ORCID Profile
0000-0001-5196-2611
Current Organisation
University of Adelaide
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Physiological Society
Date: 12-2000
DOI: 10.1152/AJPLUNG.2000.279.6.L1172
Abstract: The respiratory epithelium is vulnerable to noxious substances, resulting in the shedding of cells and decreased protection. Zinc (Zn), an antioxidant and cytoprotectant, can suppress apoptosis in a variety of cells. Here we used the novel Zn-specific fluorophore Zinquin to visualize and quantify labile intracellular Zn in respiratory epithelial cells. Zinquin fluorescence in isolated ciliated tracheobronchial epithelial cells and intact epithelium from sheep and pigs revealed an intense fluorescence in the apical and mitochondria-rich cytoplasm below the cilia. Zinquin fluorescence was quenched by the Zn chelator N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and increased by the Zn ionophore pyrithione. We also assessed whether changes in intracellular labile Zn would influence susceptibility of these cells to apoptosis by hydrogen peroxide. Our results confirm that Zn deficiency enhanced hydrogen peroxide-induced caspase activation from 1.24 ± 0.12 to 2.58 ± 0.53 units · μg protein −1 · h −1 ( P ≤ 0.05) Zn supplementation suppressed these effects. These findings are consistent with the hypothesis that Zn protects upper respiratory epithelial cells and may have implications for human asthma where there is hypozincemia and epithelial damage.
Publisher: American Thoracic Society
Date: 09-2002
Publisher: Bentham Science Publishers Ltd.
Date: 2008
DOI: 10.2174/1874467210801010038
Abstract: Airway epithelium (AE) lines the conducting airways of the respiratory system and functions to maintain airway integrity by providing both a physical barrier to inhaled noxious agents and a mechanism for their clearance via the mucociliary escalator. Normal AE cells are relatively refractory to a number of apoptotic stimuli and survival mechanisms are in place to maintain the integrity of the epithelial barrier that is exposed to agents such as reactive oxygen species (ROS) and death receptor ligands secreted by immune cells during inflammation. When damage to AE does occur, there is increased AE apoptosis, such as in the airway damage that occurs in the chronically inflamed airways in diseases like asthma where rates of AE apoptosis can be increased many-fold. The usual treatment for persistent asthma in humans involves a combination of bronchodilator and inhaled corticosteroid there is however a need to develop strategies to better control other aspects of the disease, including minimizing the ongoing damage to AE and consequent airway remodeling. Targeting of the major apoptosis-regulatory factors in AE may be one such strategy. Here we review what is known about apoptosis and its regulatory factors in normal AE and abnormalities in these factors in the inflamed airways of mice and humans.
Publisher: Elsevier BV
Date: 07-1990
DOI: 10.1016/0167-4889(90)90001-T
Abstract: At micromolar concentrations, zinc (Zn) and cadmium, but not other metals, greatly augmented binding of [3H]phorbol dibutyrate ([3H]PDBu) to protein kinase C (PKC) in cell homogenates and intact cells (in the presence of ionophore). Increased binding persisted for several hours. The heavy-metal chelating agent 1,10-phenanthroline completely reversed the increased [3H]PDBu binding in cells pretreated with 65Zn and ionophore and this was associated with a decline of about 20% in cell-associated 65Zn, suggesting that a relatively small pool of intracellular Zn acts on PKC. This may be a membrane-associated pool, since 65Zn readily bound to isolated erythrocyte inside-out membranes. Phenanthroline also partially inhibited binding of [3H]PDBu to PKC in untreated cells and extracts in a Zn-reversible manner. Therefore, cellular Zn appears to regulate the interaction of ligand with PKC. PKC bound to a Zn affinity column and was eluted by metal-chelator, confirming that Zn interacts directly with PKC.
Publisher: Wiley
Date: 11-2019
Publisher: Wiley
Date: 05-2015
DOI: 10.1111/IMJ.12752
Publisher: Springer Science and Business Media LLC
Date: 11-2004
DOI: 10.1007/S10534-004-1210-3
Abstract: Acute and chronic arsenic exposure results in toxicity in humans and causes many neurological and other manifestations. For the first time the present study reports that zinc decreases arsenic-induced apoptosis and also confirms a single report of apoptosis induced by arsenic in a neuronal cell line. Apoptosis measured by DEVD-caspase activity peaked between 10 microM and 20 microM of arsenic trioxide. Higher concentrations of arsenic up to 40 microM caused increasing cell death with diminishing DEVD-caspase activity. The beneficial effect of zinc was proportional to its concentration with a significant decrease in arsenic-induced DEVD-caspase activity at 50 microM and 75 microM zinc (P < 0.05). This finding may be of therapeutic benefit in people suffering from chronic exposure to arsenic from natural sources, a global problem especially relevant to millions of people on the Indian subcontinent.
Publisher: Wiley
Date: 24-04-1989
DOI: 10.1016/0014-5793(89)81388-2
Abstract: In the presence of pyrithione, which was used as a Zn2+ ionophore, Zn2+ (10-100 microM) increased phorbol ester binding by intact B-CLL cells in a dose-dependent fashion. Zn pyrithione increased 2-fold the number of phorbol ester receptors in B-cells (0.74 to 1.4 pmol/10(6) cells), neutrophil polymorphs (0.2 to 0.51 pmol/10(6) cells) and platelets (91 to 209 pmol/10(10) cells). Fractionation of cells after treatment with Zn pyrithione showed that increased binding of PDBu occurred in the particulate fraction of cells and this was accompanied by loss of phorbol ester receptors from the cytosol. These data are compatible with a role for Zn in the subcellular distribution and activation of protein kinase C.
Publisher: Elsevier BV
Date: 06-2201
Publisher: Elsevier BV
Date: 05-2000
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0304-3835(99)00176-7
Abstract: Activated caspase-3-like proteases promote apoptotic cell death by cleaving cellular substrates. Caspase-3-like activity was measured in colonic carcinomas and in matched normal colonic mucosa from 31 patients and was significantly elevated in 25/ 31 colonic carcinomas and adenomas when compared to normal mucosa (P < 0.0001). Caspase-3-like activity was much higher in normal mucosa and tumours of female subjects than of males (P < 0.0001). No correlation was obtained between caspase-3-like activity and location of the tumour, tumour grade, stage, or patient age. The marked increase in caspase-3-like activity in colorectal carcinomas may reflect an increase in the proportion of cells undergoing spontaneous apoptosis.
Publisher: Springer Science and Business Media LLC
Date: 08-1982
DOI: 10.1007/BF00319938
Publisher: Wiley
Date: 29-10-1990
DOI: 10.1016/0014-5793(90)81067-X
Abstract: Protein kinase C was measured in the cytoskeletal fraction of lymphocytes, platelets and HL60 cells, by specific binding of [3H]phorbol dibutyrate and by immunoblotting with antibody to a consensus sequence in the regulatory domain of alpha-, beta- and gamma-isozymes of protein kinase C. Treatment of cells for 40 min with a combination of zinc (2-50 microM), zinc ionophore pyrithione and unlabelled phorbol dibutyrate (200 nM) caused up to a ten-fold increase in cytoskeletal protein kinase C and a corresponding decrease in other cellular compartments. Omission of any of the reagents resulted in much less or no translocation. These effects were inhibited by 1,10-phenanthroline, which chelates zinc, and were not seen with calcium. Increase in cytoskeletal protein kinase C persisted for several hours and appeared to involve attachment of the enzyme to actin microfilaments. We propose that zinc, like calcium, regulates the distribution of PKC in cells. However, unlike calcium which controls the binding of PKC to the lipid component on cell membranes, zinc controls the distribution of PKC to membrane cytoskeleton, possibly actin.
Publisher: JCFCorp SG PTE LTD
Date: 2011
Publisher: MDPI AG
Date: 25-10-2011
DOI: 10.3390/NU3110910
Publisher: Wiley
Date: 04-2001
DOI: 10.1046/J.1440-1711.2001.00986.X
Abstract: Over the past 30 years, many researchers have demonstrated the critical role of zinc (Zn), a group IIb metal, in erse physiological processes, such as growth and development, maintenance and priming of the immune system, and tissue repair. This review will discuss aspects of Zn physiology and its possible beneficial role in the respiratory epithelium. Here we have detailed the mechanisms by which Zn ersely acts as: (i) an anti-oxidant (ii) an organelle stabilizer (iii) an anti-apopototic agent (iv) an important cofactor for DNA synthesis (v) a vital component for wound healing and (vi) an anti-inflammatory agent. This paper will also review studies from the authors' laboratory concerning the first attempts to map Zn in the respiratory epithelium and to elucidate its role in regulating caspase-3 activated apoptosis. We propose that Zn, being a major dietary anti-oxidant has a protective role for the airway epithelium against oxyradicals and other noxious agents. Zn may therefore have important implications for asthma and other inflammatory diseases where the physical barrier is vulnerable and compromised.
Publisher: Elsevier BV
Date: 07-1986
DOI: 10.1016/S0006-291X(86)80532-0
Abstract: The calcium ionophore A23187 synergised with phorbol dibutyrate-induced activation of human chronic lymphatic leukaemia B-cells, as assessed by modulation of the membrane receptor for mouse erythrocytes. Thus A23187 (1 microM), which alone had no effect on expression of the receptor for mouse erythrocytes, reduced the EC50 and shortened the lag period for modulation of this receptor by phorbol dibutyrate. This action of A23187 was shown to be due to enhanced binding of [3H]phorbol dibutyrate to its receptor (phospholipid/Ca++ dependent protein kinase C) whose affinity was altered from a predominantly low affinity state (Kd 83 nM) to high affinity (Kd 9 nM). A23187 had no effect on the total number of phorbol dibutyrate receptors. EDTA abolished these actions of A23187.
Publisher: Bentham Science Publishers Ltd.
Date: 25-01-2201
Publisher: Elsevier BV
Date: 02-2000
Publisher: Portland Press Ltd.
Date: 12-1993
DOI: 10.1042/BJ2960403
Abstract: Zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)-acetic acid], a membrane-permeant fluorophore specific for Zn(II), was used with spectrofluorimetry and video image analysis to reveal and quantify labile intracellular Zn. Zinquin labelled human chronic-lymphocytic-leukaemia lymphocytes, rat splenocytes and thymocytes with a weak diffuse fluorescence that was quenched when intracellular Zn was chelated with NNN‘N’-tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and was greatly intensified by pretreatment of cells with the Zn ionophore pyrithione and exogenous Zn. There was substantial heterogeneity of labile Zn among ionophore-treated cells, and fluorescence was largely extranuclear. The average contents of labile Zn in human leukaemic lymphocytes, rat splenocytes and rat thymocytes were approx. 20, 31 and 14 pmol/10(6) cells respectively. Morphological changes and internucleosomal DNA fragmentation indicated substantial apoptosis in these cells when the level of intracellular labile Zn was decreased by treatment with TPEN. Conversely, increasing labile Zn by pretreatment with Zn plus pyrithione suppressed both spontaneous DNA fragmentation and that induced by the potent apoptosis-induced agents colchicine and dexamethasone. These results suggest that prevention of apoptosis is a function of labile Zn, and that a reduction below a threshold concentration in this Zn pool induces apoptosis.
Publisher: Portland Press Ltd.
Date: 11-1994
DOI: 10.1042/BJ3030781
Abstract: Zinquin [ethyl (2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetate], a new intracellular zinc fluorophore, was used to reveal and to measure Zn in cultured rat hepatocytes before and after metallothionein (MT) induction. Hepatocytes labelled with an intense extranuclear fluorescence. Culture with combinations of Zn, dexamethasone and interleukin-6, increased intracellular MT by 24-fold, Zn 3-fold, and Zinquin fluorescence by approx. 2-fold above control values. Zinquin fluorescence correlated in descending order with the total cellular Zn (r = 0.747), exchangeable Zn (r = 0.735), soluble cytosolic Zn (r = 0.669) and MT (r = 0.666). When Zinquin was incubated with a cytosolic fraction of liver proteins before Sephadex G-75 column chromatography, it fluoresced with free, MT-incorporated and protein-bound Zn. Although only a slight attenuation of fluorescence was seen with high-molecular-mass protein-bound Zn, MT was degraded by 60% in the presence of Zinquin. The undegraded Zn-MT fluoresced at about 20% of the expected intensity. Although Zinquin fluoresces with all cytosolic Zn, caution is required when comparisons are made between s les with different concentrations of MT. This limitation was demonstrated by staining liver slices from adjuvant-treated rats where MT was increased 24-fold, intracellular Zn by 77%, but Zinquin fluorescence by only 19% above controls. Nevertheless, Zinquin should prove to be a useful tool for studying the distribution of Zn in living cells.
Publisher: SAGE Publications
Date: 07-1994
DOI: 10.1177/42.7.8014471
Abstract: We used an intracellular zinc-specific fluorophore, Zinquin, in conjunction with fluorescence video image analysis, to reveal labile zinc in pancreatic islet cells, which concentrate this metal for use in synthesis, storage, and secretion of insulin. Zinquin vividly demonstrated zinc in the islet cell secretory granules, which formed a brightly labeled crescent in the cytoplasm between one side of the nucleus and the plasma membrane. Lower but still appreciable amounts of zinc were detected in the remaining cytoplasm, but there was little labeling in the nucleus. Fluorescence intensity varied among islet cells, suggesting differences in zinc content. Their average fluorescence intensity greatly surpassed that of the surrounding pancreatic acinar cells in frozen sections of pancreas and in all other types of cell studied, including lymphocytes, neutrophils, fibroblasts, and erythrocytes. Less labile zinc was detected in cells of the mouse insulinoma cell line NIT-1, regardless of whether they were maintained in long-term culture in the presence or absence of exogenous extracellular zinc. Exposure of islet or insulinoma cells to a high concentration of glucose or other secretagogue decreased the content of labile zinc. Zinquin should be a useful probe for revealing changes in zinc homeostasis in islet B-cells that may be important in their dysfunction and death during diabetes.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2021
Publisher: Wiley
Date: 06-1999
DOI: 10.1046/J.1440-1711.1999.00825.X
Abstract: Non-toxic agents that target intracellular signalling pathways in apoptosis may have potential therapeutic use in many diseases. One such agent is the transition metal Zn, a dietary cytoprotectant and anti-oxidant, which stimulates cell proliferation and suppresses apoptosis. Zn is maintained in discrete subcellular pools that are critical for the functional and structural integrity of cells. The present review initially describes the current state of knowledge on the cellular biology of Zn, especially the critical free or loosely bound (labile) pools of Zn, which are thought to regulate apoptosis. We then review the evidence relating Zn to apoptosis, including studies from our laboratory showing potent synergy between intracellular Zn deficiency and the short chain fatty acid butyrate in induction of caspase activation and the downstream events of apoptosis. Our studies have also reported the suppressive effects of micromolar concentrations of Zn on caspase-3 activation in cell-free models. Other key issues that will be discussed include the identification of the putative molecular targets of Zn and the evidence that systemic changes in labile Zn levels are sufficient to alter susceptibility to apoptosis and lead to physiopathological changes in the human body. Finally, we propose that labile Zn may serve as a coordinate regulator of mitosis and apoptosis to regulate tissue growth.
Publisher: Wiley
Date: 10-1978
DOI: 10.1111/J.1445-5994.1978.TB02595.X
Abstract: Four cases of lymphocytic leukaemia were distinguished from CLL by surface marker analysis. CLL cells have relatively little SIg and have the mouse erythrocyte receptor. Cells in these cases had denser Slg and lacked the mouse erythrocyte receptor. The group presented a fairly uniform picture with onset in sixth or seventh decade, very high lymphocyte counts, splenomegaly (gross in three), heavy infiltration of marrow, relative resistance to chemotherapy and response to splenectomy. The lymphocytes were somewhat larger than those usually found in CLL and histological examination showed a quasi-nodular pattern in lymph nodes with diffuse infiltration of the spleen. Difficulties of classification are discussed. The addition of surface marker analysis to clinical and morphological parameters allows these cases of B-lymphocytic leukaemia (mouse erythrocyte-negative B leukaemia) to be distinguished clearly from chronic lymphocytic leukaemia. The mouse erythrocyte receptor is particularly useful in making this distinction.
Publisher: Elsevier BV
Date: 04-2000
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.YGCEN.2011.07.004
Abstract: 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. NWP islets alpha cells had high dense core surrounded by a limiting membrane, beta cells by the mixed morphology of the granule core, and delta cells by moderate opaque core. Antibody staining for insulin, glucagon, somatostatin and Glucagon-like peptide-1 (GLP-1) showed that the distribution pattern of the different cell types within islets was comparable to pig and human islets. In all three species protein expression of zinc transporter ZnT8 was detected in most of the insulin producing beta cells whereas Zip14 expression was widely expressed in alpha and beta cells. In both human and NWP little or no expression of Glut2 was observed compared to Glut1 and glucokinase at the protein level, however the messenger RNA level of Glut2 was greater than Glut1 and glucokinase. In contrast all three glucose transporters were expressed in pig islets at the protein level. The expression of Zip14 in islets is reported for the first time. In conclusion NWP pancreatic islets express comparable islet cell types and distribution to humans and pigs. Importantly, marmosets have a similar glucose transporter profile to humans, making this non-endangered primate species a useful animal model for pancreatic biology.
Publisher: Elsevier BV
Date: 04-2000
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.JNUTBIO.2012.06.020
Abstract: The essential micronutrient zinc has long been known to be a functional component of erse 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. Herein, we provide evidence that intracellular zinc is essential for maintaining intestinal epithelial integrity when cells are exposed to the inflammatory cytokine Tumor Necrosis Factor (TNF)α. Using the human intestinal Caco-2/TC7 cell line as an in vitro model, we demonstrate that depletion of intracellular zinc affects TNFα-triggered signaling by shifting intestinal cell fate from survival to death. The mechanism underlying this effect was investigated. We show that TNFα promotes a zinc-dependent survival pathway that includes modulation of gene expression of transcription factors and signaling proteins. We have identified multiple regulatory steps regulated by zinc availability which include the induction of cellular Inhibitor of APoptosis (cIAP2) mRNA, possibly through activation of Nuclear Factor-Kappa B (NF-κB), as both nuclear translocation of the p65 subunit of NF-κB and up-regulation of cIAP2 mRNA were impaired following zinc depletion. Moreover, X-linked inhibitor of apoptosis protein level was profoundly reduced by zinc depletion. Our results provide a possible molecular explanation for the clinical observation that zinc supplements ameliorate Crohn's disease symptoms and decrease intestinal permeability in experimental colitis.
Publisher: Springer Netherlands
Date: 13-05-2015
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1016/J.MRFMMM.2007.01.013
Abstract: 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. As it is now evident for most nutrients, body Zn status results from the interaction between diet and genotype. Zn ions cross biological membranes with the aid of specialized membrane proteins, belonging to the ZRT/IRT-related Proteins (ZIP) and zinc transporters (ZnT) families. The ZIPs are encoded by the Slc39A gene family and are responsible for uptake of the metal, ZnTs are encoded by the Slc30A genes and are involved in intracellular traffic and/or excretion. Both ZnTs and Zips exhibit unique tissue-specific expression, differential responsiveness to dietary Zn deficiency and excess, as well as to physiological stimuli via hormones and cytokines. Intracellular Zn concentration is buffered by metallothioneins (MTs), a class of cytosolic protein with high affinity for metals. Scattered information is available on the role of proteins responsible for regulating Zn fluxes in the onset and progression of chronic diseases. This paper reviews reports that link Zn transporter genes, their allelic variants and/or expression profiles in the context of specific diseases. Further investigation in this direction is very important, since Zn imbalance can result not only from insufficient dietary intake, but also from impaired activity of proteins that regulate Zn metabolism, thus contributing to multifactorial diseases.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.NUMECD.2008.09.004
Abstract: Zinc is abundant in pancreas, being required by endocrine islet cells for hormone secretion and by exocrine acinar cells as pancreatic juice component. ZnT8 is a member of the SLC30A family of zinc transporters whose overexpression in cultured pancreatic beta cells leads to increased insulin secretion in response to glucose, suggesting a possible role in regulating glycemia. ZnT8 was therefore proposed as a therapeutic target for diabetes, and recent genome-wide association studies identified polymorphisms in the ZNT8 gene conferring increased type 2 diabetes risk. As limited information was available on the biochemical properties of ZnT8 and on its endogenous expression, we have raised a specific polyclonal antibody and immunostained protein extracts, cell lines and tissue sections. We show that ZnT8 forms a very stable dimer that requires biological membranes to properly assemble. We demonstrate localization of murine ZnT8 to the secretory granules in pancreatic beta and alpha islet cells. Moreover, we show that ZnT8 is also expressed in other secretory cell types, namely the cubical epithelium that lines thyroid follicles and the cortex of the adrenal gland, suggesting a more widespread role in endocrine secretion. We provide novel insights into the features of the ZnT8 transporter, of special relevance in light of its proposed role as therapeutical target for diabetes treatment.
Publisher: Elsevier BV
Date: 1979
DOI: 10.3109/00313027909059023
Abstract: Immunological surface marker techniques were applied in a study of 29 cases of chronic lymphocytic leumaemia and 22 of non-Hodgkin's lymphoma. Surface marker characteristics distinguished 2 subtypes of B lymphocytes. Chronic lymphocytic leukaemia was a monoclonal proliferation of B lymphocytes which produced spontaneous rosettes with mouse erythrocytes and had faintly immunofluorescent surface immunoglobulin. The majority of non-Hodgkin's lymphomas also had their origin from B lymphocytes but in contrast, this subtype did not show receptors for mouse erythrocytes and their surface immunoglobulin was brightly staining and demonstrated "capping". The clonal origin of nodular lymphomas could also be demonstrated on frozen sections stained for surface immunoglobulin. Two cases of true histiocytic lymphoma were identified. The current information available on surface marker characteristics of the leukaemias and lymphomas is reviewed.
Publisher: No publisher found
Date: 1983
DOI: 10.1016/0005-2736(83)90201-8
Abstract: The structure of some phospholipids that cause agglutination of mouse erythrocytes has been studied. Haemagglutination is a property of non-choline-containing phospholipids the phosphate group is essential and unsaturated fatty acids optimal. A protein of Mr 70 000 was isolated from mouse erythrocyte membranes which completely inhibited phospholipid-mediated erythrocyte agglutination. It is proposed that this protein is the phospholipid binding site on mouse erythrocytes and the ligand for the human B-lymphocyte receptor for mouse erythrocytes. Preliminary investigations suggest that a similar inhibitor of phospholipid-mediated agglutination is found in serum. Agglutination of mouse erythrocytes by phospholipid and specific inhibition by the 70 kDa membrane protein constitute a simple system for studying the interaction of phospholipid with protein.
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.PHARMTHERA.2004.09.004
Abstract: In addition to basic housekeeping roles in metalloenzymes and transcription factors, dietary zinc (Zn) is an important immunoregulatory agent, growth cofactor, and cytoprotectant with anti-oxidant, anti-apoptotic, and anti-inflammatory roles. These properties of Zn are of particular importance in maintaining homeostasis of epithelial tissues which are at the front line of defense. This review is about the role of Zn in airway epithelium (AE). The first part focuses on the cellular biology of Zn, and what is known about its distribution and function in AE. The second part of the review considers evidence for altered Zn metabolism in asthma and other chronic diseases of airway inflammation. Important issues arise from a potential therapeutic perspective as to the optimal ways to monitor circulating and epithelial Zn levels in patients and the most effective means of supplementing these levels.
Publisher: Wiley
Date: 23-02-1987
DOI: 10.1016/0014-5793(87)81353-4
Abstract: The calcium ionophore A23187 acted synergistically with phorbol dibutyrate (PDBu) to stimulate human neutrophil superoxide production. A23187 shortened the lag period and markedly increased the initial rate of neutrophil superoxide production induced by suboptimal concentrations of PDBu. 1 microM A23187 reduced the EC50 value for superoxide release from 56 to 8 nM PDBu. This effect of A23187 was correlated with enhanced binding of [3H]PDBu to its receptor and a reduction in the dissociation constant (Kd) from 27 to 10 nM, without altering the apparent total number of phorbol dibutyrate receptors. These actions of A23187 were abolished in the presence of EGTA or TMB-8, confirming a dependence on Ca2+.
Publisher: Elsevier BV
Date: 02-1992
DOI: 10.1016/0014-4827(92)90393-M
Abstract: Chronic lymphocytic leukemia lymphocytes were used to study mechanisms involved in apoptosis (programmed cell death). Apoptosis, which was determined by morphological changes including cell death and by internucleosomal DNA fragmentation, occurred during culture for 1 to 2 days in a portion of the cells from three of the four patients tested. Most of the cells underwent apoptosis and DNA fragmentation was greatly enhanced when cells were cultured in the presence of the microtubule inhibitor colchicine, the topoisomerase II inhibitor etoposide, or the glucocorticoid methylprednisolone. Tumor-promoting phorbol esters inhibited spontaneous DNA fragmentation and cell death including that induced by colchicine, etoposide, and methylprednisolone, indicating that they act on an event common to apoptosis caused by erse stimuli. Phorbol esters probably act through protein phosphorylation, since they were effective at concentrations which modulated protein kinase C (PKC) and their action was prevented by H-7, which binds to and inactivates the catalytic site of PKC. In the absence of phorbol ester, H-7 itself induced some apoptosis. These findings implicate PKC in the suppression of apoptosis, but its precise role requires systematic investigation.
Publisher: Informa UK Limited
Date: 10-09-2018
DOI: 10.1080/10408398.2018.1495614
Abstract: The discovery of the roles of nitric oxide (NO) in cardiovascular signaling has led to a revolution in the understanding of cardiovascular disease. A new perspective to this story involving zinc (Zn) is emerging. Zn and its associated Zn transporter proteins are important for the integrity and functions of both the large conduit vessels and the microvascular resistance vessels. The Zn and NO pathways are tightly coordinated. Zn ions are required for the dimerization of endothelial nitric oxide synthase and subsequent generation of NO while generation of NO leads to a rapid mobilization of endothelial Zn stores. Labile Zn may mediate important downstream actions of NO including vascular cytoprotection and vasodilation. Several vascular disease risk factors (including aging, smoking and diabetes) interfere with Zn homeostatic mechanisms and both hypozincaemia and Zn transporter protein abnormalities are linked to atherosclerosis and microvascular disease. Some vegetarian diets and long-term use of certain anti-hypertensives may also impact on Zn status. The available evidence supports the existence of a Zn regulatory pathway in the vascular wall that is coupled to the generation and actions of NO and which is compromised in Zn deficiency with consequent implications for the pathogenesis and therapy of vascular disease.
Publisher: Springer Science and Business Media LLC
Date: 2001
Abstract: In addition to its erse role in many physiological systems, zinc (Zn) has now been shown to be an important regulator of apoptosis. The purpose of this review is to integrate previously published knowledge on Zn and apoptosis with current attempts to elucidate the mechanisms of action of this biometal. This paper begins with an introduction to apoptosis and then briefly reviews the evidence relating Zn to apoptosis. The major focus of this review is the mechanistic actions of Zn and its candidate intracellular targets. In particular, we examine the cytoprotective functions of Zn which suppress major pathways leading to apoptosis, as well as the more direct influence of Zn on the apoptotic regulators, especially the caspase family of enzymes. These two mechanisms are closely related since a decline in intracellular Zn below a critical threshold level may not only trigger pathways leading to caspase activation but may also facilitate the process by which the caspases are activated. Studies by our laboratory in airway epithelial cells show that Zn is co-localized with the precursor form of caspase-3, mitochondria and microtubules, suggesting this Zn is critically placed to control apoptosis. Further understanding the different pools of Zn and how they interact with apoptotic pathways should have importance in human disease.
Publisher: Elsevier BV
Date: 12-1991
DOI: 10.1016/0006-291X(91)91278-K
Abstract: Ca2+/Mg(2+)-dependent endonuclease has been implicated in the extensive internucleosomal DNA fragmentation that accompanies apoptosis (gene-directed cell death). We present further evidence that this enzyme is involved in apoptosis. Ca2+/Mg2+ nuclease activity was increased about 6-fold during colchicine-induced apoptosis in human chronic lymphocytic leukaemia cells. The increase in activity coincided with onset of DNA fragmentation. Spleen, liver, kidney and thymus expressed high levels of this enzyme while lung, brain, heart and testis contained little activity. Cells from tissues with high Ca2+/Mg2+ nuclease activity underwent rapid DNA fragmentation in response to a Ca2+ flux. Physiological concentrations of Zn2+ known to inhibit both apoptosis and DNA fragmentation also inhibited Ca2+/Mg2+ nuclease activity.
Publisher: No publisher found
Date: 1984
DOI: 10.1016/0005-2736(84)90104-4
Abstract: Agglutination of mouse erythrocytes by non-choline phospholipids is inhibited by a factor in mammalian sera. The inhibitor cochromatographed with albumin on dye-agarose conjugates, was retained by an anti-albumin affinity column, was neutralized by anti-albumin antibody and found in a serum fraction in which only albumin could be detected. A variety of commercial preparations of albumin (fraction V, crystalline) did not inhibit. However, they acquired potent inhibitory activity when treated with low molecular weight thiols. The inhibitory activity of serum was increased 8-fold by treatment with dithiothreitol. Other proteins were not activated in this way. Inhibitory activity increased with average free sulphydryl content of treated albumin, up to six thiol groups per molecule. Alkylation of these sulphydryl groups did not diminish inhibitory activity. Thiols also induced polymerization of albumin. Inhibitory albumin in serum was largely monomeric. We propose that the inhibitor is a type of serum albumin which is lost or inactivated during preparation of commercial albumin, and which shares a structural feature, necessary for inhibition, with thiol-reduced albumin and the ligand on mouse erythrocytes.
Publisher: Elsevier BV
Date: 10-1982
Publisher: The American Association of Immunologists
Date: 15-11-2004
DOI: 10.4049/JIMMUNOL.172.12.7750
Abstract: The granules of mast cells and other inflammatory cells are known to be rich in zinc (Zn), a potent caspase inhibitor. The functions of granular Zn, its mechanism of uptake, and its relationship to caspase activation in apoptosis are unclear. The granules of a variety of mast cell types fluoresced intensely with the Zn-specific fluorophore Zinquin, and fluorescence was quenched by functional depletion of Zn using a membrane-permeable Zn chelator N, N, N′, N′-tetrakis (2-pyridyl-methyl)ethylenediamine (TPEN). Zn levels were also depleted by various mast cell activators, including IgE/anti-IgE, and Zn was rapidly replenished during subsequent culture, suggesting an active uptake mechanism. In support of the latter, mast cells contained high levels of the vesicular Zn transporter ZnT4, especially in the more apical granules. Immunofluorescence and immunogold labeling studies revealed significant pools of procaspase-3 and -4 in mast cell granules and their release during degranulation. Functional depletion of Zn by chelation with TPEN, but not by degranulation, resulted in greatly increased susceptibility of mast cells to toxin-induced caspase activation, as detected using a fluorogenic substrate assay. Release of caspases during degranulation was accompanied by a decreased susceptibility to toxins. Zn depletion by chelation, but not by degranulation, also resulted in nuclear translocation of the antiapoptotic, proinflammatory transcription factor NF-κB. These findings implicate a role for ZnT4 in mast cell Zn homeostasis and suggest that granule pools of Zn may be distinct from those regulating activation of procaspase-3 and NF-κB.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2010
Publisher: Oxford University Press (OUP)
Date: 09-2000
DOI: 10.1086/315914
Abstract: To better understand the mechanisms by which zinc deficiency induces epithelial cell death, studies were done of the effects of intracellular zinc depletion induced by the zinc chelator TPEN on apoptosis-related events in human malignant epithelial cell lines LIM1215 (colonic), NCI-H292 (bronchial), and A549 (alveolar type II). In TPEN-treated cells, depletion of zinc was followed by activation of caspase-3 (as demonstrated by enzymatic assay and Western blotting), DNA fragmentation, and morphologic changes. Increase in caspase-3 activity began 12 h after addition of TPEN, suggesting that zinc may suppress a step just before the activation of this caspase. Caspase-6, a mediator of caspase-3 processing, also increased, but later than caspase-3. Effects of TPEN on apoptosis were completely prevented by exogenous ZnSO4 and partially prevented by peptide caspase inhibitors. A critical substrate of caspase-3 may be the cell cycle regulator p21Waf1/Cip1, which was rapidly cleaved in TPEN-treated cells to a 15-kDa fragment before further degradation.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.MRFMMM.2011.08.009
Abstract: 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. This review focuses on the role of Zn in the maintenance of genome integrity and the effects of deficiency or excess on genomic stability events and cell death.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.COPH.2006.01.005
Abstract: Zinc, an essential dietary metal, has special roles in the conducting airways. Under the control of specific zinc transporters, abundant labile zinc localizes to the apical cytoplasm of airway epithelium. Zinc influences a number of important airway proteins, including ADAM33 metalloproteinase, beta2 adrenoreceptors and nuclear factor-kappabeta, and has anti-inflammatory, anti-oxidant and pro-survival actions. Zinc deficiency results in enhanced oxidative damage in the airways by causing infiltration of inflammatory cells and increased superoxide and nitric oxide production. When zinc deficiency occurs in conjunction with acute lung injury or asthma, a more intense inflammation is produced. Zinc is also able to restore chloride secretion in cystic fibrosis models. Research priorities include the development of safe and non-invasive ways to monitor airway zinc levels and to supplement airway zinc when needed.
Publisher: Informa UK Limited
Date: 12-2017
DOI: 10.2147/COPD.S149589
Publisher: Elsevier BV
Date: 11-1994
DOI: 10.1016/1074-5521(94)90005-1
Abstract: The transition metal Zn(II) is thought to regulate cell and tissue growth by enhancing mitosis (cell proliferation) and suppressing the counterbalancing process of apoptosis (gene-directed cell death). To investigate the role of Zn(II) further, we have used a UV-excitable Zn(II)-specific fluorophore, Zinquin. The ester group of Zinquin is hydrolyzed by living cells, ensuring its intracellular retention this allows the visualization and measurement of free or loosely-bound (labile) intracellular Zn(II) by fluorescence video image analysis or fluorimetric spectroscopy. Here we show that in cells undergoing early events of apoptosis, induced spontaneously or by erse agents, there is a substantial increase in their Zinquin-detectable Zn(II). This increase occurred in the absence of exogenous Zn(II) and before changes in membrane permeability, consistent with a release of Zn(II) from intracellular stores or metalloproteins rather than enhanced uptake from the medium. We propose that there is a major redistribution of Zn(II) during the induction of apoptosis, which may influence or precipitate some of the later biochemical and morphological changes. The phenomenon of Zn(II) mobilization, revealed by Zinquin, presents a new element in the process of apoptosis for investigation and may permit rapid and sensitive identification of apoptotic cells, particularly in those tissues where their frequency is low.
Publisher: American Physiological Society
Date: 02-2007
DOI: 10.1152/AJPLUNG.00280.2006
Abstract: 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). Moreover, mild nutritional Zn deficiency worsens lung function. Recently, a number of proteins belonging to the Solute Carrier Family 39 (ZIP) and Solute Carrier Family 30 (ZnT) have been identified that bind Zn and regulate Zn homeostasis. Mice were sensitized, and subsequently aerochallenged, with ovalbumin to induce acute and chronic airway inflammation. Mice received 0, 54, or 100 μg of Zn intraperitoneally. Tissues were analyzed for Zn content and histopathology. Inflammatory cells were counted in bronchoalveolar lavage fluid. Cytokine and Zn transporter mRNA levels were determined by cDNA gene array and/or real-time PCR. Zn supplementation decreased bronchoalveolar lavage fluid eosinophils by 40 and 80%, and lymphocytes by 55 and 66%, in the acute and chronic models, respectively. Alterations in Zn transporter expression were observed during acute inflammation, including increases in ZIP1 and ZIP14 and decreases in ZIP4 and ZnT4. Zn supplementation normalized ZIP1 and ZIP14, but it did not affect mRNA levels of cytokines or their receptors. Our results indicate that inflammation-induced alterations in Zn transporter gene expression are directed toward increasing Zn uptake. Increases in Zn uptake may be needed to counteract the local loss of Zn in the airway and to meet an increased demand for Zn-dependent proteins. The reduction of inflammatory cells by Zn in the airways provides support for Zn supplementation trials in human asthmatic in iduals.
Publisher: Elsevier BV
Date: 11-1981
DOI: 10.1016/0304-3835(81)90129-4
Abstract: The tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induced differentiation in lymphocytes from patients with chronic lymphocytic leukaemia (CLL). The differentiation was detected by the appearance of cytoplasmic immunoglobulin (CIg) and a plasmacytoid morphology, and was accompanied by the loss of the ability of the CLL cells to rosette with mouse erythrocytes (M). Loss of M rosetting occurred rapidly (within 10 min), was not prevented by cycloheximide or actinomycin D and was elicited by low concentrations of TPA (ED50 8 X 10(-10) M). Inhibition of rosette formation was induced by other phorbol diester promoters, but not non-promoting derivatives. Loss of the capacity to form M rosettes occurs before events which are evidently related to genome activation.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.MRGENTOX.2010.12.004
Abstract: 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. DNA damage was determined by the use of both the comet assay and the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. Zn-deficient medium (0μM) was produced using Chelex treatment, and the two Zn compounds (i.e. ZnSO(4) and ZnC) were tested at concentrations of 0.0, 0.4, 4.0, 16.0, 32.0 and 100.0μM. Results from an MTT assay showed that cell growth and viability were decreased in Zn-depleted cells (0μM) as well as at 32μM and 100μM for both Zn compounds (P<0.0001). DNA strand-breaks, as measured by the comet assay, were found to be increased in Zn-depleted cells compared with the other treatment groups (P<0.05). The CBMN-Cyt assay showed a significant increase in the frequency of both apoptotic and necrotic cells under Zn-deficient conditions (P<0.0001). Elevated frequencies of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBuds) were induced in Zn-depleted cells (P<0.0001), whereas genome damage was reduced in supplemented cultures for both Zn compounds at 4μM and 16μM, possibly suggesting that these concentrations may be optimal for genome stability. The potential protective effect of ZnSO(4) and ZnC was also investigated following exposure to 1.0Gy γ-radiation. Culture in medium containing these compounds at 4-32μM prior to irradiation displayed significantly reduced frequencies of MNi, NPBs and NBuds compared with cells maintained in 0μM medium (P<0.0001). Expression of γ-H2AX and 8-oxoguanine glycosylase measured by western blotting was increased in Zn-depleted cells. These results suggest that Zn plays important role in genomic stability and that the optimal Zn concentration-range for prevention of DNA damage and cytotoxicity in vitro lies between 4 and 16μM.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2011
DOI: 10.1007/S10534-010-9370-9
Abstract: 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. Mice were exposed to CS [2× 2RF, 3×/day 15 min/cigarette] and fed diets containing 2, 20 or 140 mg/kg Zn ad libitum. Airway cells were collected by bronchoalveolar lavage (BAL). Plasma Zn was measured by fluorometric assay. Inflammatory, metabolic and Zn transport markers were measured by real-time RT-PCR. Mice fed low Zn diets had less plasma labile zinc (0-0.18 μM) than mice fed moderate (0.61-0.98 μM) or high (0.77-1.1 μM) Zn diets (SDs 0.1-0.4, n = 8-10). Smoke exposure increased plasma and BAL labile Zn (1.5-2.5 fold, P < 0.001), bronchoalveolar macrophages (2.0 fold, P < 0.0001) and MT-1 (1.5 fold), MIP-2 (2.3 fold) and MMP-12 (3.5 fold) mRNA. Zn supplementation reduced alveolar macrophage numbers by 62 and 52% in sham and smoke-exposed mice, respectively (Zn effect: P = 0.011). Gastrocnemius, soleus and tibialis anterior muscle mass were affected by both smoke and dietary Zn in the order of 3-7%. The 50-60% reduction in alveolar macrophages in Zn-supplemented mice supports our evolving hypothesis that Zn is an important anti-inflammatory mediator of airway inflammation. Restoring airway Zn levels through dietary supplementation may lessen the severity of lung inflammation when Zn intake is low.
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0006-291X(02)02292-1
Abstract: Airway epithelial cells (AEC) contain both pro- and anti-apoptotic factors but little is known about mechanisms regulating apoptosis of these cells. In this study we have examined the localization of pro-caspase-3 and Zn(2+), a cellular regulator of pro-caspase-3, in primary sheep and human AEC. Zn(2+) was concentrated in both cytoplasmic vesicles and ciliary basal bodies, in the vicinity of both pro-caspase-3 and the antioxidant Cu/Zn superoxide dismutase (Cu/Zn SOD). Depletion of intracellular Zn(2+) in sheep AEC, using the membrane permeant Zn(2+) chelator TPEN, increased lipid peroxidation in the apical cell membranes (as assessed by immunofluorescence with anti-hydroxynonenal) as well as increasing activated pro-caspase-3 and apoptosis. There were smaller increases in caspase-2 and -6 but not other caspases. Activation of caspase-3 in TPEN-treated AEC was inhibited strongly by N-acetylcysteine and partially by vitamin C and vitamin E. These findings suggest that cytoplasmic pro-caspase-3 is positioned near the lumenal surface of AEC where it is under the influence of Zn(2+) and other anti-oxidants.
Publisher: Elsevier BV
Date: 04-1988
DOI: 10.1016/0006-2952(88)90802-7
Abstract: Various treatment modalities have been described for the treatment of extra-articular distal radius fractures each with its own merits and demerits. Most of the work done with percutaneous pinning has shown a significant residual stiffness of the hand and wrist. Our technique involves percutaneous pinning of the fracture and immobilization in neutral position of the wrist for three weeks. This study's aim was to examine the functional outcome of percutaneous K-wiring of these extra-articular distal radius fractures with immobilization in neutral position of the wrist. This is a prospective study of 32 patients aged between 18 and 70 years with extra-articular distal radius fracture. Patients were treated with closed reduction and percutaneous pinning using two or three K-wires. A below- elbow plaster of paris dorsoradial slab was applied in neutral position of the wrist for 3 weeks. At the end of 3 weeks, the slab was removed and wrist physiotherapy started. The radiographs were taken postoperatively, at 3 weeks, 6 weeks and 6 months. The functional evaluation of the patients was done at 6 months follow-up. We used Sarmiento's modification of Lindstrom criteria and Gartland and Werley's criteria for evaluation of results. Excellent to good results were seen in 93.75% of the cases while 6.25% had fair results. The complications observed were pin loosening (n=13), pin tract infection (n=2), malunion (n=2), wrist joint stiffness (n=2), reduced grip strength (n=2) and injury to the superficial radial nerve (n=1). Percutaneous pinning followed by immobilization of the wrist in neutral position is a simple and effective method to maintain reduction and prevent stiffness of wrist and hand.
Publisher: Oxford University Press (OUP)
Date: 2000
Abstract: Butyrate, a short chain fatty acid produced in the colon, induces apoptosis in cancer cell lines by a sequential process involving inhibition of histone deacetylase, de novo protein synthesis and activation of DEVD-caspase, a major effector of apoptotic DNA fragmentation and membrane blebbing. We now show, in LIM 1215 colorectal cancer cells, that butyrate, in addition to activating DEVD-caspase and inducing apoptosis, also increases expression and cleavage of the universal cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and leads to hypo-phosphorylation of retinoblastoma protein. Accompanying these molecular changes was a progressive loss of G(0)/G(1) and S phase cells. Expression of p21 had similar kinetics to that of the essential protein required for DEVD-caspase activation, indicating parallel effects of butyrate on anti-apoptotic and pro-apoptotic mechanisms. LIM 1215 cells, which were resistant to butyrate-induced apoptosis, were selected by three cycles of exposure to butyrate and removal of floating apoptotic cells. These cells showed markedly enhanced p21 expression and were in cell cycle arrest as determined by flow cytometry. On the other hand, subsequent culture of these cells for 2-3 days in the absence of butyrate resulted in down-regulation of p21 and restoration of sensitivity to apoptosis by butyrate. Western blots of butyrate-treated cells undergoing apoptosis consistently demonstrated a 15 kDa band (p15) that was not present in control cultures. This band became apparent immediately after the onset of DEVD-caspase activation, was enriched in the floating apoptotic cell population when compared with the adherent, non-apoptotic cells and was absent in butyrate-resistant cells lacking DEVD-caspase activity. Peptide caspase inhibitors partially blocked appearance of p15. Here we show, for the first time, that p21 is a target of effector caspases in colorectal cancer cells and that the resistance to butyrate-induced apoptosis is characterized by failure of p21 cleavage.
Publisher: Wiley
Date: 15-08-2021
DOI: 10.1002/CBIN.11682
Abstract: 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. Multifluorescence quantitative confocal microscopy (MQCM) was applied for analysis of protein expression and localization of markers of vascular remodeling ( α SMA and BMPR2), parameters of zinc homeostasis (zinc transporter SLC39A/ZIP family members 1, 10, 12 and 14 and metallothionein MT3) and S1P extracellular signaling (SPHK1, SPNS2, S1P receptor isoforms 1, 2, 3, 5) in 20–200 µm pulmonary microvessels. ZIP12 expression in whole lung tissue lysates was assessed by western blot. Spearman nonparametric correlations between MQCM readouts and hemodynamic parameters, Fulton index (FI), and right ventricular systolic pressure (RVSP) were measured. In line with PAH status, pulmonary microvessels in monocrotaline‐treated animals demonstrated significant ( p .05, n = 6 per group) upregulation of α SMA (twofold) and downregulation of BMPR2 (20%). Upregulated ZIP12 (92%), MT3 (57.7%), S1PR2 (54.8%), and S1PR3 (30.3%) were also observed. Significant positive and negative correlations were demonstrated between parameters of zinc homeostasis (ZIP12, MT3), S1P signaling (S1PRs, SPNS2), and vascular remodeling ( α SMA, FI, RVSP). MQCM and western blot analysis showed that monocrotaline‐induced ZIP12 upregulation could be partially negated by BMPR2‐targeted therapy. Our results indicate that altered zinc transport/storage and S1P signaling in the monocrotaline‐induced PAH rat model are linked to each other, and could be alleviated by BMPR2‐targeted therapy.
Publisher: Bentham Science Publishers Ltd.
Date: 28-06-2012
Publisher: Elsevier BV
Date: 05-2019
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S0006-2952(03)00498-2
Abstract: The epithelium lining the airways is a physical barrier as well as a regulator of physiological and pathological events in the respiratory system. Damage to the epithelium by oxidants released from inflammatory cells is a critical factor in the pathogenesis of airway inflammatory diseases such as bronchial asthma. In these diseases, excessive apoptosis may be a likely mechanism responsible for damage to, and sloughing, of airway epithelial cells. Factors that increase the airway epithelium's resilience to apoptosis are likely to lessen the severity of this disease. One such factor is the dietary metal zinc. A special role for labile intracellular pools of zinc as anti-apoptotic agents in the regulation of the caspases, has emerged over the past two decades. This review focuses on caspase-inhibitory functions of zinc in airway epithelial cells, apparent abnormalities of zinc homeostasis in asthmatics and studies from the authors' laboratory which showed that zinc was strategically localized in the apical cytoplasm of airway epithelium to control caspase-3 activated apoptosis. These findings are discussed in the context of recent data from a murine model of allergic asthma, showing that loss of airway epithelial zinc was accompanied by changes in levels of both procaspase-3 and active caspase-3 and that nutritional zinc deprivation further increased airway epithelial apoptosis. We hypothesize that zinc has a protective role for the airway epithelium against oxyradicals and other noxious agents, with important implications for asthma and other inflammatory diseases where the epithelial barrier is vulnerable and compromised.
Publisher: Elsevier BV
Date: 08-1979
Publisher: Wiley
Date: 02-1979
DOI: 10.5694/J.1326-5377.1979.TB112003.X
Abstract: Lymphocytes lacking receptors for sheep erythrocytes and surface immunoglobulin were present in the blood in large numbers at some stage in four cases of chronic lymphocytic leukaemia (which included a mother and son), and formed a substantial proportion of the circulating lymphocytes in other cases. These null cells possessed receptors for mouse erythrocytes. Other B-cell markers were also found on these cells. Serial studies showed a great variation in the number of null cells during the course of the disease (which may be associated with treatment), suggesting variation in the the maturation of leukaemic cells, and indicating that the surface marker complement may not reflect the constitution of the cell undergoing the original malignant change.
Publisher: Wiley
Date: 09-2013
DOI: 10.1038/ICB.2013.39
Publisher: Bentham Science Publishers Ltd.
Date: 05-2006
DOI: 10.2174/138945006776818683
Abstract: The dietary group IIb metal zinc (Zn) plays essential housekeeping roles in cellular metabolism and gene expression. It regulates a number of cellular processes including mitosis, apoptosis, secretion and signal transduction as well as critical events in physiological processes as erse as insulin release, T cell cytokine production, wound healing, vision and neurotransmission. Critical to these processes are the mechanisms that regulate Zn homeostasis in cells and tissues. The proteins that control Zn uptake and compartmentalization are rapidly being identified and characterized. Recently, the first images of sub-cellular pools of Zn in airway epithelium have been obtained. This review discusses what we currently know about Zn in the airways, both in the normal and inflamed states, and then considers how we might target Zn metabolism by developing strategies to monitor and manipulate airway Zn levels in airway disease.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2013
Abstract: Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT) however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes. We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC s les from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. There was no significant prognostic association in the global nor estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042 OS, P = .018). In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted. Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes.
Publisher: Oxford University Press (OUP)
Date: 07-1978
DOI: 10.1111/J.1365-2133.1978.TB01967.X
Abstract: A case is described in which the initial manifestation of a malignant lymphoma was an erythematous skin rash over the face, scalp and trunk. Immunological surface marker analysis showed the malignant cells to be of B lymphocyte origin with a homogeneous secretion of IgM-K. Repeated skin and lymph node biopsies and finally post mortem documented the progression of the lymphoma from that of a mixed lymphocytic-histiocytic type with a nodular pattern of growth to a diffuse histiocytic lymphoma with frequently bizarre cells. The theory of ecotaxis or homing of lymphocytes to the skin and other non-lymphoid organs of the body is discussed in an attempt to explain the occurrence of cutaneous involvement as a primary manifestation of lymphoma.
Publisher: Wiley
Date: 13-05-2015
Abstract: 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. A 12-week placebo-controlled intervention trial was performed with 84 volunteers completing the study, (placebo, n = 42) and (Zn group, n = 42). Plasma Zn was significantly increased (p < 0.05) by 5.69% in the Zn supplemented group after 12 weeks. A significant (p < 0.05) decrease in the micronucleus frequency (-24.18%) was observed for the Zn supplemented cohort relative to baseline compared to the placebo group. Reductions of -7.09% for tail moment and -8.76% for tail intensity were observed for the Zn group (relative to baseline) (p < 0.05). Telomere base damage was found to be also significantly decreased in the Zn group (p < 0.05). Both MT1A and ZIP1 expression showed a significant increase in the Zn supplemented group (p < 0.05). Zn supplementation may have a beneficial effect in an elderly population with low Zn levels by improving Zn status, antioxidant profile, and lowering DNA damage.
Publisher: Future Science Ltd
Date: 04-2006
DOI: 10.2144/06404RR02
Abstract: Here we describe a rapid and sensitive zinquin-based fluorometric assay that enables one to monitor levels of labile Zn(II) in body fluids, buffers, and cell-conditioned culture media as well as changes in these pools in disease. Labile pools of Zn(II) are free or loosely bound pools and more tightly bound but zinquin-accessible pools in contrast to the fixed pools of Zn(II) within metalloproteins. In human plasma, mean labile Zn(II) was 8.1 µM (SEM 0.53 n = 81) and constituted about 70% of the total plasma Zn(II) and % of human plasma albumin Zn(II). Plasma labile Zn(II) was significantly depleted after 7 days of Zn(II) deprivation in mice, despite only small changes in body weight. Labile Zn(II) concentrations were also measured in the induced sputum plugs, saliva, and urine of normal adults and were 1.30 µM (SEM 0.27 n = 73), 0.11 µM (SEM 0.11 n = 6), and 0.23 µM (SEM 0.08 n = 8), respectively. Urinary labile Zn(II) concentration was significantly increased in some patients with type II diabetes mellitus (overall mean was 0.90 µM, (SEM 0.30 n = 12). The technique may be particularly useful in assessing extracellular Zn(II) levels in diseases associated with altered Zn(II) homeostasis, identifying those subjects most in need of Zn(II) supplementation, and defining the optimum concentrations of available Zn(II) in buffers and culture media.
Publisher: Springer Science and Business Media LLC
Date: 03-1989
DOI: 10.1007/BF00270979
Publisher: American Physiological Society
Date: 12-2002
DOI: 10.1152/AJPRENAL.00094.2002
Abstract: Kidneys play a key role in zinc balance. The portion of Zn(II) that enters the glomerular filtrate is efficiently reabsorbed along the nephron through a mechanism yet to be identified. We used the Zn(II)-specific fluorophore Zinquin to visualize intracellular Zn(II) accumulated in the kidney epithelium and compared it with the intracellular localization of the vesicular zinc transporter ZnT4 both in vivo and in vitro. The Madin-Darby canine kidney (MDCK) cell line, stably overexpressing rat ZnT4, was used as a tissue culture model of the kidney epithelium. Zinquin labeling of MDCK cells revealed rapid internalization of Zn(II) and compartmentalization in intracellular bodies interspersed throughout the cytoplasm. In polarized kidney cells, ZnT4 protein was localized on the membrane of intracellular vesicles concentrated around the nucleus, mostly on the basal side. Results of double stainings demonstrated that ZnT4-containing vesicles do not overlap with Zn(II) bodies. Zinquin fluorescence, confirmed by autometallography in rat kidney, indicated that consistent with its physiological role, the central glomerulus was weakly stained, whereas the epithelium that lines convoluted tubules was strongly labeled. Double staining of rat kidney with Zinquin and anti-ZnT4 antibodies confirmed the in vitro observations, as Zinquin fluorescence appeared to be distinct from ZnT4 immunofluorescence. To gain further insight into which of the known zinc transporters might be involved in Zn(II) metabolism in the kidney, we have also characterized by RT-PCR the expression of other proteins involved in Zn(II) transport. All of the mRNAs examined [ZnT1, -T2, -T4, and human Zrt, Irt-like protein 1 (hZIP1)], with the exception of hZIP2, were present in adult rat kidney.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2201
Publisher: Elsevier BV
Date: 07-1991
DOI: 10.1016/0014-4827(91)90521-U
Abstract: Recent studies have suggested a role for Zn2+, distinct from that of Ca2+, in the subcellular distribution and activation of protein kinase C (PKC). Here we show that Zn2+ is required for a cellular response mediated by PKC, the rapid loss of expression of a human B cell receptor MER, detected by rosetting with mouse erythrocytes. Zn2+, in the presence of the Zn2+ ionophore pyrithione, caused rapid inhibition of MER rosetting at concentrations which induce the translocation and activation of PKC. This required cellular uptake of Zn2+ and was blocked by 1,10-phenanthroline and TPEN which chelate Zn2+ but not Ca2+. Gold, a metal with similar properties, also induced translocation of PKC and inhibition of MER. By contrast, Ca2+ ionophores A23187 and ionomycin, which induce a different pathway of translocation of PKC, had no effect on MER. Phenanthroline and TPEN also blocked the inhibition of MER induced by the PKC activators phorbol ester and sodium fluoride, suggesting that endogenous cellular Zn2+ is required. We propose that some cellular actions of PKC require a Zn(2+)-dependent event and that these may be a target for gold during chrysotherapy in rheumatoid arthritis.
Publisher: Wiley
Date: 30-03-2011
DOI: 10.1111/J.1440-1843.2011.01932.X
Abstract: 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. Examination of induced sputum is an established technique for measuring AI and mediators of inflammation. Recent advances allow measurement of the rapidly exchangeable (labile) and total zinc pools in sputum. The aims of this study were to measure labile and total [Zn] in sputum and plasma of subjects with or without asthma, and second to correlate [Zn] with symptoms, asthma severity, lung function (FEV(1)) and airway hyper-responsiveness. A total of 163 subjects (114 with asthma) completed a single visit for sputum induction and a blood test. Labile and total [Zn] were measured by Zinquin fluorescence and atomic absorption spectrophotometry. The mean (SD) age of subjects with and without asthma was 55 (14) and 57 (14) years, respectively. Baseline FEV(1) was significantly lower in subjects with asthma (94.2 (16)%) than in those without asthma (103 (16.6)%). Sputum total and labile [Zn] were lower in subjects with asthma compared with control subjects, with median (interquartile range) values of 31.8 (117) versus 50 (188.5), P = 0.02 and 0 (48) versus 26 (84.5) µg/L, P = 0.05, respectively. Increased frequency of wheeze, as well as asthma severity and reduced FEV(1), was associated with significantly lower labile sputum [Zn]. These findings suggest that sputum [Zn] reflect clinical outcomes and underlying AI, suggesting a potential role for zinc as a biomarker in asthma.
Publisher: CSIRO Publishing
Date: 1996
DOI: 10.1071/RD9961097
Abstract: The Zn(II)-specific fluorophore Zinquin was used to determine the regional distribution of free or loosely-bound Zn(II) in mouse spermatozoa. Spermatozoa from the testes exhibited bright fluorescence over the entire head those from the caput epididymides generally fluoresced more brightly in the post-acrosomal region and spermatozoa from the caudae epididymides fluoresced less brightly, with foci of fluorescence over the sperm head which were lost after extraction with Triton X-100 and hence appeared to be membrane-associated. Treatment of cauda sperm with sodium dodecyl sulfate resulted in a bright uniform Zinquin fluorescence in the heads, similar to that observed in caput sperm, indicating that the two types of sperm have similar amounts of head Zn(II) but that the availability of Zn(II) for binding Zinquin is different. By contrast, the intensity of tail fluorescence was similar in spermatozoa from different regions of the male reproductive tract and was largely unaffected by Triton X-100 extraction, consistent with an intracellular location. Similar differences were observed between caput sperm and cauda sperm in the rat. It is concluded that visualization and measurement of free or loosely-bound Zn(II) in subcellular compartments of spermatozoa should facilitate investigation of the role of this metal in the development and function of spermatozoa and abnormalities that might accompany infertility and Zn(II) deficiency.
Publisher: Hindawi Limited
Date: 18-03-2012
DOI: 10.1155/2012/819176
Abstract: 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-1 β and IL-18, indicating possible activation of the NLRP3 inflammasome. Active caspase-1, NLRP3, and other inflammasome components were also detected in tissue eosinophils from OVA mice, and may potentially contribute to IL-1 β and IL-18 production. In whole lung, inRNA expression of NAIP and procaspase-1 was increased in OVA mice, whereas NLRP3, IL-1 β and IL-18 decreased. Some OVA-treated mice also had significantly elevated and tightly correlated serum levels of IL-1 β and TNF α . In cultured normal human bronchial epithelial cells, LPS priming resulted in a significant increase in NLRP3 and II-lp protein expression. This study is the first to demonstrate NLRP3 inflammasome components in normal airway epithelium and changes with inflammation. We propose activation and/or luminal release of the inflammasome is a feature of allergic airway inflammation which may contribute to disease pathogenesis.
Publisher: Elsevier BV
Date: 1979
Publisher: CSIRO Publishing
Date: 1996
DOI: 10.1071/CH9960561
Abstract: The syntheses of Zinquin ester [ethyl [2-methyl-8-(p- tolylsulfonylamino )-6-quinolyloxy]acetate] and the corresponding acid, both of which are zinc(II)-specific fluorophores , are described. 6-Methoxy-2-methyl-8-(p- tolylsulfonylamino ) quinoline (2) can be demethylated , with boron tribromide, to form either the expected phenol or a mixture of the phenol and the corresponding 5-bromo derivative depending upon the reaction conditions. These compounds react with ethyl bromoacetate to give the corresponding esters, as well as the 5-ethoxycarbonyl derivative formed by electrophilic substitution. Halogenation of the sulfonamide (2) occurs readily at the 5-position. The 5-iodo product undergoes a Heck coupling with ethyl acrylate . The crystal structures of ethyl [5-ethoxycarbonylmethyl-2-methyl-8-(p- tolylsulfonylamino )-6-quinolyloxy]acetate and [5-carboxymethyl-2-methyl-8-(p- tolylsulfonylamino )-6-quinolyloxy]acetic acid are described.
Publisher: American Physiological Society
Date: 11-09-2017
DOI: 10.1152/AJPLUNG.00083.2017
Abstract: 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. We applied a human ex vivo air-liquid interface model, a murine model of smoke exposure, and human lung tissues and investigated Zn, ZIP1, and ZIP2 Zn-influx proteins, autophagy [microtubule-associated 1A/1B-light chain-3 (LC3), Beclin-1], autophagic flux (Sequestosome), apoptosis [Bcl2 X-linked inhibitor of apoptosis (XIAP), poly (ADP)-ribose polymerase (PARP)], and inflammation [thymic stromal lymphopoietin (TSLP), regulated on activation, normal T cell expressed and secreted (RANTES), and IL-1β]. Lung tissues from CS-exposed mice exhibit reduced free-Zn in AECs, with elevated ZIP1 and diminished ZIP2 expression. Interestingly, increased LC3 colocalized with ZIP1, suggesting an autophagic requirement for free-Zn to support its catabolic function. In human AECs, autophagy was initiated but was unable to efficiently degrade cellular debris, as evidenced by stable Beclin-1 and increased LC3-II, but with a concomitant elevation in Sequestosome. Autophagic dysfunction due to CS exposure coupled with Zn depletion also induced apoptosis, with the reduction of antiapoptotic and antiautophagic proteins Bcl2 and XIAP and PARP cleavage. This was accompanied by an increase in RANTES and TSLP, an activator of adaptive immunity. We conclude that the uncoupling of Zn trafficking and autophagy in AECs constitutes a fundamental disease-related mechanism for COPD pathogenesis and could provide a new therapeutic target.
Publisher: Royal Society of Chemistry (RSC)
Date: 1997
DOI: 10.1039/A703433D
Start Date: 2010
End Date: 2013
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2008
End Date: 2011
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2018
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2020
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2004
End Date: 2006
Funder: National Health and Medical Research Council
View Funded Activity