Trace elements in human physiology and pathology: zinc and metallothioneins.

Background— Chronic obstructive pulmonary disease (COPD) increases the risk of cardiovascular disease 2- to 3-fold. The factors responsible for this association remain largely unknown. Methods and Results— We analyzed data from participants, ≥50 years of age, of the Third National Health and Nutrition Examination Survey (n=6629) to determine whether C-reactive protein (CRP) and other systemic inflammatory markers are present in participants with chronic airflow obstruction and are associated with cardiac injury. Participants with severe airflow obstruction had circulating leukocyte, platelet, and fibrinogen levels that were 460/μL (95% confidence interval [CI], 30 to 890/μL), 39 510/μL (95% CI, 21 730 to 57 290/μL), and 41.63 mg/dL (95% CI, 19.87 to 63.39 mg/dL) higher, respectively, than in those without airflow obstruction. They were also 2.18 times (95% CI, 1.46 to 3.27) more likely to have an elevated circulating CRP level. Moderate airflow obstruction was associated with smaller but still significant...

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Why Are Patients With Chronic Obstructive Pulmonary Disease at Increased Risk of Cardiovascular Diseases? The Potential Role of Systemic Inflammation in Chronic Obstructive Pulmonary Disease

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 critical effect in 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 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 and human health: an update.

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. High dosages of zinc evoke negative effects on immune cells and show alterations that are similar to those observed with zinc deficiency. Furthermore, when peripheral blood mononuclear cells are incubated with zinc in vitro, the release of cytokines such as interleukins (IL)-1 and -6, tumor necrosis factor-alpha, soluble IL-2R and interferon-gamma is induced. In a concentration of 100 micro mol/L, zinc suppresses natural killer cell killing and T-cell functions whereas monocytes are activated directly, and in a concentration of 500 micro mol/L, zinc evokes a direct chemotactic activation of neutrophil granulocytes. All of these effects are discussed in this short overview.

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Zinc-Altered Immune Function

β-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor-mediated activation of PKA and EPAC signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression and now suggest a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and pre-clinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology.

https://clincancerres.aacrjournals.org/content/clincanres/18/5/1201.full.pdf

Molecular pathways: beta-adrenergic signaling in cancer.

The results of more than three decades of work indicate that zinc deficiency rapidly diminishes antibody- and cell-mediated responses in both humans and animals. The moderate deficiencies in zinc noted in sickle cell anemia, renal disease, chronic gastrointestinal disorders and acrodermatitis enteropathica; subjects with human immunodeficiency virus; children with diarrhea; and elderly persons can greatly alter host defense systems, leading to increases in opportunistic infections and mortality rates. Conversely, short periods of zinc supplementation substantially improve immune defense in individuals with these diseases. Mouse models demonstrate that 30 d of suboptimal intake of zinc can lead to 30-80% losses in defense capacity. Collectively, the data clearly demonstrate that immune integrity is tightly linked to zinc status. Lymphopenia and thymic atrophy, which were the early hallmarks of zinc deficiency, are now known to be due to high losses of precursor T and B cells in the bone marrow. This ultimately leads to lymphopenia or a failure to replenish the lymphocytic system. Glucocorticoid-mediated apoptosis induced by zinc deficiency causes down-regulation of lymphopoiesis. Indeed, zinc itself can modulate death processes in precursor lymphocytes. Finally, there is substantial evidence that zinc supplementation may well reduce the impact of many of the aforementioned diseases by preventing the dismantling of the immune system. The latter represents an important area for research.

The Dynamic Link between the Integrity of the Immune System and Zinc Status

Versatility of merocyanine 540 for the flow cytometric detection of apoptosis in human and murine cells.

Summary


Exposure to concentrations of glucocorticoids analogous to those produced during stress, trauma and malnutrition had rapid but varying effects on the major classes of cells within the marrow. Corticosterone (CS) was given as a subdermal implant in young mice and generated 60–95 µg CS/dl of blood compared to 5–15 µg CS/dl for sham controls over a period of 36 hr. Within 24 hr CS had caused losses of 30–70% among the early pro-B, pre-B and immature B cells. The pre-B cells were virtually eliminated by 36 hr and the capacity of surviving pro- and pre-B cells to cycle was reduced by 70–80%. Interestingly, the earliest of B cells, the prepro-B cells, showed considerable resistance to CS, being reduced by only 20% at 36 hr. Thus, the pattern of survival within the B-cell compartment paralleled the expression of Bcl-2. At the 36-hr time-point there were no changes in the proportion of progenitor cells, erythroid or monocytic cells, or number of nucleated cells in the marrow. By contrast, 36 hr after exposure to CS there was an increase of 30% in the proportion and absolute number of cells in the granulocytic compartment. Chronic production of CS appears to reprogramme lymphopoiesis and myelopoiesis, perhaps to preserve the first line of immune defence at the expense of the lymphoid branch. Resistance to apoptosis and modifications in the activity of the glucocorticoid receptor and cytokines produced by stromal cells are postulated as targets for CS-driven changes.

Tonya Laakko

Papers

The Dynamic Link between the Integrity of the Immune System and Zinc Status

Versatility of merocyanine 540 for the flow cytometric detection of apoptosis in human and murine cells.

Rapid changes in the lymphopoietic and granulopoietic compartments of the marrow caused by stress levels of corticosterone

IL-7-mediated protection of pro and pre-B cells from the adverse effects of corticosterone