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Structures for model ternary platinum-DNA-protein complexes and zinc ejection from zinc fingers by platinum were deduced from the ESI-MS spectra of the interaction of model Zn and Pt complexes.
The 5-day pretreatment of rats with zinc sulfate (50 or 150 mg/kg/day per os) significantly reduce the rate, the number, and area of cystamine-induced duodenal lesions in rats. Pretreatment with zinc sulfate in a dose of 15 mg/kg/day over a 5-day period or single administration of zinc sulfate (50 mg/kg) did not markedly reduce the above-mentioned lesion parameters. The administration of zinc sulfate (50 or 150 mg/kg/day per os) during 7 days results in a dose-dependent, significant decrease in the area of chronic acetate-induced gastric and duodenal lesions in rats. The results of clinical and experimental study indicate that zinc-containing compounds can be successfully used both for prophylaxis and treatment of duodenal ulcer.
Prior brain injury is a major risk factor in the development of Alzheimer's disease. This is true for traumatic brain injury, stroke or ischemic brain injury, and (more speculatively) for brain injury resulting from the hypo-perfusion-reperfusion in cardiac arrest or cardiac bypass surgery and even hypo- or hypertension. Here we propose that the release of excess, toxic, "floods" of free zinc into the brain that occurs during and after all excitotoxic brain injury is a key factor that sets the stage for the later development of Alzheimer's disease. Rapid and aggressive administration of zinc buffering compounds to patients suffering brain injury may therefore not only ameliorate the acute injury but might also reduce the risk of subsequent development of Alzheimer's disease.
The properties of soil Fe-humic sorbent complexes proved to determine the level of exogenous Zn binding and the toxicity of Zn-compounds for soil microbiota. The properties of Fe-humic complexes were profoundly altered under the action of phosphate anions as potential ligands. Distinct properties of Fe-humic complexes modified by ortho- and pyrophosphates were revealed.
Proton nuclear magnetic relaxation dispersion (NMRD) profiles were recorded between 0.24 mT and 1.4 T for lanthanum(III)- and gadolinium(III)-containing [15]metallacrown-5 complexes derived from alpha-aminohydroxamic acids and with copper(II) as the ring metal. The influence of the different R-groups on the proton relaxivity was investigated, and a linear relationship between the relaxivity and the molecular mass of the metallacrown complex was found. The selectivity of the metallacrown complexes was tested by transmetalation experiments with zinc(II) ions. The crystal structure of the copper [15]metallacrown-5 gadolinium complex with glycine hydroximate ligands is reported.
'The highly packed chromatin of mature spermatozoa results from replacement of somatic-like histones by highly basic arginine- and cysteine-rich protamines during spermatogenesis, with additional conformational changes in chromatin structure during epididymal transit. The objective of the present study was to compare the nuclear characteristics of immature and mature epididymal stallion spermatozoa, using a variety of experimental approaches. Resistance to in vitro decondensation of chromatin, following exposure to SDS-DTT and alkaline thioglycolate, increased significantly in mature spermatozoa. Evaluation of the thiol-disulfide status (monobromobimane labeling) demonstrated that immature cells obtained from ductulli efferentes contained mostly thiol groups, whereas these groups were oxidized in mature cells collected from the cauda epididymidis. Based on atomic absorption spectrophotometry, maturation of stallion spermatozoa was accompanied by a 60% reduction in the Zn(2+) content of sperm cells, concomitant with increased concentrations of this ion in epididymal fluid. Furthermore, the degree of disulfide bonding was inversely correlated with susceptibility of chromatin to acid denaturation (SCSA). Collectively, these data were consistent with the hypothesis that maturation of stallion spermatozoa involves oxidation of sulphydryl groups to form intra- and intermolecular disulfide links between adjacent protamines, with loss of zinc as an integral feature. These changes endow mechanical and chemical resistance to the nucleus, ensuring efficient transmission of the paternal genome at fertilization.
Excess brain zinc has been implicated in Alzheimer's neuropathology. Here we evaluated that hypothesis by searching the brains of Alzheimer's patients for abnormal zinc deposits. Using histochemical methods, we found vivid Zn2+ staining in the amyloid deposits of dense-core (senile) plaques, in the amyloid angiopathy surrounding diseased blood vessels, and in the somata and dendrites of neurons showing the characteristic neurofibrillary tangles (NFT) of Alzheimer's. In contrast, brains from age-matched, non-demented subjects showed only occasional staining for Zn2+ in scattered neurons and possible plaques. A role of abnormal zinc metabolism in Alzheimer's neuropathology is suggested.
A novel N3S1 typed tripodal ligand bearing an SH group, N-(mercaptoethyl)-di(2-pyridylmethyl)amine, DPASH, was prepared and its zinc(II) complex, [ZnII(DPAS)Cl], was structurally characterized by X-ray crystallography. [ZnII(DPAS)Cl] promoted hydrolysis of sodium bis(p-nitrophenyl)hydrogenphosphate), BNP-.
Alcohol dependence development is accompanied by zinc content decrease in the hippocampus. Young age, repeated physical loads and immobilization are factors, that promote such changes development in more expressed degree.
A method for cytochemical detection of zinc in peripheral blood granulocytes with selective reaction of 8-(p-toluenesulfonyl amino)-quinoline was developed. Zinc levels in granular leukocytes were found reduced in chronic myeloleukemia and elevated in leukemoid reactions. The method may be used for the differential diagnosis of these diseases.
The presence of zinc in synaptic terminals in the lamprey spinal cord was examined utilizing a modification of the Timm's sulfide silver method and with the fluorescent marker 6-methoxy-8-quinolyl-p-toluenesulfonamide (TSQ). Axons labeled with a Timm's staining method were predominantly located in the lateral region of the dorsal column. This correlated with a maximum of TSQ fluorescence in this region of the spinal cord. Single labeled terminals accumulating Timm reaction product were also found throughout the gray matter and fiber tracts. At the ultrastructural level, zinc was located in a population of synaptic terminals that co-localized gamma-aminobutyric acid (GABA) and glycine. Possible effects of Zn2+ on neuronal activity were examined. In spinobulbar interneurons, which receive GABAergic input in the dorsal column, zinc potentiated responses to GABA application, but it did not affect responses to GABA in motoneurons. Responses in motoneurons to pressure application of glycine were also not affected by Zn2+. Zinc, however, potentiated monosynaptic glycinergic inhibitory postsynaptic potentials (IPSPs) evoked in motoneurons by inhibitory locomotor network interneurons and increased frequency, but not amplitude of spontaneous miniature IPSPs recorded in the presence of tetrodotoxin (TTX), suggesting presynaptic effects. Glutamate responses and the amplitude of monosynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons were reduced by zinc. These effects appeared to be mediated largely postsynaptically through an effect on the N-methyl-D-aspartate (NMDA) component of the glutamatergic input. Our results thus show that free zinc is present in inhibitory synaptic terminals in the lamprey spinal cord, and that it may function as a modulator of inhibitory synaptic transmission.
Glucosamine-6-phosphate isomerase deaminase from Escherichia coli, a typical allosteric enzyme, becomes less cooperative and 50% inhibited when treated with zinc. This metal cation behaving as a tight-bound and slow partial inhibitor. Modification of a pair of vicinal reactive thiols with some sulfhydryl reagents mimics this effect. On the other hand, sulfhydryl reactivity disappears in the presence of saturating concentrations of Zn2+, which does not modify the kinetics of S-methylated enzyme, a finding that indicates that vicinal thiols are an essential part of the zinc-binding site. Allosteric activation of the deaminase causes trapping of the metal, which cannot be released by dialysis against a buffer containing EDTA. Cadmium and nickel(II) cations also produce a similar effect.
Zinc chelation and non-steroidal anti-inflammatory drugs (NSAIDs) have been explored as potential neuroprotective agents. However, it remains unknown whether NSAIDs and zinc chelation may converge on a similar cellular process. Using two-photon microscopy to observe hippocampal neurons labeled with a zinc-sensitive dye, we provide evidence that three chemically unrelated NSAIDs, niflumic acid, ibuprofen, and naproxen, acutely increase intracellular zinc stores from extracellular metal pools. Phospholipase A2 inhibitors triggered similar responses, suggesting that NSAIDs likely control zinc stores by their activity as cyclooxygenase inhibitors. These results provide evidence for a new link between cyclooxygenase metabolites and the mechanisms controlling neuronal zinc pools.
Zinc deficiency leads to pathological signs that are related to impaired function of plasma membrane proteins. The purpose of this study was to assess the effect of dietary zinc status on the sulfhydryl (SH) content of erythrocyte plasma membranes and erythrocyte function. Three experiments were performed. In the first, immature male rats were fed for 21 d either a low-zinc (<1.0 mg/kg) diet free choice (-ZnAL), an adequate-zinc (100 mg/kg) diet free choice (+ZnAL), or the adequate-zinc diet limited to the intake of -ZnAL pair-mates (+ZnPF). Tail blood was sampled to measure osmotic fragility and SH concentration of erythrocyte membrane proteins. The zinc-deficient rats were then repleted for 2 d and erythrocytes assayed for fragility and SH content. In the second experiment blood was sampled at 3-d intervals to determine the time course of change in fragility and SH concentration. In the third experiment the SH concentration of erythrocyte band 3 protein and the binding of zinc to isolated plasma membranes were measured. SH concentration decreased from approximately 75 nmol/mg protein to 68 nmol/mg protein during 21 d of depletion and returned to control level within 2 d of repletion. There was an inverse relationship between osmotic fragility and SH concentration of erythrocyte membrane proteins. Maximal decrease in SH occurred within 6 d of consuming the low-zinc diet. The SH content of band 3 protein isolated from deficient rats was also significantly lower than that of pair-fed controls (45 vs. 51 nmol/mg protein). The zinc-binding affinity of plasma membrane proteins tended to be decreased by zinc deficiency. In summary, low-zinc status lowers the plasma membrane SH concentration, and the decreased reducing potential is inversely related to osmotic fragility, and presumably, with impaired volume recovery of erythrocytes.
The tannins are natural polyphenols, able to precipitate water-soluble alkaloids and possess an inhibitory action on the angiotensin converting enzyme (ACE). We identified 18 polyphenolic compounds (tannins) from Chinese herbs and examined the in vitro effects of these tannins on ACE activity, including determination of the 50% inhibitory concentrations (IC50), specificity and mode of inhibition. We also assessed the in vivo inhibitory effect of the tannins on angiotensin I-induced blood pressure elevation in spontaneously hypertensive rats (SHR). Nine tannins with an IC50 <200 microM for ACE inhibitors were identified belonging to three tannin classes: caffeoylquinates, flavan-3-ols and gallotannins. In vitro, we found caffeoylquinates chelate the ACE zinc cofactor. Two of the flavan-3-ols: epigallocatechin-3-O-gallate and epigallocatechin-3-O-methylgallate, and one of gallotannin: 1, 2, 3, 4, 6-penta-O-galloyl-beta-D-glucose were non-specific inhibitors because also reduced the activity of trypsin and chymotrypsin. The ACE inhibition of 1, 2, 3, 4, 6-penta-O-galloyl-beta-D-glucose was also reduced after addition of bovine serum albumin, suggesting a non-specific mode of action. In vivo, 1,2,3,6-tetra-O-galloyl-beta-D-glucose and epigallocatechin-3-O-methylgallate had a strong dose-dependent hypotensive effect reducing the blood pressure significantly in the SHR with infusion of the angiotensin I. These findings indicate that some of the tannins isolated from herbs inhibit ACE activity non-specifically. The ACE inhibitory effect of these tannins may explain the hypotensive effects of some traditional Chinese herbs.
The binding properties of [(3)H]-LY354740 were characterized on rat metabotropic glutamate receptors mGlu2 and mGlu3 expressed in Chinese hamster ovary (CHO) cells using Semliki Forest virus vectors. The saturation isotherm gave K(D) values of 20+/-5 and 53+/-8 nM and B(max) values of 474+/-161 and 667+/-89 fmol/mg protein for mGlu2 and mGlu3 receptors, respectively. NMDA, CaCl(2), DHPG and kainate were inactive up to 1 mM, whereas LY341495, DCG IV and ibotenate inhibited [(3)H]-LY354740 binding with similar potencies on both receptors. L-CCG I, L-AP4, L-AP5, LY354740 and 1S,3R-ACPD were 2- to 4-fold more potent inhibitors of [(3)H]-LY354740 binding to mGlu2 than mGlu3 receptors. However, MPPG and L-AP3 had a 6-fold and DTT a 28-fold preference for mGlu2 over mGlu3. ZnCl(2), at 10 mM, inhibited more than 70% of [(3)H]-LY354740 binding to mGlu2 receptors. At the same concentration it did not affect significantly [(3)H]-LY354740 binding to mGlu3 receptors. On the contrary, glutamate, quisqualate, EGLU and NAAG showed a 3-, 5-, 7- and 12-fold preference for mGlu3 over mGlu2. Finally, GTPgammaS, which partially inhibited the binding on mGlu2 receptors, was inactive to inhibit [(3)H]-LY354740 binding on mGlu3 receptors.
At the zinc-enriched mossy fiber synapses from hippocampal CA3 area, electrical or chemical stimulation evokes zinc release from glutamatergic synaptic vesicles that may cause different pre- or postsynaptic actions. Besides zinc that can be co-localized with glutamate and GABA, the mossy fibers contain a very high density of ATP-sensitive potassium channels that are activated by zinc. We have investigated the possibility that intensely released zinc inhibits presynaptic calcium changes and consequently zinc and glutamate release. The studies were made combining optical recording of fast presynaptic calcium and zinc signals, using the fluorescent indicators Fura-2 and N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide, respectively, with measurements of field potentials. We have observed that strong tetanic stimulation caused posttetanic depressions of electrically induced presynaptic calcium and zinc signals and of synaptic responses, the depressions being blocked by zinc chelators. These results suggest that endogenously released zinc has an inhibitory role, mediated by presynaptic ATP-sensitive potassium channels and/or presynaptic calcium channels, that leads to the depression of zinc and glutamate release.
Prior evidence indicates that synaptically-released zinc enters postsynaptic neurons in toxic excess during ischemia and seizures. In addition, prevention of this zinc translocation has been shown to be neuroprotective in both ischemia and seizures. Here we show evidence that the same translocation of zinc from presynaptic boutons into postsynaptic neurons occurs after mechanical injury to the brain. Specifically, using a rat model of traumatic brain injury, we show that trauma is associated with (i) loss of zinc from presynaptic boutons (ii) appearance of zinc in injured neurons, and (iii) neuroprotection by intraventricular administration of a zinc chelator just prior to brain impact. The possible use of zinc chelators for neuroprotection after head trauma is considered.