A genetic variant near the equine interleukin 6 gene associated with copper:zinc ratio.

The aim of this study was to validate an A/T single nucleotide polymorphism (SNP) corresponding to a LINE2 sequence located ∼1.1kb downstream of the IL-6 gene (SNP BIEC2-911738) and to determine if this variant is correlated with interleukin 6 (IL-6) modulation or with different plasma concentrations of Zn, Cu, Se and Fe. The frequency of the newly described variant T ranged from 0 to 23.

In vivo effect of alpha-bisabolol, a nontoxic sesquiterpene alcohol, on the induction of spontaneous mammary tumors in HER-2/neu transgenic mice.

Breast cancer represents the most commonly diagnosed invasive malignancy in pre- and postmenopausal women in both developed and underdeveloped countries. Taking into account that treatment options, including surgery, have not been able to deal with the growing incidence of breast malignancy, it is required to develop mechanism-based novel agents for its prevention. Wide interest in some natural compounds as antiinflammatory agents and as alternative to the traditional medicines is increasing because they do not provoke any adverse effects and are effective in multiple organs, alpha-Bisabolol (BISA), a small oily sesquiterpene alcohol, was reported as chemopreventive agent in induced rat mammary carcinogenesis.

Association of MT1A haplotype with cardiovascular disease and antioxidant enzyme defense in elderly Greek population: comparison with an Italian cohort.

Metallothioneins (MT), the antioxidant zinc-binding proteins, seem to mediate cardioprotection. It has been postulated that zinc homeostasis and MT function may be altered, as a consequence of oxidative stress, in cardiovascular disease (CVD), with a potential implication of MT genetic polymorphisms. The present study explores the role of +647A/C and +1245A/G MT1A polymorphisms on the susceptibility to CVD, zinc status and enzyme antioxidant activity, in the Greek and Italian populations.

Plasma copper/zinc ratio: an inflammatory/nutritional biomarker as predictor of all-cause mortality in elderly population.

Associations have been reported between plasma Cu and Zn levels and the incidence of the most important age-related diseases. Previously proposed methods of using plasma Cu/Zn as a predictor of all-cause mortality have been derived from populations in which old and very old subjects were underrepresented. The purpose of this paper is to estimate the usefulness of plasma Cu/Zn as a sensitive biomarker of harmful inflammatory or nutritional changes in the elderly and its incremental prognostic utility as a predictor of all-cause mortality in a functionally independent elderly Italian cohort.

l-Arginine normalizes NOS activity and zinc-MT homeostasis in the kidney of mice chronically exposed to inorganic mercury.

Inorganic mercury (HgCl2) exposure provokes damage in many organs, especially kidney. Inducible nitric oxide synthase (iNOS) expression, total NOS activity and the profiles of zinc (Zn), copper (Cu) and Hg as well as their distribution when bound to specific intracellular proteins, including metallothioneins (MT), were studied during HgCl2 exposure and after l-arginine treatment in C57BL/6 mouse kidney. HgCl2 exposure modulates differently iNOS expression and NOS activity, increasing iNOS expression but, conversely, decreasing total NOS activity in the mouse kidney.

Distinctive modulation of inflammatory and metabolic parameters in relation to zinc nutritional status in adult overweight/obese subjects.

Overweight and obesity are associated with low grade of inflammation and chronic inflammatory response characterized by abnormal production and activation of some pro-inflammatory signalling pathways. Taking into account that obesity is the direct result of an imbalance between energy intake and energy expenditure, the nutritional factors in the diet, with particular focus on zinc, may play a pivotal role in the development of obesity-associated comorbidities. Considering the potential interactions among zinc nutritional status, inflammation, overweight/obesity and insulin secretion, the aim of the present work was to clarify the influence of zinc dietary intake on some metabolic, inflammatory and zinc status parameters in adult overweight/obese subjects.

NK and NKT cells in aging and longevity: role of zinc and metallothioneins.

Introduction: During aging, dysregulated immune functions occur contributing to increased susceptibility to morbidity and mortality. However, these dysregulations are normally counterbalanced by continuous adaptation of the body to the deteriorative changes occurring over time. These adaptive changes well occur in healthy centenarians.

Accumulation of cells with short telomeres is associated with impaired zinc homeostasis and inflammation in old hypertensive participants.

Critical shortening of telomeres, likely associated with a considerable increase of senescent cells, can be observed in PBMC of individuals aged 80 and older. We investigated the relationship between critical telomere shortening and zinc status in healthy or hypertensive participants with or without cardiovascular disease in old and very old participants. Telomere shortening and accumulation of cells with short telomeres (percent of cells with short telomeres) in advancing age was evident in patients and healthy controls, but exacerbated in those patients aged 80 and older.

Metallothionein downregulation in very old age: a phenomenon associated with cellular senescence?

It is known that metallothionein (MT) mRNA expression first increases with age, but then decreases again in the very elderly. Here we report that MT protein levels also decrease in very old age, and that this is independent of dietary zinc intake. Age-related changes of MT, as well as alterations of zinc homeostasis (intracellular labile zinc and NO-induced zinc release), occur both in human PBMCs ex vivo and also in CD4+ T cell clones progressing through their finite life span in vitro.

Modulation of genes involved in zinc homeostasis in old low-grade atherosclerotic patients under effects of HMG-CoA reductase inhibitors.

Taking into account the antioxidant properties of zinc, it is difficult to explain the beneficial effects of HMG-CoA reductase inhibitors in the context of a well-known decreased zinc status. Therefore, intracellular zinc homeostasis was studied in patients with low-grade carotid atherosclerosis under treatment with HMG-CoA reductase inhibitors using a custom microarray-based approach developed by pooling information across microarray studies. Experimental data unravel an active zinc signaling in PBMC from low-grade atherosclerotic patients under lipid reduction therapy, suggesting that monitoring intracellular zinc status could be a key factor for an optimal strategy and targeting a level of intervention.

A novel Zip2 Gln/Arg/Leu codon 2 polymorphism is associated with carotid artery disease in aging.

Zinc deficiency represents a risk factor for carotid stenosis (CS) development. In mammals, members of the ZIP family regulate zinc uptake, and hZip2 is a human zinc importer upregulated by zinc depletion. The purpose of this study was to investigate the association of a novel Zip2 Gln/Arg/Leu codon 2 polymorphism with CS, analyzing 250 CS patients and 259 elderly controls.

Zinc deficiency and IL-6 -174G/C polymorphism in old people from different European countries: effect of zinc supplementation. ZINCAGE study.

IL-6 SNP at position -174 is associated with age-related diseases characterized by an impaired Zn status. This polymorphism seems also relevant in regulating the expression of proteins, such as Metallothioneins (MT), involved in the modulation of Zn homeostasis. Since high IL-6 levels in elderly induce hypozinchemia, the IL-6-174 SNP may be useful to identify old subjects who are at risk for Zn deficiency.

Zinc, metallothioneins, and longevity--effect of zinc supplementation: zincage study.

Aging is an inevitable biological process that is associated with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. Because nutritional factors are involved in improving immune functions, metabolic harmony, and antioxidant defense, some nutritional factors, such as zinc, may modify susceptibility to disease and promote healthy aging. In vitro (human lymphocytes exposed to endotoxins) and in vivo (old or young mice fed with low zinc dietary intake) studies revealed that zinc is important for immune efficiency (innate and adaptive), antioxidant activity (supeoxide dismutase), and cell differentiation via clusterin/apolipoprotein J.

Zinc-bound metallothioneins and immune plasticity: lessons from very old mice and humans.

The capacity of the remodelling immune responses during stress (named immune plasticity) is fundamental to reach successful ageing. We herein report two pivotal experimental models in order to demonstrate the relevance of the immune plasticity in ageing and successful ageing. These two experimental models will be compared with the capacity in remodelling the immune response in human centenarians.

The +838 C/G MT2A polymorphism, metals, and the inflammatory/immune response in carotid artery stenosis in elderly people.

Carotid artery stenosis (CS) is a well-established risk factor for stroke. Increased proinflammatory chemokines, enhanced metallothionein (MT), and altered metal homeostasis may play roles in atherosclerosis progression and plaque destabilization. MT may sequester zinc during chronic inflammation, provoke zinc deficiency, and modulate NK cell cytotoxicity.

CD14 C (-260)T polymorphism, atherosclerosis, elderly: role of cytokines and metallothioneins.

Background: CD14 receptor is a mediator of the inflammatory response to bacterial products. A functional polymorphism in the promoter of the CD14 gene (CD14 C-260T) was associated with coronary heart disease and atherosclerosis albeit with conflicting data.

Methods: To better clarify the role of CD14 in atherosclerosis, we typed CD14 C-260T polymorphism in old Italian (Central of Italy) atherosclerotic patients with carotid stenosis related to lipid assessment, inflammation (soluble CD14, IL-6 serum levels) and IL-6, TNF-alpha, IL-10, Metallothioneins (MT) gene expressions in carotid plaques.

Zinc-binding proteins (metallothionein and alpha-2 macroglobulin) and immunosenescence.

Zinc is a relevant trace element for the efficiency of the entire immune system. The binding of zinc with some proteins, such as metallothioneins (MT) and alpha-2 macroglobulin (alpha-2M) is crucial for the immune efficiency during ageing and in age-related diseases, because these proteins may be involved in antagonistic pleiotropic effects. Indeed, the presence of chronic inflammation during ageing, generally, induces overexpression of these proteins that, due to their original biological function in fighting stressor agents, continuously sequester intracellular zinc.

Single and three-color flow cytometry assay for intracellular zinc ion availability in human lymphocytes with Zinpyr-1 and double immunofluorescence: relationship with metallothioneins.

Background: : The amount of available intracellular zinc is pivotal to regulate many cellular processes, including oxidative stress response and apoptotic mechanisms. Therefore it is not surprising that zinc homeostasis and dyshomeostasis is involved in many physiological and pathological states, respectively. Cell permeable zinc probes allow intracellular applications with microscopy technology, but flow cytometry (FC) applications have been scarcely explored, albeit they can be suited to study zinc homeostasis in different cell types, including rare cells.

Inflammation, genes and zinc in ageing and age-related diseases.

Lifelong antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and pro-inflammatory cytokine production. A large number of studies have documented changes in Zn metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory diseases. In particular, modification of zinc plasma concentration as well as intracellular disturbance of antioxidant intracellular pathways have been found associated to age-related inflammatory diseases, like atherosclerosis.

Polymorphisms in MT1a gene coding region are associated with longevity in Italian Central female population.

Metallothioneins (MTs) play a pivotal role in zinc-related cell homeostasis because of their high affinity for zinc, which is in turn fundamental for immune response and antioxidant activity. MTs regulate zinc homeostasis by binding zinc and releasing zinc at the occurrence for immune response. The zinc release by MT is very limited in chronic inflammation and ageing.

Involvement of -308 TNF-alpha and 1267 Hsp70-2 polymorphisms and zinc status in the susceptibility of coronary artery disease (CAD) in old patients.

Coronary artery disease (CAD) is characterized by an inflammatory status and it represents the major cause of death in elderly. Zinc deficiency and inflammatory genes within major histocompatibility complex (MHC) region are implicated in ischaemic heart diseases. TNF-alpha is present in coronary artery plaques and may provoke plaque instability.

Plasticity of neuroendocrine-thymus interactions during ontogeny and ageing: role of zinc and arginine.

Thymic re-growth and reactivation of thymic functions may be achieved in old animals by different endocrinological or nutritional manipulations such as, (a) treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumour cell line (GH3 cells) or treatment with exogenous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone (LHRH), (d) treatment with exogenous thyroxin or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of these interactions in old age that is responsible for age-associated immune-neuroendocrine dysfunctions. The targets involved in hormones-induced thymic reconstitution may directly or indirectly involve hormone receptors, cytokines, arginine, and a trace element such as zinc, which is pivotal for the efficiency of neuroendocrine-immune network during the whole life of an organism.

Frequency of polymorphisms of signal peptide of TGF-beta1 and -1082G/A SNP at the promoter region of Il-10 gene in patients with carotid stenosis.

The role of inflammation in atherosclerosis is well recognized. We have evaluated the allele frequencies of the +869T/C and +915G/C polymorphisms (SNPs) at the TGF-beta1 gene and -1082G/A SNP at IL-10 promoter sequence, two well-known immunosuppressive and anti-inflammatory cytokines, in patients with carotid stenosis. Our data suggest a lack of association between these SNPs and the susceptibility to atherosclerosis although other reports have demonstrated this association.

Zinc homeostasis in aging: two elusive faces of the same "metal".

Proteins involved in zinc homeostasis may be altered in aging. This phenomenon may lead to zinc deficiency in the peripheral blood and an accumulation of zinc bound to insoluble aggregates at the extracellular level in the brain. Therefore, it should be more correct to talk about aging as a condition associated with zinc dyshomeostasis rather than deficiency.

Novel -209A/G MT2A polymorphism in old patients with type 2 diabetes and atherosclerosis: relationship with inflammation (IL-6) and zinc.

Vascular complications, including ischaemic cardiomyopathy, are the major causes of death in old diabetic patients. Chronic inflammation due to high IL-6 production occurs in type 2 diabetes (NIDDM) and atherosclerosis. High levels of IL-6 are associated with hyperglycaemia, dyslipidemia and provoke insulin resistance.