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PubMed2006

Zinc blocks gene expression of mitochondrial aconitase in human prostatic carcinoma cells.

Mitochondrial aconitase (mACON) contains a [4Fe-4S] cluster as the key enzyme for citrate oxidation in the human prostatic epithelial cell. Although there is accumulating evidence indicating that accumulation of high levels of zinc in prostate epithelial cells causes reduced efficiency of citrate oxidation, zinc regulation on the mACON is still not well understood. From in vitro studies, zinc chloride treatment has been developed using humic acid as the carrier (Zn-HA) in human prostatic carcinoma cells, PC-3. Zn-HA treatment (0.1-10 microM) restricts mACON enzymatic activity, which attenuates citrate utility and decreases intracellular ATP levels in PC-3 cells, whereas the effect is blocked by adding the zinc chelator, diethylenetriaminepentaacetic acid (DTPA). Immunoblot, ribonuclease-protection and transient gene-expression assays indicate that Zn-HA treatments inhibit mACON gene expression. Mutation of the putative metal response element (MRE) from CTCGCCTTCA to TGATCCTTCA abolishes Zn-HA inhibition of mACON promoter activity. Our results have demonstrated that zinc possesses a specific regulatory mechanism on the mACON gene, and a biologic function of the putative metal regulatory system in mACON gene transcription has been identified.

Aconitate Hydratase↗

PubMed1984

Relationship of a novel extracellular matrix glycoprotein to cell detachment in highly metastatic B16 melanoma: modulating effect of bromodeoxyuridine.

Growth of highly invasive B16 melanoma BL6 cells with bromodeoxyuridine (BUdR) decreases in vitro cell detachment and modulates extrapulmonary growth in vivo. We now show: (1) The presence of an 80 kd glycoprotein in the Triton-insoluble matrix of control BL6 cells but not in the corresponding fractions from BUdR-treated BL6 cells and poorly metastatic F1r cells. (2) The matrix fractions from the two last mentioned cells reveal Triton-insoluble glycoproteins of about 55-58 kd. (3) Mild trypsin treatment of intact cells before matrix preparation leads to the preferential disappearance of the 80 kd component from control BL6 matrix, suggesting its extracellular localization. (4) Prevention of Triton-mediated BL6 matrix detachment by zinc chloride pretreatment, and analysis of different BL6 clones with significant metastatic behavior, also revealed the presence of 80-90 kd matrix-associated glycoproteins in control but not in corresponding BUdR-grown cultures. Since BUdR decreases cell detachment, extrapulmonary metastasis and the levels of the 80-90 kd Triton-insoluble glycoprotein species in metastatic B16 melanoma, and this matrix component is also decreased in poorly metastatic F1r cells, we propose an involvement of this glycoconjugate in tumor cell detachment and metastatic behavior.

Animals↗

PubMed1985

Improved detection of labile cell-surface components with zinc chloride-aprotinin: demonstration of glycoprotein differences in K-1735 metastatic melanoma variants.

Metabolic labelling of K-1735 melanoma variants with 3H-glucosamine and cell harvesting with the commonly used protease inhibitor phenylmethylsulfonylfluoride revealed a Triton-insoluble fibronection-like 230 kd component in poorly metastatic cells. This component was not evident in highly metastatic cells. Significantly improved surface labelling and detection of the 230 kd glycoprotein in the highly metastatic variant was achieved by zinc chloride-aprotinin treatment of cells prior to harvesting. This procedure also revealed an increase in a trypsin-sensitive glycoprotein of higher molecular weight in the Triton-insoluble fraction of the highly metastatic cell variant. Glycoprotein labelling in this fraction showed an electrophoretic pattern strongly resembling that reported by others for the high-molecular-weight human melanoma-associated glycoprotein complex. The differential detection of the high-molecular-weight glycoprotein species in melanoma variants with differing metastatic abilities in an animal model provides a means of studying their possible relevance to metastatic melanoma. Our data also suggest that zinc chloride-aprotinin can be used to improve the detection of labile cell-surface components.

Animals↗

PubMed1995

Effectiveness of cleaning surgical implants: quantitative analysis of contaminant removal.

Surgical implants need to be free from contaminants before implantation. The effectiveness of a presently used Clemson bioengineering cleaning (CBC) protocol was evaluated for cleaning three different biomaterials (titanium, aluminum oxide, and polyethylene terephthalate, PET) contaminated with three different contaminants (calcium chloride, zinc chloride, and hexadecane). Radiolabeled tracer analysis (RTA), with the use of liquid scintillation, was used as the surface analytical technique to quantitatively determine the percent contaminant removed from the biomaterial surface. On average, the ultrasonic cleaning step removed 99.96% of all three contaminants from both titanium and aluminum oxide. The CBC protocol did not sufficiently clean PET fabric contaminated with hexadecane leaving 11.76% of the contaminant after the ultrasonic step. With the use of isopropyl alcohol in series with 1% Liquinox, the ultrasonic step cleaned the fabric soiled with hexadecane within 30 min, removing 99.85% of the hexadecane initially on the surface. RTA proved to be an excellent method of quantifying surface contamination on implant materials, and for assessing the effectiveness of cleaning protocols in question.

Alkanes↗

PubMed1987

Studies on the mechanism of toxicity of the mycotoxin, sporidesmin. V. Generation of hydroxyl radical by sporidesmin.

Sporidesmin, the mycotoxin responsible for "facial eczema' in ruminants, has previously been shown to generate superoxide radical and hydrogen peroxide. In the present study, the formation of the third "active oxygen' species, hydroxyl radical, has been demonstrated. This species is produced both during the autoxidation of the reduced (dithiol) form of the mycotoxin and in the cyclic reduction/autoxidation reaction between sporidesmin and glutathione. In view of the exceptional reactivity of the hydroxyl radical, this substance may be the proximate agent responsible for the toxic effects of sporidesmin.

Catalase↗

PubMed2005

Surface modification of gold and quantum dot nanoparticles with chitosan for bioapplications.

Gold (Au) and quantum dot (QD) nanoparticles, which have been extensively used in many fields, were encapsulated with a natural polymer, chitosan, to improve their biocompatibility. Characterization was performed using ultraviolet-visible, dynamic light scattering, atomic force microscopy, and transmission electron microscope analyses. It was found that a Au/chitosan ratio of 1:1 and smaller produced chitosan-encapsulated Au nanoparticles of a sufficiently small size, and this result was then applied in the chitosan encapsulation of QDs. The biocompatibility of both types of nanoparticles was assessed in cell culture studies using HT29 human colon carcinoma and NIH 3T3 mouse fibroblast cells. MTT and trypan blue exclusion assays revealed that both chitosan-encapsulated Au nanoparticles and QDs exhibited improved biocompatibility over their bare, nonencapsulated counterparts. Therefore, this study showed that chitosan could be used to encapsulate both Au nanoparticles and QDs in order to enhance their biocompatibility. The approaches developed in this study can also be extended to other nanoparticles for bioapplications as well.

Animals↗

PubMed2004

Zinc stabilizes adenomatous polyposis coli (APC) protein levels and induces cell cycle arrest in colon cancer cells.

In the present study, we investigated the mechanisms by which zinc causes growth arrest in colon cancer cells. The results suggest that zinc treatment stabilizes the levels of the wild-type adenomatous polyposis coli (APC) protein at the post-translational level since the APC mRNA levels and the promoter activity of the APC gene were decreased in HCT-116 cells (which express the wild-type APC gene) after treatment with ZnCl2. Increased levels of wild-type but not truncated APC proteins were required for the ZnCl2-mediated G2/M phase arrest in different colon cancer cell lines. We further tested whether serum-stimulation, which induces cell cycle arrest in the S phase, can relieve ZnCl2-induced G2/M phase arrest of HCT-116 cells. Results showed that in the HCT-116 cells pretreated with ZnCl2, the serum-stimulation neither changed the distribution of G2/M phase arrested cells nor the increased levels of APC protein. The G2/M phase arrest correlated with retarded growth of HCT-116 cells. To further establish that wild-type APC protein plays a role in ZnCl2-induced G2/M arrest, we treated SW480 colon cancer cells that express truncated APC protein. We found that ZnCl2 treatment did not induce G2/M phase arrest in SW480 cells; however, the cell growth was retarded due to the loss of E-cadherin and alpha-tubulin levels. These results suggest that ZnCl2 inhibits the proliferation of colon cancer cells (which carry the wild-type APC gene) through stabilization of the APC protein and cell cycle arrest in the G2/M phase. On the other hand, ZnCl2 inhibits the proliferation of colon cancer cells (which carry the mutant APC gene) by disrupting cellular attachment and microtubule stability.

Adenomatous Polyposis Coli Protein↗

PubMed2001

Regulation of human eosinophil NADPH oxidase activity: a central role for PKCdelta.

Eosinophils play a primary role in the pathophysiology of asthma. In the lung, the activation state of the infiltrating eosinophils determines the extent of tissue damage. Interleukin-5 (IL-5) and leukotriene B4 (LTB4) are important signaling molecules involved in eosinophil recruitment and activation. However, the physiological processes that regulate these activation events are largely unknown. In this study we have examined the mechanisms of human eosinophil NADPH oxidase regulation by IL-5, LTB4, and phorbol ester (PMA). These stimuli activate a Zn2+-sensitive plasma membrane proton channel, and treatment of eosinophils with Zn2+ blocks superoxide production. We have demonstrated that eosinophil intracellular pH is not altered by IL-5 activation of NADPH oxidase. Additionally, PKCdelta inhibitors block PMA, IL-5 and LTB4 mediated superoxide formation. Interestingly, the PKCdelta-selective inhibitor, rottlerin, does not block proton channel activation by PMA indicating that the oxidase and the proton conductance are regulated at distinct phosphorylation sites. IL-5 and LTB4, but not PMA, stimulated superoxide production is also blocked by inhibitors of PI 3-kinase indicating that activation of this enzyme is an upstream event common to both receptor signaling pathways. Our results indicate that the G-protein-coupled LTB4 receptor and the IL-5 cytokine receptor converge on a common signaling pathway involving PI 3-kinase and PKCdelta to regulate NADPH oxidase activity in human eosinophils.

Acetophenones↗

PubMedDate not supplied

Zinc improves gene transfer mediated by DNA/cationic polymer complexes.

BACKGROUND: The weak efficiency of plasmid transfer into the cytosol remains one of the major limiting factors to achieve an efficient transfection with DNA/cationic polymer complexes. We found that divalent metal Zn2+ can improve the polyfection efficiency, especially with DNA/histidylated polylysine (His-pLK) complexes. METHODS AND RESULTS: The supplementation of the transfection medium with 250 micro M ZnCl2 increased the polyfection of human hepatocarcinoma (HepG2) cells with a plasmid encoding EGFP complexed with pLK, polyethyleneimine and His-pLK. Zn2+ is more efficient on DNA/His-pLK complexes: the number of EGFP-positive cells increased from 1% to more than 40%. This phenomenon is selective to Zn2+ because no effect was obtained with other divalent cations. The effect of zinc varies from cell to cell. The binding of Zn2+ to histidyl residues might increase zinc endosomal concentration favoring membrane fusion. Flow cytometry and confocal microscopy studies clearly indicate that with His-pLK, the plasmid is better delivered in the cytosol as well as in the cell nucleus in zinc-treated cells. An investigation conducted with the histidine-rich peptide H5WYG showed that zinc inhibits membrane permeabilization but promotes membrane fusion as evidenced by resonance energy transfer. CONCLUSIONS: Data reported here imply that the addition of zinc ions in the transfection medium can trigger an increase of the fusion of endosomes containing polyplexes which is more effective in the presence of histidine-rich molecules. Consequently, the amount of plasmid in the cytosol available to reach the nucleus is increased leading to an improvement of polyfection.

Carcinoma, Hepatocellular↗

PubMed2004

Optimization of in vitro vascular cell transfection with non-viral vectors for in vivo applications.

BACKGROUND: Syngeneic vascular cells are interesting tools for indirect gene therapy in the cardiovascular system. This study aims to optimize transfection conditions of primary cultures of vascular smooth muscle cells (VSMCs) using different non-viral vectors and zinc as an adjuvant and to implant these transfected cells in vivo. METHODS: Non-liposomal cationic vectors (FuGene 6), polyethylenimines (ExGen 500), and histidylated polylysine (HPL) were used as non-viral vectors in vitro with secreted alkaline phosphatase (SEAP) as reporter gene. Transfection efficiency was compared in cultured rat, rabbit and human VSMCs and fibroblasts. Zinc chloride (ZnCl2) was added to optimize transfection of rat VSMCs in vitro which were then seeded in vivo. RESULTS: Much higher SEAP levels were obtained in rabbit cells with FuGene 6 (p <0.0001) at day 2 than in equivalent rat and human cells. Rat VSMCs transfected in vitro with FuGene 6 and ExGen 500 expressed higher SEAP levels than with HPL. In rat VSMCs, SEAP secretion was more than doubled by addition of 250 microM ZnCl2 (p <0.0001) for all vectors. Seeding of syngeneic VSMCs transfected under optimized conditions (FuGene 6/pcDNA3-SEAP +250 microM ZnCl2) into healthy Lewis rats using various routes or into post-infarct myocardial scar resulted in a peak of SEAP expression at day 2 and detectable activity in the plasma for at least 8 days. CONCLUSIONS: FuGene 6 is an efficient non-viral transfection reagent for gene transfer in somatic smooth muscle cells in vitro and ZnCl2 enhances its efficiency. This increased expression of the transgene product is maintained after seeding in vivo.

Alkaline Phosphatase↗

PubMed1994

Cellular depletion of p56lck during thymocyte apoptosis.

The src-related protein tyrosine kinase p56lck is thought to be important in regulating maturation and functional responsiveness of T cells and thymocytes. In the present studies we report that expression of p56lck is suppressed during apoptosis. Using primary cultures of rat thymocytes, we found that agents that are effective in inducing apoptosis, including okadaic acid, dexamethasone, and antibodies to the CD3 receptor, also deplete cells of p56lck. This process is rapid, occurring within 24 h, and is not due to cytotoxicity. Inhibition of DNA fragmentation in apoptotic cells with the endonuclease inhibitor ZnCl2 failed to prevent depletion of p56lck, suggesting that it was not a consequence of the DNA degradation process. Using the thymic lymphoma cell line LSTRA, apoptosis was also associated with cellular depletion of p56lck. In contrast to thymocytes, this process required 48-72 h possibly because these cells overexpress p56lck. Although at this time we are uncertain as to the precise role of p56lck in the process of apoptosis, our results indicate that changes in the expression of this protein in thymocytes is an important marker of programmed cell death.

Animals↗

PubMed2006

A study of the glutathione metaboloma peptides by energy-resolved mass spectrometry as a tool to investigate into the interference of toxic heavy metals with their metabolic processes.

To better understand the fragmentation processes of the metal-biothiol conjugates and their possible significance in biological terms, an energy-resolved mass spectrometric study of the glutathione conjugates of heavy metals, of several thiols and disulfides of the glutathione metaboloma has been carried out. The main fragmentation process of gamma-glutamyl compounds, whether in the thiol, disulfide, thioether or metal-bis-thiolate form, is the loss of the gamma-glutamyl residue, a process which ERMS data showed to be hardly influenced by the sulfur substitution. However, loss of the gamma-glutamyl residue from the mono-S-glutathionyl-mercury (II) cation is a much more energetic process, possibly pointing at a strong coordination of the carboxylic group to the metal. Moreover, loss of neutral mercury from ions containing the gamma-glutamyl residue to yield a sulfenium cation was a much more energetic process than those not containing them, suggesting that the redox potential of the thiol/disulfide system plays a role in the formal reduction of the mercury dication in the gas phase. Occurrence of complementary sulfenium and protonated thiol fragments in the spectra of protonated disulfides of the glutathione metaboloma mirrors the thiol/disulfide redox process of biological importance. The intensity ratio of the fragments is proportional to the reduction potential in solution of the corresponding redox pairs. This finding has allowed the calculation of the previously unreported reduction potentials for the disulfide/thiol pair of cysteinylglycine, thereby confirming the decomposition scheme of bis- and mono-S-glutathionyl-mercury (II) ions. Finally, on the sole basis of the mass spectrometric fragmentation of the glutathione-mercury conjugates, and supported by independent literature evidence, an unprecedented mechanism for mercury ion-induced cellular oxidative stress could be proposed, based on the depletion of the glutathione pool by a catalytic mechanism acting on the metal (II)-thiol conjugates and involving as a necessary step the enzymatic removal of the glutamic acid residue to yield a mercury (II)-cysteinyl-glycine conjugate capable of regenerating neutral mercury through the oxidation of glutathione thiols to the corresponding disulfides.

Amino Acids↗

PubMed2004

Differential effects of zinc on glutamatergic and GABAergic neurotransmitter systems in the hippocampus.

Approximately 10% of total zinc in the brain exists in synaptic vesicles of glutamatergic neurons; however, the function of vesicular zinc is poorly understood. The presynaptic action of zinc against excitatory and inhibitory neurotransmission was studied in rat hippocampus using in vivo microdialysis. When the hippocampal CA3 region was perfused with 10-300 microM ZnCl(2), the level of glutamate in the perfusate was decreased, whereas the level of gamma-aminobutyric acid (GABA) was increased. Chelation of endogenous zinc with CaEDTA increased the glutamate level in the perfusate but decreased the GABA level, suggesting that zinc released into the synaptic cleft acts differentially on glutamatergic and GABAergic neurons in the CA3 region. The increase of GABA level by zinc was antagonized by 2,3-dioxo-6-nitro-1,2.3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide (NBQX), an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors, but not affected by MK801, an antagonist of N-methyl-D-aspartate (NMDA) receptors, and verapamil, a blocker of voltage-dependent calcium channels. The present study suggests that zinc enhances GABA release via potentiation of AMPA/kainate receptors in the CA3 region, followed by a decrease in presynaptic glutamate release in the same region. Zinc seems to be an inhibitory neuromodulator of glutamate release.

Animals↗

PubMed2005

Kainate-induced zinc translocation from presynaptic terminals causes neuronal and astroglial cell death and mRNA loss of BDNF receptors in the hippocampal formation and amygdala.

To evaluate the potential role of endogenous zinc in the pathophysiology of epilepsy, we injected kainic acid into the medial septum, which evokes seizure activity and delayed hippocampal degeneration. Different approaches were used. In the hippocampus, we found a movement of zinc from the synaptic compartment to CA1 pyramidal neurons and astrocytes after kainate. The same was true in the amygdala. We found that in those areas showing intense zinc bleaching there was also a loss of reactive astrocytes, which supports the view that release of synaptic zinc induces astrocytic cell death. We have also tested whether the kainate-induced zinc movement from the synaptic compartment to neuronal or glial cells alters the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, trkB. There was a prominent loss of expression of trkB mRNA in areas that coincided precisely with those displaying astrocyte loss and zinc bleaching. In the amygdala, these events were accompanied by a high upregulation of BDNF mRNA. To demonstrate further a role of synaptic zinc in hippocampal pathology, we used two different approaches. We first injected different doses of zinc chloride in the CA1 area. At lower doses (0.1-10 nmol), zinc chloride selectively induced apoptosis in CA1 pyramidal neurons and dentate granular neurons. In a second approach, we found that hippocampal zinc chelation was effective in protecting CA1 pyramidal neurons against kainate-induced cell death.

Amygdala↗

PubMed1967