Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.
The importance of micronutrients in health and nutrition is undisputable, and among them, zinc is an essential element whose significance to health is increasingly appreciated and whose deficiency may play an important role in the appearance of diseases. Zinc is one of the most important trace elements in the organism, with three major biological roles, as catalyst, structural, and regulatory ion. Zinc-binding motifs are found in many proteins encoded by the human genome physiologically, and free zinc is mainly regulated at the single-cell level. Zinc has a critical effect on homeostasis, in immune function, in oxidative stress, in apoptosis, and in aging, and significant disorders of great public health interest are associated with zinc deficiency. In many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, autoimmune diseases, aging, age-related degenerative diseases, and Wilson’s disease, the concurrent zinc deficiency may complicate the clinical features, affect the adversely immunological status, increase oxidative stress, and lead to the generation of inflammatory cytokines. In these diseases, oxidative stress and chronic inflammation may play important causative roles. It is therefore important that the status of zinc is assessed in any case and zinc deficiency is corrected, since the unique properties of zinc may have significant therapeutic benefits in these diseases. In the present paper, we review the zinc as a multipurpose trace element, its biological role in homeostasis, proliferation and apoptosis and its role in immunity and in chronic diseases, such as cancer, diabetes, depression, Wilson’s disease, Alzheimer’s disease, and other age-related diseases.
Research Department, Italian National Research Center on Aging (I.N.R.C.A.), Ancona.
Zinc is one of the most important trace elements in the body for many biological functions; it is required as a catalytic component for more than 200 enzymes, and as a structural constituent of many proteins, hormones, neuropeptides, hormone receptors, and probably polynucleotides. Due to its role in cell division and differentiation, programmed cell death, gene transcription, biomembrane functioning, and obviously many enzymatic activities, zinc is considered a major element in assuring the correct functioning of an organism, from the very first embryonic stages to the last periods of life.
This biological role together with the many factors that modulate zinc turnover explains, on one hand, the variety of clinical and laboratory signs resulting from its reduced bioavailability, and on the other, the high number of human pathologies characterized by alterations in the zinc pool. As zinc supplementation is efficacious in most of these conditions, it is regarded more as oriented therapeutical support, than a simple dietary integrator. Furthermore, the relevance of zinc status to many age-associated diseases and, according to experimental studies, the aging itself of the major homeostatic mechanisms of the body, i.e., the nervous, neuroendocrine, and immune systems, places zinc in a pivotal position in the economy of the aging organism.
Wong, C., Ho, E. Zinc, and its Role in Age-Related Inflammation and Immune Dysfunction. Molecular Nutrition and Food Research. 2012. 56, 77-87.
Zinc is an essential micronutrient required for many cellular processes, especially for the normal development and function of the immune system. Zinc homeostasis and signaling are critical in immune activation, and an imbalance in zinc homeostasis is associated with the development of chronic diseases. Zinc deficiency causes significant impairment in both adaptive and innate immune responses and promotes systemic inflammation. The elderly are a population particularly susceptible to zinc deficiency. National surveys indicate that a significant portion of the aged population has inadequate zinc intake, and a decline in zinc status is observed with age.
There are remarkable similarities between the hallmarks of zinc deficiency and immunological dysfunction in aged individuals. Both zinc deficiency and the aging process are characterized by impaired immune responses and systemic low-grade chronic inflammation. It has been hypothesized that age-related zinc deficiency may be an important factor contributing to immune dysfunction and chronic inflammation during the aging process. In this review, we discuss the effects of zinc status on aging, potential molecular and epigenetic mechanisms contributing to age-related decline in zinc status, and the role of zinc in age-related immune dysfunction and chronic inflammation.
European Food Safety Authority (EFSA), Parma, Italy
Scientific Opinion on safety and efficacy of zinc compounds (E6) as a feed additive for all species: zinc sulfate monohydrate, based on a dossier submitted by Grillo-Werke AG/EMFEMA. Zinc sulfate monohydrate is considered as a safe source of zinc for all animal species, regarding the maximum contents for total zinc in feedingstuffs set by the EU. Based on data on consumer exposure and the tolerable upper intake level determined for zinc, no concerns for consumer safety are expected from the use of zinc sulfate monohydrate in animal nutrition. The hazards associated with the handling of zinc sulfate monohydrate are well recognized and documented. In particular, zinc sulfate monohydrate is considered as a severe irritant to eyes. The zinc sulfate monohydrate under application is considered a compound with high dusting potential, which may result in the exposure of users by inhalation. In the view of the FEEDAP Panel, it would be prudent to take measures to avoid exposure by inhalation. The use of zinc-containing feed additives does not pose a direct environmental concern for agricultural soils, but the available data were not sufficient to exclude any risk related to drainage and the run-off of zinc to surface water. The use of zinc-containing additives in aquaculture up to maximum authorized zinc level in feeds is not expected to pose an appreciable risk to the environment. Zinc sulfate monohydrate is an efficacious source of zinc in meeting animal requirements.
Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Clarendon Way, Leeds LS2 9JT, UK
Zinc, the most abundant trace metal in the brain, has numerous functions, both in health and in disease. Zinc is released into the synaptic cleft of glutamatergic neurons alongside glutamate from where it interacts and modulates NMDA and AMPA receptors. In addition, zinc has multifactorial functions in Alzheimer’s disease (AD). Zinc is critical in the enzymatic nonamyloidogenic processing of the amyloid precursor protein (APP) and in the enzymatic degradation of the amyloid-β (Aβ) peptide. Zinc binds to Aβ promoting its aggregation into neurotoxic species, and disruption of zinc homeostasis in the brain results in synaptic and memory deficits.
Thus, zinc dyshomeostasis may have a critical role to play in the pathogenesis of AD, and the chelation of zinc is a potential therapeutic approach.
It is clear that zinc not only plays critical roles in the structural and functional integrity of many proteins but that it also modulates the activity of glutamatergic synapses and indeed may act as a neurotransmitter in its own right. Several of the enzymes involved in processing APP and Aβ are zinc metalloproteases, with an essential requirement for zinc in their catalytic activity. Zinc binds to Aβ, promoting its aggregation and thereby modulating its neurotoxicity. Although zinc dyshomeostasis may contribute to the development of AD, further work is required to clarify the molecular and cellular mechanisms affected by zinc under both normal and disease situations.
King’s College London, Metal Metabolism Group, Division of Diabetes and Nutritional Sciences, School of Medicine, London, United Kingdom
The nutritional essentiality of zinc for the growth of living organisms had been recognized long before zinc biochemistry began with the discovery of zinc in carbonic anhydrase in 1939. Painstaking analytical work then demonstrated the presence of zinc as a catalytic and structural cofactor in a few hundred enzymes. In the 1980s, the field again gained momentum with the new principle of “zinc finger” proteins, in which zinc has structural functions in domains that interact with other biomolecules. Advances in structural biology and a rapid increase in the availability of gene/protein databases now made it possible to predict zinc-binding sites from metal-binding motifs detected in sequences. This procedure resulted in the definition of zinc proteomes and the remarkable estimate that the human genome encodes ∼3000 zinc proteins.
More recent developments focus on the regulatory functions of zinc(II) ions in intercellular information transfer and have tantalizing implications for yet additional functions of zinc in signal transduction and cellular control. At least three dozen proteins homeostatically control the vesicular storage and subcellular distribution of zinc and the concentrations of zinc(II) ions. Novel principles emerge from quantitative investigations on how strongly zinc interacts with proteins and how it is buffered to control the remarkably low cellular and subcellular concentrations of free zinc(II) ions. It is fair to conclude that the impact of zinc for health and disease will be at least as far-reaching as that of iron.
Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation Frederiksberg, Denmark; Copenhagen Plant Science Centre, Department of Plant and Environmental Sciences, University of Copenhagen Frederiksberg, Denmark.
An important goal of micronutrient biofortification is to enhance the amount of bioavailable zinc in the edible seed of cereals and more specifically in the endosperm.
The picture is starting to emerge for how zinc is translocated from the soil through the mother plant to the developing seed. On this journey, zinc is transported from symplast to symplast via multiple apoplastic spaces. During each step, zinc is imported into a symplast before it is exported again. Cellular import and export of zinc require passage through biological membranes, which makes membrane-bound transporters of zinc especially interesting as potential transport bottlenecks.
Inside the cell, zinc can be imported into or exported out of organelles by other transporters. The function of several membrane proteins involved in the transport of zinc across the tonoplast, chloroplast, or plasma membranes is currently known. These include members of the ZIP (ZRT-IRT-like Protein), and MTP (Metal Tolerance Protein) and heavy metal ATPase (HMA) families. An important player in the transport process is the ligand nicotianamine that binds zinc to increase its solubility in living cells and in this way buffers the intracellular zinc concentration.
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation, and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.
Code of Federal Regulations] [Title 21, Volume 3] [Revised as of April 1, 2014] [CITE: 21CFR182.8997] TITLE 21–FOOD AND DRUGS CHAPTER I–FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER B–FOOD FOR HUMAN CONSUMPTION (CONTINUED) PART 182 — SUBSTANCES GENERALLY RECOGNIZED AS SAFE Subpart I–Nutrients Sec. 182.8997 Zinc sulfate. (a) Product. Zinc sulfate. (b) Conditions of use. This substance is generally recognized as safe when used in accordance with a good manufacturing practice.
Department of International Health, The Johns Hopkins University School of Public Health, Baltimore, MD 21205, USA
Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for the normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects the development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators are rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency.
Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation.
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