Zinc and human health: an update
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 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 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.
Zinc, human diseases and aging
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. 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.
The biological inorganic chemistry of zinc ions
Changes in zinc species are important when zinc is transported through membrane proteins. Hydration chemistry and the ionization of its bound water are important for its function in enzymes (Zn-OH as a nucleophile), where it also forms complexes with anions and chelating ligands. Furthermore, knowledge of zinc species informs the formulation of zinc complexes for use in animal feed, often ZnO is used, for bioavailability when supplemented in the human diet, when performing experiments with cultured cells to increase cellular zinc, to treat a zinc deficiency, or when chelating agents are employed to decrease zinc concentrations.
Zinc Biochemistry: From a Single Zinc Enzyme to a Key Element of Life
Zinc is used as a cofactor in proteins much more frequently than most vitamins. The control of a fluctuating pool of zinc(II) ions at remarkably low concentrations and with the participation of many proteins provides a new perspective on the molecular functions of zinc in biology in general and for the impact of zinc on human health in particular. Roles of zinc(II) ions in biological phosphorylations and in redox signaling are already well documented and are part of the spectrum of actions of zinc in cellular proliferation, differentiation, and cell death.
Zinc-altered immune function
Zinc is known to be essential for all highly proliferating cells in the human body, especially the immune system. A variety of in vivo and in vitro effects of zinc on immune cells mainly depend on the zinc concentration. All kinds of immune cells show decreased function after zinc depletion. In monocytes, all functions are impaired, whereas in natural killer cells, cytotoxicity is decreased, and in neutrophil granulocytes, phagocytosis is reduced. The normal functions of T cells are impaired, but autoreactivity and alloreactivity are increased. B cells undergo apoptosis. Impaired immune functions due to zinc deficiency are shown to be reversed by an adequate zinc supplementation, which must be adapted to the actual requirements of the patient.
Regulation of T cell receptor signaling by activation-induced zinc influx
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.
Zinc and its role in age-related inflammation and immune dysfunction
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.
A Feedback Loop between Inflammation and Zn Uptake
Exposure to IL-17 and TNF-α enhanced expression of the Zn-importer ZIP-8, regardless of the concentration of Zn in the culture medium. In contrast, the expression of the Zn-exporter ZnT1 and of the MTs was primarily dependent on Zn levels. Addition of Zn also increased the production of IL-6, thus further stimulating the inflammatory response.
Inflammation, genes and zinc in ageing and age-related diseases.
Plasma concentration of metallic ions like Zn is influenced by pro-inflammatory cytokines production. A major target of Zn may be NF-kB, a transcription factor critical for the expression of many proinflammatory cytokines whose production is finely regulated by extra- and intracellular activating and inhibiting factors interacting with regulatory elements on cytokine genes. Therefore, Zn deficiency in individuals genetically predisposed to a dis-regulation of inflammatory response, may play a crucial role, in causing adverse events and in reducing the probability of a successful aging.
Effects of zinc supplementation on plasma copper-zinc ratios, oxidative stress, and immunological status
Zn supplementation ameliorates abnormally high plasma Cu/Zn ratios and may reduce oxidative stress, improve inflammatory status, and maintain immune function in patients undergoing long-term HD.
The Role of Zinc in Alzheimer's Disease
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.
Serum Levels of Copper and Zinc in Patients with Rheumatoid Arthritis: a Meta-analysis.
Pooled analysis found that patients with RA had a higher serum level of Cu and a lower serum Zn level than the healthy controls (Cu (μg/dl), WMD = 31.824, 95 % CI = 20.334, 43.314; Zn (μg/dl), WMD = -12.683, 95 % CI = -19.783, -5.584). Subgroup analysis showed that ethnicity had influence on the serum level of Cu (μg/dl) (Caucasian, WMD = 43.907, 95 % CI = 35.090, 52.723, P < 0.001; Asian, WMD = 14.545, 95 % CI = -12.365, 41.455, P = 0.289) and Zn (μg/dl) (Caucasian, WMD = -11.038, 95 % CI = -23.420, 1.344, P = 0.081; Asian, WMD = -14.179, 95 % CI = -18.963, -9.394, P < 0.001) in RA and healthy controls.
Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation.
Zinc deficiency induced inflammatory response in part by eliciting aberrant immune cell activation and altered promoter methylation. Results suggested potential interactions between zinc status, epigenetics, and immune function, and how their dysregulation could contribute to chronic inflammation.
Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury
The observed Zn2+ binding to histidine-rich glycoprotein appears to regulate its function at sites pertaining to wound healing and is mediated through the pH and Zn2+-sensing ability of the histidine-rich region. It is evident that the large number of proposed HRG ligands cannot be accommodated simultaneously, therefore it is plausible the HRR may finely tune individual interactions by modifying the native or cleaved form of HRG by altering its conformational structure through the charged state of histidine, induced by acidic pH or binding to Zn2+
The antimicrobial action of zinc ion/antioxidant combinations
The potentiation of action of antimicrobial preservatives/antiseptics by, respectively, antioxidants and metal ions has been established. In this investigation the antimicrobial effect of two antioxidants (Butylated hydroxyanisole and Propyl Gallate) and zinc ions, both separately and combined, was determined against three organisms at 37°C. With the exception of Escherichia coli at low zinc concentrations, definite potentiation occurred, as reflected by a decrease in killing times.
Marginal dietary zinc deficiency in vivo induces vascular smooth muscle cell apoptosis in large arteries
Dietary zinc deficiency has been associated with the development of atherosclerosis although the effects on vascular smooth muscle cells (VSMCs), important in maintaining atherosclerotic plaque integrity, are unknown. The main aim of this study was to elucidate the effect of a zinc-deficient environment on VSMCs using an in vivo model. In conclusion, a marginally zinc-deficient diet is pro-apoptotic for VSMCs and this may contribute to cardiovascular disease.
Analysis of serum zinc and copper concentrations in hair loss
It is well known that some trace elements such as zinc and copper play a significant role in many forms of hair loss. However, the effect of zinc and copper in the pathogenesis of hair loss is still unknown. The data led to the hypothesis of zinc metabolism disturbances playing a key role in hair loss, especially AA and TE, whereas the effect of copper on hair growth and shedding cycles still needs more study.
Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial.
Zinc supplementation at 30 mg/d for 3 mo is effective in increasing serum zinc concentrations in nursing home elderly; however, not all zinc-deficient elderly reached adequate concentrations. The increase in serum zinc concentration was associated with the enhancement of T cell function mainly because of an increase in the number of T cells.
Efficacy and tolerability of nitric-zinc complex in the treatment of external genital warts and "difficult-to-treat" warts: a "proof of concept", prospective, multicentre, open study.
Nitric-zinc complex topical solution has shown to be an effective and well tolerated treatment of EGW and "difficult-to-treat" warts with a 90% of subjects with a total cure after one or up to four applications. A total or partial response was observed in 99% of the subjects. Nitric-zinc complex could be considered an easy-to-use effective treatment strategy of "difficult-to-treat" warts and external genital warts.
Treatment of localized psoriasis with a topical formulation of zinc pyrithione.
Of 60 participants, 30 patients in group A and 30 patients in group B completed the study. The mean PASI scores before and after treatment were 3.4±1.8 and 0.9±1.3 in group A (p<0.01), and 4.3±2 and 3.9±1.3 in group B (p>0.05), and there was a significant difference between the two groups' mean PASI scores at the end of the study (p<0.01). A topical formulation of zinc pyrithione can be used to treat localized psoriasis.
Comparison of the Effect of Ginger and Zinc Sulfate on Primary Dysmenorrhea: A Placebo-Controlled Randomized Trial
The severity of pain was significantly different between, before, and after the intervention in both the ginger and the zinc sulfate groups (p < .001). Compared with the placebo receiving group, participants receiving ginger and zinc sulfate reported more alleviation of pain during the intervention (p < .05). Ginger and zinc sulfate had similar positive effects on the improvement of primary dysmenorrhea pain in young women.
Zinc treatment prevents dysmenorrhea
Primary dysmenorrhea, menstrual cramps in otherwise well women, produces mild to debilitating cramping of the uterus. More than half, and by some estimates 90% of all American women experience menstrual cramps during the first several days of menstruation. Protocols using 30 mg of zinc once to three times a day for one to four days immediately prior to menses to prevent dysmenorrhea are described and they are recommended for additional study. The side effect from the absence of all warning of pending menses due to zinc treatment was concern of possible pregnancy. The United States RDA for zinc appears to be too low to optimize women’s health and prevent menstrual cramps.
The discovery of vanadyl and zinc complexes for treating diabetes and metabolic syndromes
Type 1 diabetes mellitus is due to the autoimmune-mediated destruction of pancreatic β cells, resulting in absolute insulin deficiency; the patients require exogenous insulin injections. Type 2 is characterized by insulin resistance and abnormal insulin secretion and the patients require exercise, diet control and/or oral hypoglycemics. However, each treatment has some adverse effects, including physical burden, formation of self-antibodies for insulin injections, the severe side effects of hypoglycemics and the discontinuation of insulin synthesis in the pancreas. To overcome these adverse effects and replace the use of these agents, the author attempted to develop new antidiabetic agents with novel structures and mechanisms. This review focuses on the author's' recent development of vanadium and zinc complexes for antidiabetic and anti metabolic syndromes.
The Role of Metal Complexes in the Treatment of Diabetes Mellitus - An Overview
Recent advancement in medicinal chemistry the metal complexes play a significant role in treating DM. In this review, the metal complexes being a platform in designing novel therapeutic drugs has found to be effective in treating this chronic disorder, which cannot be fulfilled by pure organic compounds. Metallo–allixinate complexes are now evolving in a new Metallomics world, and the fruitful outcome may offer a novel medicine with high quality of anti-diabetic and anti-metabolic syndrome activity for humans in the future. Further for their therapeutic applications, it is necessary to know their mechanism of action, cellular target and toxicological studies and that can be done with the aid of molecular docking studies.
The role of zinc in the prevention of diabetic cardiomyopathy and nephropathy
Zn acts as an antioxidant and also as a part of other antioxidant related proteins, such as metallothionein (MT) and Zn-copper superoxide dismutase. Zn deficiency often occurs in patients with diabetes. Therefore, the effect of Zn deficiency or Zn supplementation on diabetes-induced cardiac and renal pathogeneses has been explored. Therefore, Zn plays an important role in the protection of the heart and kidney against diabetes-induced oxidative damage, inflammation, and fibrosis. These studies suggested that diabetic patients should be monitored and treated for Zn deficiency to avoid the acceleration of diabetes-induced cardiac and renal injury.
Double-blind, placebo-controlled study of zinc sulfate in the treatment of attention deficit hyperactivity disorder
Zinc monotherapy was significantly superior to placebo in reducing symptoms of hyperactivity, impulsivity and impaired socialization in patients with ADHD. Although by themselves, these findings may not be sufficient, it may well be considered that zinc treatment appears to be an efficacious treatment for ADHD patients having older age and high BMI score with low zinc and FFA levels.
Zinc supplementation does not alter sensitive biomarkers of copper status in healthy boys
The tolerable upper intake levels (UL) for zinc for children were based on limited data and there is concern that the UL may be set too low. The first effect of excessive zinc intake is a reduction in copper status. The primary objective of this study was to examine the effect of zinc supplementation on copper status in children. Traditional (plasma copper and ceruloplasmin activity) and more sensitive biomarkers of copper status, including erythrocyte SOD1 activity and the erythrocyte CCS:SOD1 protein ratio, were unchanged in zinc-supplemented boys, demonstrating that copper status was not depressed. Serum lipid measures and hemoglobin concentrations were also unaffected and gastrointestinal symptoms were not reported. These data provide evidence in support of the need for reexamining the current UL for zinc for children.
Effect of zinc supplementation on antioxidant activity in young wrestlers
This study aims to examine the effect of zinc supplementation on free-radical formation and antioxidant systems in individuals who are actively engaged in wrestling as a sport. Results obtained at the end of the study indicate that zinc supplementation prevents production of free radicals by activating the antioxidant system. In conclusion, physiologic doses of zinc supplementation to athletes may beneficially contribute to their health and performance.