Immunolocalization of zinc transporters and metallothioneins reveals links to microvascular morphology and functions.

Zinc homeostasis is vital to immune and other organ system functions, yet over a quarter of the world's population is zinc deficient. Abnormal zinc transport or storage protein expression has been linked to diseases, such as cancer and chronic obstructive pulmonary disorder. Although recent studies indicate a role for zinc regulation in vascular functions and diseases, detailed knowledge of the mechanisms involved remains unknown.

Dysregulated zinc and sphingosine-1-phosphate signaling in pulmonary hypertension: Potential effects by targeting of bone morphogenetic protein receptor type 2 in pulmonary microvessels.

Recently identified molecular targets in pulmonary artery hypertension (PAH) include sphingosine-1-phosphate (S1P) and zinc transporter ZIP12 signaling. This study sought to determine linkages between these pathways, and with BMPR2 signaling. Lung tissues from a rat model of monocrotaline-induced PAH and therapeutic treatment with bone marrow-derived endothelial-like progenitor cells transduced to overexpress BMPR2 were studied.

Zinc Homeostasis Alters Zinc Transporter Protein Expression in Vascular Endothelial and Smooth Muscle Cells.

Introduction: Zinc is an important essential micronutrient with anti-oxidative and anti-inflammatory properties in humans. The role of zinc in signalling has been characterized in the nervous, endocrine, gastrointestinal, renal and reproductive systems. Relatively little is known regarding its role in the vascular system, but the role of zinc homeostasis in augmenting vascular health and vasorelaxation is emerging.

Zinc deficiency as a codeterminant for airway epithelial barrier dysfunction in an ex vivo model of COPD.

There is now convincing evidence that the airway epithelium drives the pathogenesis of COPD. A major aspect of this is the disease-related reduction in barrier function that is potentiated by dysregulation of tight junction (TJ) protein complexes. However, a significant number of studies using in vitro smoke exposure models have not observed alterations in barrier permeability.

The uncoupling of autophagy and zinc homeostasis in airway epithelial cells as a fundamental contributor to COPD.

The proper regulation of zinc (Zn) trafficking proteins and the cellular distribution of Zn are critical for the maintenance of autophagic processes. However, there have been no studies that have examined Zn dyshomeostasis and the disease-related modulation of autophagy observed in the airways afflicted with chronic obstructive pulmonary disease (COPD). We hypothesized that dysregulated autophagy in airway epithelial cells (AECs) is related to Zn dysregulation in cigarette smoke (CS)-induced COPD.

BIRC3 single nucleotide polymorphism associate with asthma susceptibility and the abundance of eosinophils and neutrophils.

Background And Objective: Aberrant apoptosis is a disease susceptibility mechanism relevant for asthma, whereby fragility of the airway epithelium and enhanced survival of inflammatory cells, contributes to its pathogenesis and prolongation. Cellular Inhibitor of Apoptosis Proteins (cIAP) suppress apoptosis, and participate in the immune response. In this study, single nucleotide polymorphisms (SNP) in the BIRC2 (codes cIAP1) and BIRC3 (cIAP2) genes were evaluated for an association with asthma.

No Zinc Deficiency But a Putative Immunosuppressive Role for Labile Zn in Patients with Systemic Autoimmune Disease.

Background: Zn (Zn) is an essential trace element with important roles in protein structure and function. Labile Zn is the fraction available for regulatory functions through it loose binding to albumin. As Zn deprivation reduces labile Zn levels and leads to an immune compromised state, we investigated labile Zn levels in the context of systemic autoimmune disease.

Zinc supplementation influences genomic stability biomarkers, antioxidant activity, and zinc transporter genes in an elderly Australian population with low zinc status.

Scope: An increased intake of Zinc (Zn) may reduce the risk of degenerative diseases but may prove to be toxic if taken in excess. This study aimed to investigate whether zinc carnosine supplement can improve Zn status, genome stability events, and Zn transporter gene expression in an elderly (65-85 years) South Australian cohort with low plasma Zn levels.

Methods And Results: A 12-week placebo-controlled intervention trial was performed with 84 volunteers completing the study, (placebo, n = 42) and (Zn group, n = 42).

Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD.

Our previous studies have shown that nutritional zinc restriction exacerbates airway inflammation accompanied by an increase in caspase-3 activation and an accumulation of apoptotic epithelial cells in the bronchioles of the mice. Normally, apoptotic cells are rapidly cleared by macrophage efferocytosis, limiting any secondary necrosis and inflammation. We therefore hypothesized that zinc deficiency is not only pro-apoptotic but also impairs macrophage efferocytosis.

Cellular inhibitor of apoptosis-2 is a critical regulator of apoptosis in airway epithelial cells treated with asthma-related inflammatory cytokines.

Aberrant apoptosis of airway epithelial cells (AECs) is a disease contributing feature in the airways of asthmatics. The proinflammatory cytokines tumor necrosis factor α (TNFα) and interferon γ (IFNγ) are increased in asthma and have been shown to contribute to apoptosis at the airways. In the present study, we investigated the role of the inhibitor of apoptosis protein (IAP) family in primary AECs exposed to TNFα and IFNγ.

Zinc-rich inhibitor of apoptosis proteins (IAPs) as regulatory factors in the epithelium of normal and inflamed airways.

Integrity of the airway epithelium (AE) is important in the context of inhaled allergens and noxious substances, particularly during asthma-related airway inflammation where there is increased vulnerability of the AE to cell death. Apoptosis involves a number of signaling pathways which activate procaspases leading to cleavage of critical substrates. Understanding the factors which regulate AE caspases is important for development of strategies to minimize AE damage and airway inflammation, and therefore to better control asthma.

X-linked inhibitor of apoptosis single nucleotide polymorphisms and copy number variation are not risk factors for asthma.

Background And Objective: Aberrant apoptosis in asthma contributes to airway inflammation. Early apoptosis and fragility of airway epithelial cells and delayed apoptosis of inflammatory lymphocytes can cooperate to increase airway inflammation. In this study, single nucleotide polymorphisms (SNPs) and copy number variation (CNV) in the Baculoviral inhibitor of apoptosis protein repeat-containing 4 (BIRC4) gene (which encodes X-linked inhibitor of apoptosis protein) were evaluated for associations with asthma.

Intracellular zinc is required for intestinal cell survival signals triggered by the inflammatory cytokine TNFα.

The essential micronutrient zinc has long been known to be a functional component of diverse structural proteins and enzymes. More recently, important roles for free or loosely bound intracellular zinc as a signaling factor have been reported. Insufficient zinc intake was shown to exacerbate symptoms in mouse models of inflammation such as experimental colitis, while zinc supplementation was found to improve intestinal barrier function.

Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation.

Little is known about innate immunity and components of inflammasomes in airway epithelium. This study evaluated immunohistological evidence for NLRP3 inflammasomes in normal and inflamed murine (Balb/c) airway epithelium in a model of ovalbumin (OVA) induced allergic airway inflammation. The airway epithelium of control mice exhibited strong cytoplasmic staining for total caspase-1, ASC, and NLRP3, whereas the OVA mice exhibited strong staining for active caspase-1, with redistribution of caspase-1, IL-1β and IL-18, indicating possible activation of the NLRP3 inflammasome.

Apical localization of zinc transporter ZnT4 in human airway epithelial cells and its loss in a murine model of allergic airway inflammation.

The apical cytoplasm of airway epithelium (AE) contains abundant labile zinc (Zn) ions that are involved in the protection of AE from oxidants and inhaled noxious substances. A major question is how dietary Zn traffics to this compartment. In rat airways, in vivo selenite autometallographic (Se-AMG)-electron microscopy revealed labile Zn-selenium nanocrystals in structures resembling secretory vesicles in the apical cytoplasm.

The role of zinc in genomic stability.

Zinc (Zn) is an essential trace element required for maintaining both optimal human health and genomic stability. Zn plays a critical role in the regulation of DNA repair mechanisms, cell proliferation, differentiation and apoptosis involving the action of various transcriptional factors and DNA or RNA polymerases. Zn is an essential cofactor or structural component for important antioxidant defence proteins and DNA repair enzymes such as Cu/Zn SOD, OGG1, APE and PARP and may also affect activities of enzymes such as BHMT and MTR involved in methylation reactions in the folate-methionine cycle.

Zinc deficiency or excess within the physiological range increases genome instability and cytotoxicity, respectively, in human oral keratinocyte cells.

Zinc (Zn) is an essential component of Zn-finger proteins and acts as a cofactor for enzymes required for cellular metabolism and in the maintenance of DNA integrity. The study investigated the genotoxic and cytotoxic effects of Zn deficiency or excess in a primary human oral keratinocyte cell line and determined the optimal concentration of two Zn compounds (Zn Sulphate (ZnSO(4)) and Zn Carnosine (ZnC)) to minimise DNA damage. Zn-deficient medium (0 μM) was produced using Chelex treatment, and the two Zn compounds ZnSO(4) and ZnC were tested at concentrations of 0.

Ultrastructural analysis, zinc transporters, glucose transporters and hormones expression in New world primate (Callithrix jacchus) and human pancreatic islets.

The New world primates (NWP) Callithrix jacchus separated from man approximately 50 million years ago and is a potential alternative small non-human primate model for diabetes research. Ultrastructure, and gene expression of pancreatic islets and the recently described diabetes auto antigenic zinc transporters families in human, NWP and pig pancreas were studied. Morphologically NWP islets were larger than pig islets and similar in size to human islets.

Sputum zinc concentration and clinical outcome in older asthmatics.

Background And Objective: Mouse models of asthma show that zinc deficiency is associated with airway inflammation (AI), which is attenuated by zinc supplements. Whether zinc has a similar role in the human airway remains controversial, with studies demonstrating both high and low plasma zinc concentrations [Zn] in asthmatic patients compared with control subjects. This variability may reflect the inability of plasma measurements to accurately assess airway zinc levels.

The effect of zinc sulphate and zinc carnosine on genome stability and cytotoxicity in the WIL2-NS human lymphoblastoid cell line.

Zinc (Zn) is an essential cofactor required by numerous enzymes that are essential for cell metabolism and the maintenance of DNA integrity. We investigated the effect of Zn deficiency or excess on genomic instability events and determined the optimal concentration of two Zn compounds that minimize DNA-damage events. The effects of Zn sulphate (ZnSO(4)) and Zn carnosine (ZnC) on cell proliferation were investigated in the WIL2-NS human lymphoblastoid cell line.

Dietary zinc mediates inflammation and protects against wasting and metabolic derangement caused by sustained cigarette smoke exposure in mice.

In mouse asthma models, inflammation can be modulated by zinc (Zn). Given that appetite loss, muscle wasting and poor nutrition are features of chronic obstructive pulmonary disease (COPD) and that poor dietary Zn intake is in itself accompanied by growth retardation and appetite loss, we hypothesised that dietary Zn limitation would not only worsen airway inflammation but also exaggerate metabolic effects of cigarette smoke (CS) exposure in mice. Conversely, Zn supplementation would lessen inflammation.

Zinc and zinc transporter regulation in pancreatic islets and the potential role of zinc in islet transplantation.

The critical trace element zinc is essential for normal insulin production, and plays a central role in cellular protection against apoptosis and oxidative stress. The regulation of zinc within the pancreas and β-cells is controlled by the zinc transporter families ZnT and ZIP. Pancreatic islets display wide variability in the occurrence of these molecules.

Zinc fluxes and zinc transporter genes in chronic diseases.

The group IIb metal zinc (Zn) is an essential dietary component that can be found in protein rich foods such as meat, seafood and legumes. Thousands of genes encoding Zn binding proteins were identified, especially after the completion of genome projects, an indication that a great number of biological processes are Zn dependent. Imbalance in Zn homeostasis was found to be associated with several chronic diseases such as asthma, diabetes and Alzheimer's disease.

Anti-inflammatory effects of zinc and alterations in zinc transporter mRNA in mouse models of allergic inflammation.

There is clinical evidence linking asthma with the trace element, zinc (Zn). Using a mouse model of allergic inflammation, we have previously shown that labile Zn decreases in inflamed airway epithelium (Truong-Tran AQ, Ruffin RE, Foster PS, Koskinen AM, Coyle P, Philcox JC, Rofe AM, Zalewski PD. Am J Respir Cell Mol Biol 27: 286-296, 2002).