysfunctions, and abnormal neurosensory disorders. A conditioned deficiency of zinc has been observed in many diseased states. In this work I have summarized our current knowledge concerning the molecular mechanisms of zinc action on T helper cells. Our studies showed that in zinc-deficient HUT-78 cells, phosphorylated IκB and Iκk, ubiquitinated IκB, and binding of nuclear factor (NF)-κB to DNA were significantly decreased. Zinc increased the translocation of NF-κB from cytosol to nucleus. These data show that zinc plays an important role in the activation of NF-κB in HUT-78 cells. We showed a significant effect of zinc on gene expression of interleukin (IL)-2 and IL-2 receptors α and β. We also showed that a decrease in gene expression of IL-2 and its receptors in zinc-deficient HUT-78 cells may be the result of decreased activation of NF-κB in zinc-deficient cells. J. Trace Elem. Exp. Med. 16:139–163, 2003. © 2003 Wiley-Liss, Inc.

Epidemiologic studies suggest that zinc deficiency may be associated with increased risk of cancer. However, few studies have been conducted with zinc supplementation in animals and humans. Most previous intervention studies have used zinc in combination with several other micronutrients, which make them difficult to interpret. Zinc supplementation is associated with decreased oxidative stress and improved immune function, which may be among the possible mechanisms for its cancer preventive activity. Preclinical and clinical studies need to investigate modulation of genetic and epigenetic pathways of carcinogenesis by zinc.

The essentiality of zinc was recognized 46 years ago. Zinc deficiency resulting in growth retardation, hypogonadism, immune dysfunction and cognitive impairment affects nearly 2 billion subjects in the developing world. High phytate content of the cereal proteins consumed in the developing world, results in decreased availability of zinc for absorption. Zinc therapy has been very successful and life saving measure in patients with acrodermatitis enteropathica and Wilson's disease. Beneficial therapeutic responses of zinc supplementation have been ovserved in acute diarrhea in children, chronic hepatitis C, shigellosis, leprosy, leishmaniasis, and common cold. Zinc supplementation was effective in decreasing incidences of infection in elderly and patients with sickle cell disease. Zinc supplementation was effective in preventing blindness in 25% of the elderly with dry type of age related macular degeneration. Zinc supplementation in the elderly decreased oxidative stress and decreased generation of inflammatory cytokines. Zinc is an intracellular signaling molecule in monocytes, dendritic cells and macrophages and it plays an important role in cell-mediated immune functions and oxidative stress. Zinc is also an anti-inflammatory agent. These unique properties of zinc may have significant therapeutic benefits in several diseases in humans. In many diseases concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress and increase generation of inflammatory cytokines. Oxidative stress and chronic inflammation may play important causative roles in many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, and auto-immune diseases. It is therefore, important that status of zinc is assessed and zinc deficiency corrected in these chronic diseases. A controlled clinical trial of zinc supplementation in these disorders in order to document the preventive and therapeutic effects of zinc is warranted.

Zinc supplementation trials in the elderly showed that the incidence of infections was decreased by approximately 66% in the zinc group. Zinc supplementation also decreased oxidative stress biomarkers and decreased inflammatory cytokines in the elderly. In our studies in the experimental model of zinc deficiency in humans, we showed that zinc deficiency per se increased the generation of IL-1β and its mRNA in human mononuclear cells following LPS stimulation. Zinc supplementation upregulated A20, a zinc transcription factor, which inhibited the activation of NF-κB, resulting in decreased generation of inflammatory cytokines. Oxidative stress and chronic inflammation are important contributing factors for several chronic diseases attributed to aging, such as atherosclerosis and related cardiac disorders, cancer, neurodegeneration, immunologic disorders and the aging process itself. Zinc is very effective in decreasing reactive oxygen species (ROS). In this review, the mechanism of zinc actions on oxidative stress and generation of inflammatory cytokines and its impact on health in humans will be presented.

Inflammation is a complex and critical immunological process resulting from host defense mechanisms against trauma, microorganism infection, or other adverse environmental stress or complex combinations of many biological insults sustained by humans. Such inflammatory processes, especially the sustained chronic condition of inflammation, along with inflammation-induced oxidative stress, can lead to irreversible cellular or tissue damage over time, which further contributes to the development of chronic degenerative diseases including cancers. The aging process is another complicated, multifactorial, and inherent biological process that progressively accumulates deleterious damage at the molecular, cellular, tissue, and even organ levels in the body during its maturation following birth, giving rise to alterations in physiological and biochemical functions, and eventually leading to increased vulnerability to diseases including cancers. In this chapter, we will discuss the role of chronic inflammation, oxidative stress, and DNA damage in the aging process, especially in age-related degenerative diseases including cancer. We will also discuss the role of zinc as an anti-inflammatory and antioxidant agent in human health and disease, and its potential role as an anti-aging agent. Finally, we will discuss the detailed mechanisms of the protective action of zinc as a potential anti-aging agent in age-related cellular signaling involving the NF-κB, A20, Nrf2, and p53 pathways.

In the syndrome of iron-deficiency anemia, hepatosplenomegaly, dwarfism, and hypogonadism, zinc deficiency accounts for dwarfism and hypogonadism and the anemia is due to iron deficiency. The ocular manifestations of zinc deficiency in humans include impaired dark adaptation and nyctalopia. The mechanism of retinal dysfunction in zinc deficiency is not well understood, although several mechanisms have been proposed. The results of the Age-Related Eye Disease Study (AREDS) demonstrate a role for the specific AREDS antioxidant with zinc formulation for the prevention of advanced age-related macular degeneration (AMD). The AREDS formulation is recommended as a treatment for nonsmokers with extensive intermediate drusen, large drusen, noncentral geographic atrophy, or unilateral advanced AMD. AREDS2 is an ongoing study of supplements for patients at risk of vision loss due to AMD, and it will compare a lower zinc dose (25 mg) with the current AREDS dose (80 mg). Severe zinc deficiency, particularly in the form of acrodermatitis enteropathica, is associated with ocular surface disease. Randomized trials of zinc supplementation have not shown a clear benefit for cataract.

The essentiality of zinc for humans was established only 50 years ago. Zinc deficiency is now known to affect nearly two billion people in the developing world. It adversely affects cell-mediated immunity and increases oxidative stress and inflammatory cytokines. In the developed countries nearly 30% of the elderly are zinc deficient. Many chronic diseases seen in the elderly – such as atherosclerosis, diabetes, neurodegenerative disorders, Parkinson’s disease and age-related macular degeneration (AMD) – may be due to chronic inflammation and increased oxidative stress. Zinc supplementation studies in the elderly have shown a decreased incidence of infections, decreased oxidative stress and decreased generation of inflammatory cytokines. A decreased incidence of blindness in patients with AMD and an increased atheroprotective effect have been observed in the zinc-supplemented elderly. Zinc is a molecular signal for immune cells, and many transcription factors involved in gene expression of inflammatory cytokines and adhesion molecules are regulated by zinc.