Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zinc has been closely linked to toxic injury in stroke; changes of 4-hydroxynonenal (HNE) and glutamate transporter (GLT-1) are implicated in cell death in amyotrophic lateral sclerosis (ALS). However, the effect of zinc exposure on the expression of HNE and GLT-1, and the survival of spinal cord motor neuron remains unknown. Here we demonstrate that under the activation of Ca2+ permeable AMPA/kainate (Ca-A/K) channels, zinc exposure for 1 h significantly increases the expression of HNE, decreases the expression of GLT-1 by immunostaining and Western blot, induces strong increase in reactive oxygen species (ROS) generation in Ca-A/K (+) neurons by hydroethidine (HEt) imaging and cobalt staining, and decreases the motor neuron survival in spinal cord culture. Interestingly, GLT-1 positive granules appear within the soma of glial cells 1h after zinc exposure, while these granules are absent in the untreated control group. The increase of HNE and decrease of GLT-1 production caused by prolonged kainate stimulated zinc exposure may play a key role in oxidative neurotoxicity in spinal cord motor neurons, and may be relevant to chronic neurodegeneration.
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PMID:Effect of zinc exposure on HNE and GLT-1 in spinal cord culture. 1906 13

Zinc dyshomeostasis in brain might be involved in the pathogenesis of a series of brain diseases such as Alzheimer's disease and stroke. It is essential that the level of intracellular free Zn2+ in neurons is tightly controlled to maintain a narrow window of optimal concentration. The plasma membrane bound transporter ZnT1 is suggested to lower intracellular Zn2+ concentration. In this study, the function of ZnT1 in cultured cortical neurons was studied. Using vector-based shRNA interference, the expression of this protein was reduced approximately 40% in cultured rat cortical neurons when measured by immunofluorescence using a ZnT1 antibody. Changes in intracellular Zn2+ levels were tracked in individual neurons by microfluorometry using the Zn2+ selective fluorophore, FluoZin3. Unopposed Zn2+ efflux was measured by first loading cultured cortical neurons with Zn2+ then reducing extracellular Zn2+ to near zero by addition of EDTA. Reducing ZnT1 expression caused Zn2+ efflux to decrease compared with the Zn2+ efflux measured in nonsense transfected neurons, suggesting that ZnT1 plays a direct role in Zn2+ efflux. ZnT1 dependent Zn2+ efflux rate was higher in the first 10 min than at later time periods suggesting that ZnT1-mediated efflux was heavily dependent on the intracellular free Zn2+ concentration and/or required an outwardly directed Zn2+ gradient.
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PMID:Silencing of ZnT1 reduces Zn2+ efflux in cultured cortical neurons. 1909 42

The dry fruits of Hippophae rhamnoides (so-called "Saji" or "Sea buckthorn") are used in China as a herbal medicine. The present work studied the effects on microvessels in the left ventricular wall, hematological parameters, cardiovascular performance and plasma constituents in spontaneously hypertensive stroke-prone rats (SHRSP/EZO) treated with Hippophae for 60 days. Analyses showed that the powder made of dry Hippophae fruits contains the vitamins C, B1, B2 and E, provitamin A, rutin, serotonin, cytosterol, selenium and zinc, among other constituents. The experimental rats were fed ad libitum with blocks of rat chow supplemented with Hippophae powder at a concentration of 0.7 g/kg in rat powder chow, while control rats were unsupplemented chow. The mean arterial blood pressure, heart rate, total plasma cholesterol, triglycerides, and glycated hemoglobin were significantly decreased by the Hippophae treatment. The arteriolar capillary portions of microvessels expressing alkaline phosphatase decreased, but there was a trend for an increase in the total capillary density. It was concluded that Hippophae fruits improved the metabolic processes accompanied by reduction of hypertensive stress on the ventricular microvessels.
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PMID:Effects of a herbal medicine, Hippophae rhamnoides, on cardiovascular functions and coronary microvessels in the spontaneously hypertensive stroke-prone rat. 1913 38

Extracellular superoxide dismutase (SOD3) is a homotetrameric copper- and zinc-containing glycoprotein with affinity for heparin. The level of SOD3 is particularly high in blood vessel walls and in the lungs. The enzyme has multiple roles including protection of the lungs against hyperoxia and preservation of nitric oxide. The common mutation R213G, which reduces the heparin affinity of SOD3, is associated with increased risk of myocardial infarctions and stroke. We report the first crystal structure of human SOD3 at 1.7 A resolution. The overall subunit fold and the subunit-subunit interface of the SOD3 dimer are similar to the corresponding structures in Cu-Zn SOD (SOD1). The metal-binding sites are similar to those found in SOD1, but with Asn180 replacing Thr137 at the Cu-binding site and a much shorter loop at the zinc-binding site. The dimers form a functional homotetramer that is fashioned through contacts between two extended loops on each subunit. The N- and C-terminal end regions required for tetramerisation and heparin binding, respectively, are highly flexible. Two grooves fashioned by the tetramer interface are suggestive as the probable sites for heparin and collagen binding.
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PMID:The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding. 1928 27

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels that are highly permeable to calcium and mediate activity-dependent synaptic plasticity. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia. NMDARs exist as multiple subtypes with distinct pharmacological and biophysical properties that are largely determined by the type of NR2 subunit (NR2A to NR2D) incorporated in the heteromeric NR1/NR2 complex. A fundamental difference between NMDAR subtypes is their channel maximal open probability (P(o)), which spans a 50-fold range from about 0.5 for NR2A-containing receptors to about 0.01 for receptors containing NR2C and NR2D; NR2B-containing receptors have an intermediate value (about 0.1). These differences in P(o) confer unique charge transfer capacities and signalling properties on each receptor subtype. The molecular basis for this profound difference in activity between NMDAR subtypes is unknown. Here we show that the subunit-specific gating of NMDARs is controlled by the region formed by the NR2 amino-terminal domain (NTD), an extracellular clamshell-like domain previously shown to bind allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). The subtype specificity of NMDAR P(o) largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2-NTD. This NTD-driven gating control also affects pharmacological properties by setting the sensitivity to the endogenous inhibitors zinc and protons. Our results provide a proof of concept for a drug-based bidirectional control of NMDAR activity by using molecules acting either as NR2-NTD 'closers' or 'openers' promoting receptor inhibition or potentiation, respectively.
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PMID:Mechanism of differential control of NMDA receptor activity by NR2 subunits. 1940 60

The content of elements in rainwater is an indirect indicator of its occurrence in air dust. This is sometimes referred to as rain fallout and is investigated in applied environmental pollution monitoring schemes. The annual content of elements in rainwater may be recognized as good index for assessing influence of those environmental factors on human body. The possible relationship between the concentrations of selected elements in rainwater and the frequency of hospitalization by reason of angina pectoris, stroke, and peripheral venous thrombosis was investigated in the Opole Voivodship (Poland) area during the period 2000-2002. There is a relatively high or partly significant correlation between frequency of hospitalization by reason of these conditions and content of lead, cadmium, chromium, zinc, and chloride in rainwater. Significant gender-dependent differences were observed only in peripheral venous thrombosis, where important correlations with lead, cadmium, and chromium were found only in men.
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PMID:Frequency of hospitalization for angina pectoris, stroke, and peripheral venous thrombosis and its relationship to elements in rainwater in Opole Voivodship, Poland, during 2000-2002. 1955 75

High levels of labile zinc accumulate in degenerating neurons after brain injury, such as ischemic stroke, trauma, epilepsy, and hypoglycemia. Cytosolic zinc accumulation is also found in brain neurons undergoing apoptosis during development or after neuronal target ablation. Thus, staining with zinc-specific probes can be used to identify neuronal death in the brain. In this study, mice were intraperitoneally given four 20 mg/kg doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 2-hour intervals, and dopaminergic neurons were then evaluated for zinc accumulation and apoptosis. In the substantia nigra pars compacta, zinc-specific fluorescent dyes revealed that all degenerating neurons, identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL), or acid fuchsin or Fluoro-Jade C staining, contained high levels of cytosolic labile zinc. Nuclear condensation/fragmentation was noted in dopaminergic neurons with cytosolic zinc accumulation, indicating apoptotic cell death. These findings support the supposition that cytosolic labile zinc accumulation is an indicator of degenerating dopaminergic neurons in animal models of Parkinson's disease.
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PMID:Cytosolic labile zinc accumulation in degenerating dopaminergic neurons of mouse brain after MPTP treatment. 1955 9

Zinc plays a key pathophysiological role in major neurological disorders as well as diabetes, while being essential for the activity of numerous zinc binding proteins. A major challenge in chelation based therapy must take into consideration these apparently conflicting effects of zinc. One approach is to limit the activity of the chelator to regions and levels of zinc pathology, making normal zinc-dependent processes invisible to the chelator. Combining fluorescent zinc imaging with cytotoxicity assays we studied the zinc chelation efficacy and neuroprotective effect of the lipophilic divalent transition metal chelator DP-b99 (1,2-Bis(2-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid-N-N'-di[2-(octyloxy)ethyl ester],-N,N'-disodium salt). The affinity of DP-b99 to Zn(2+) and Ca(2+) ions is moderate in water and enhanced significantly in the lipid milieu. Application of DP-b99 to MIN6 beta-cells that were preloaded with zinc was followed by a decrease in fluorescence of the intracellular Zn(2+) sensitive dye, ZnAF-2DA, to resting levels. Preloading of MIN6 cells with DP-b99 was also effective in attenuating subsequent cellular zinc rise. Concentration-dependence analysis of zinc accumulation indicated that DP-b99 acts as a zinc chelator with moderate affinity. DP-b99 preapplication attenuated both Zn(2+) and Ca(2+) rise in neuronal cultures and also Zn(2+) rise in brain slices. Finally, DP-b99 attenuated Zn(2+)-induced neuronal death. Our results indicate that DP-b99 is effective in attenuating Zn(2+) and Ca(2+) surges and protecting neurons against a toxic Zn(2+)-rise. This may underlie the efficacy of DP-b99 in stroke treatment.
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PMID:The lipophilic zinc chelator DP-b99 prevents zinc induced neuronal death. 1962 52

Abstract Deposition of ubiquitinated protein aggregates is a hallmark of neurodegeneration in both acute neural injuries, such as stroke, and chronic conditions, such as Parkinson's disease, but the underlying mechanisms are poorly understood. In the present study, we examined the role of Zn2+ in ischemia-induced impairment of the ubiquitin-proteasome system in the CA1 region of rat hippocampus after transient global ischemia. We found that scavenging endogenous Zn2+ reduced ischemia-induced ubiquitin conjugation and free ubiquitin depletion. Furthermore, exposure to zinc chloride increased ubiquitination and inhibited proteasomal enzyme activity in cultured hippocampal neurons in a concentration- and time-dependent manner. Further studies of the underlying mechanisms showed that Zn(2+)-induced ubiquitination required p38 activation. These findings indicate that alterations in Zn2+ homeostasis impair the protein degradation pathway.
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PMID:Zn2+ mediates ischemia-induced impairment of the ubiquitin-proteasome system in the rat hippocampus. 1978 Sep 4

Coronary heart disease and in particular its most serious form - acute myocardial infarction (AMI) - represents the most common cause of mortality in developed countries. Better prognosis may be achieved by understanding the etiopathogenetic mechanisms of AMI. Therefore, a catecholamine model of myocardial injury, which has appeared to be very similar to AMI in human in some aspect, was used. Male Wistar:Han rats were randomly divided into two groups: control group (saline) and isoprenaline group (ISO; synthetic catecholamine, 100 mg.kg(- 1) subcutaneously [s.c.]). After 24 hours, functional parameters were measured, biochemical markers in the blood and metals content in the heart tissue were analysed and histological examination was performed. ISO caused marked myocardial injury that was associated with myocardial calcium overload. Close correlation between myocardial impairment (i.e. serum TnT, stroke volume index and wet ventricles weight) and the levels of myocardial calcium was observed. Direct reactive oxygen species (ROS) involvement was documented only by non-significant increase in malonyldialdehyde 24 hours after ISO injury. Moreover, myocardial element analysis revealed no significant changes as for the content of zinc and iron while selenium and copper increased in the ISO group although it reached statistical significance only for the latter.
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PMID:Cardiac biomarkers in a model of acute catecholamine cardiotoxicity. 1981 20


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