UMLS:C0038454 - FACTA Search

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two groups of 20 stroke prone spontaneously hypertensive rats (SHRSP) at 5 weeks old were fed a diet containing 10 w/w% rapeseed (canola) oil or soybean oil as the only dietary fat, and given drinking water containing 1% NaCl. Life span of the canola oil group (62+/-2 days) was shorter than that of the soybean oil group (68+/-3 days). Stroke-related symptoms were observed in every animal, but the onset of those in the canola oil group, at 47+/-1 days after starting the administration was earlier than that in the soybean oil group, 52+/-2 days. Incidence of cerebral hemorrhage was similar in these groups, and no differences were found between lesions of organs in the groups. In another experiment, two groups of ten SHRSP at 5 weeks of age were fed the defatted diet and given canola oil or soybean oil by gavage at 10 w/w% of consumed food for 4 weeks without NaCl loading. After the 4-week administration, mean systolic blood pressure in the canola oil group and the soybean oil group were 233+/-2 and 223+/-0.3 mmHg, respectively. Phytosterol levels in both plasma and erythrocyte membranes reflected those contained in the oils ingested. Na(+), K(+)-ATPase activities in the brain, heart and kidney were enhanced in the canola oil group. These results indicate that promotion of hypertension-related deterioration in organs is likely to have relevance to the short life span in the canola oil group. Enhanced Na(+), K(+)-ATPase activity by phytosterols in the oil ingested may play a role in these changes.
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PMID:Rapeseed oil ingestion and exacerbation of hypertension-related conditions in stroke prone spontaneously hypertensive rats. 1269 9

For many years, it has been known that myosin binds to actin tightly, but it had not been possible to devise a muscle fiber experiment to determine whether this binding energy is directly coupled to the working stroke of the actomyosin crossbridge cycle. Addressing the question at the single-molecule level with optical tweezers allows the problem to be resolved. We have compared the working stroke on the binding of four myosin complexes (myosin, myosin-ADP, myosin-pyrophosphate, and myosin-adenyl-5'yl imidodiphosphate) with that observed while hydrolyzing ATP. None of the four was observed to give a working stroke significantly different from zero. A working stroke (5.4 nm) was observed only with ATP, which indicates that the other states bind to actin in a rigor-like conformation and that myosin products (M.ADP.Pi), the state that binds to actin during ATPase activity, binds in a different, prestroke conformation. We conclude that myosin, while dissociated from actin, must be able to take up at least two mechanical conformations and show that our results are consistent with these conformations corresponding to the two states characterized at high resolution, which are commonly referred to in terms of having open and closed nucleotide binding pockets.
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PMID:The working stroke upon myosin-nucleotide complexes binding to actin. 1275 Apr 65

FK506, a calcineurin inhibitor, shows potent neuroprotective effects in animal models such as those of stroke and neurodegenerative diseases. However, the mechanism underlying these neuroprotective effects is unclear. In this study, an in vitro model, in which FK506 protected the cells against cell death, was established and analyzed in detail by pharmacological experiments. Thapsigargin (TG), an inhibitor of endoplasmic reticulum calcium-ATPase, induced SH-SY5Y cell death. FK506 concentration-dependently protected the cells from this type of death. In contrast, FK506 did not suppress SH-SY5Y cell death caused by the following molecules: tunicamycin (TM), an inhibitor of N-linked glycosylation; etoposide (Eto), a topoisomerase II inhibitor; and staurosporine (STS), a phospholipid/calcium-dependent protein kinase inhibitor. Additionally, FK506 did not inhibit TG-induced cell death in either SK-N-MC or HeLa cell lines. FK506 completely inhibited caspase-3 activation and apoptosis caused by TG in a concentration-dependent manner, but not that caused by TM, Eto, and STS. TG did not activate caspase-3 in SK-N-MC cells, although it slightly activated caspase-3 in HeLa cells. FK506 did not change caspase-3 activity in either SK-N-MC or HeLa cell lines. Cyclosporin A, another calcineurin inhibitor, showed the same results as FK506 in this study, whereas rapamycin, an immunosuppressant not associated with calcineurin activity, did not have any effect in this context. Thus, the suppressive effects of FK506 on cell death are specific to SH-SY5Y cells treated with TG and are caused by the inhibition of calcineurin and subsequent suppression of caspase-3 activation. Therefore, an in vitro system using SH-SY5Y cells treated with TG could provide a model reflective of certain aspects of the neuroprotective activity of FK506.
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PMID:Detailed in vitro pharmacological analysis of FK506-induced neuroprotection. 1287 56

Myosin is a molecular motor and a member of a protein family comprising at least 18 classes. There is an about 1,000-fold difference in the in vitro sliding velocity between the fastest myosin and the slowest one. Previous studies revealed that the hydrophobic triplet in the motor domain (Val534, Phe535, and Pro536 in Dictyostelium myosin) is important for the strong binding of myosin to actin. We studied the role of the triplet in the sliding motion of myosin by means of site directed mutagenesis because the sliding velocity is determined by the time that myosin interacts with actin strongly. We produced mutant Dictyostelium myosins and subfragment-1s that have the triplet sequences of various classes of myosin with different sliding velocities. The V(max) and K(actin) values of the actin-activated ATPase for all these mutant subfragment-1s were lower than those of the wild-type Dictyostelium myosin. The mutant myosins exhibited much lower sliding velocities than the wild type. The time that the mutant subfragment-1s are in the strongly bound state did not correlate well with the sliding velocity. Our results suggested that (i) the hydrophobic triplet alone does not determine the sliding velocity of myosin, (ii) the size of the amino acid side chain in the triplet is crucial for the ATPase activity and the motility of myosin, and (iii) the hydrophobic triplet is important not only for strong binding to actin but also for the structural change of the myosin motor domain during the power stroke.
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PMID:Roles of the hydrophobic triplet in the motor domain of myosin in the interaction between myosin and actin. 1294 84

White matter of the brain and spinal cord is susceptible to anoxia, ischemia, trauma and autoimmune attack. Irreversible injury to this tissue can have serious consequences for the overall function of the CNS through disruption of signal transmission. Like neurons, central myelinated axons are critically dependent on a continuous supply of oxygen and glucose. Injury causes failure of the Na-K-ATPase and accumulation of axoplasmic Na through non-inactivating Na channels, which, together with membrane depolarization, promotes reverse Na-Ca exchange and axonal Ca overload. An equally important source of deleterious Ca originates from intracellular stores, released in part by a mechanism similar to "excitation-contraction coupling" in muscle, involving activation of ryanodine receptors by L-type Ca channels. Excitotoxic mechanisms also play an important role: glutamate released by reversal of Na-dependent glutamate transporters activates AMPA/kainate receptors to cause injury to glia and myelin. Excessive accumulation of cytosolic Ca in turn activates various Ca-dependent enzymes such as calpains, phospholipases and others resulting in irreversible injury. Reoxygenation paradoxically accelerates injury in many axons, and promotes cytoskeletal degradation. Blockers of voltage-gated Na channels represent an attractive therapeutic target because of their ability to simultaneously interfere indirectly with several Ca sourcing pathways. Alternatively, or additionally, AMPA/kainate receptor inhibition has also been shown to be neuroprotective in several white matter injury paradigms. In the clinical setting, optimal protection of the CNS as a whole in common disorders such as stroke, traumatic brain and spinal cord injury, will likely require combination therapy aimed at unique steps in gray and white matter regions, or intervention at common points in the injury cascades.
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PMID:White matter injury mechanisms. 1503 8

Dynein ATPases contain six concatenated AAA modules within the motor region of their heavy chains. Additional regions of sequence are required to form a functional ATPase, which a previous study suggested forms seven or eight subdomains arranged in either a ring or hollow sphere. A more recent homology model of the six AAA modules suggests that these form a ring. Therefore both the number and arrangement of subdomains remain uncertain. We show two-dimensional projection images of dynein-c in negative stain which reveal new details of its structure. Initial electron cryomicroscopy shows a similar overall morphology. The molecule consists of three domains: stem, head, and stalk. In the absence of nucleotide the head has seven lobes of density forming an asymmetric ring. An eighth lobe protrudes from one side of this heptameric ring and appears to join the elongated cargo-binding stem. The proximal stem is flexible, as is the stalk, suggesting that they act as compliant elements within the motor. A new analysis of pre- and post-power stroke conformations shows the combined effect of their flexibility on the spatial distribution of the microtubule-binding domain and therefore the potential range of power stroke sizes. We present and compare two alternative models of the structure of dynein.
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PMID:The structure of dynein-c by negative stain electron microscopy. 1503 51

A cytoplasmic dynein is a microtubule-based motor protein involved in diverse cellular functions, such as organelle transport and chromosome segregation. The dynein has two ring-shaped heads that contain six repeats of the AAA domain responsible for ATP hydrolysis. It has been proposed that the ATPase-dependent swing of a stalk and a stem emerging from each of the heads generates the power stroke (Burgess, S.A. (2003) Nature 421, 715-718). To understand the molecular mechanism of the dynein power stroke, it is essential to establish an easy and reproducible method to express and purify the recombinant dynein with full motor activities. Here we report the expression and purification of the C-terminal 380-kDa fragment of the Dictyostelium cytoplasmic dynein heavy-chain fused with an affinity tag and green fluorescent protein. The purified single-headed recombinant protein drove the robust minus-end-directed sliding of microtubules at a velocity of 1.2 microm/s. This recombinant protein had a high basal ATPase activity (approximately 4s(-1)), which was further activated by >15-fold on the addition of 40 microM microtubules. These results show that the 380-kDa recombinant fragment retains all the structures required for motor functions, i.e. the ATPase activity highly stimulated by microtubules and the robust motility.
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PMID:A single-headed recombinant fragment of Dictyostelium cytoplasmic dynein can drive the robust sliding of microtubules. 1505 17

Nicotine, a major constituent of tobacco smoke, has important effects on brain recovery after focal ischemia (Wang et al., 1997). The purpose of this work is to systematically test the effects of nicotine during stroke conditions on blood-brain barrier (BBB) potassium transport, protein expression of the Na,K,2Cl-cotransporter (NKCC), and cell signaling pathways that control NKCC activity at the BBB. Confluent bovine brain microvessel endothelial cells (BBMECs) were exposed to both a hypoxic/aglycemic (H/A) environment to model BBB function during stroke conditions and nicotine and cotinine (N/C) to model plasma levels seen in smokers. BBMECs exhibit both Na,K-ATPase and NKCC activity (60 and 34 nmol/min/g, respectively) that contribute to 98% of the K(+) uptake in cultured endothelial cells. An adaptive up-regulation of NKCC activity was identified to occur on the basolateral surface of the BBB after in vitro stroke conditions. Twenty-four hours of N/C exposure, at doses equivalent to plasma levels of smokers, combined with 6 h of H/A, reduced NKCC protein expression and total NKCC activity (shown by bumetanide-sensitive (86)RB uptake) compared with 6 h of H/A alone (P < 0.01). Basolateral K(+) transport was found to be modulated by nicotinic acetylcholine receptors expressed at the BBB. NKCC activity on the basolateral surface of the BBB is controlled by an ongoing phosphorylation/dephosphorylation processes. We have identified a potential mechanism in altered BBB response to stroke conditions with prior N/C exposure directly implicating damage to brain-to-blood K(+) transport mediated at the BBB and perhaps neuronal recovery after stroke.
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PMID:Regulation of blood-brain barrier Na,K,2Cl-cotransporter through phosphorylation during in vitro stroke conditions and nicotine exposure. 1505 2

Significant amounts of di(2-ethylhexyl) phthalate (DEHP) leach out into blood stored in DEHP plasticized polyvinyl chloride (PVC) bags resulting in the exposure of recipients of blood transfusion to this compound. The aim of this study was to find out whether DEHP at these low levels has any effect on the activity of membrane Na(+)-K+ ATPase, since a decrease in this enzyme activity has been reported to take place in a number of disorders like neurodegenerative and psychiatric disorders, coronary artery disease and stroke, syndrome-X, tumours etc. DEHP was administered (ip) at a low dose of 750 microg/100 g body weight to rats and the activity of membrane Na(+)-K+ ATPase in liver, brain and RBC was estimated. Histopathology of brain, activity of HMG CoA reductase (a major rate limiting enzyme in the isoprenoid pathway of which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is a product), intracellular concentration of Ca2+ and Mg2+ in RBC (which is altered as a result of inhibition of Na(+)-K+ ATPase) were also studied. (In the light of the observation of increase of intracellular Ca2+ load and intracellular depletion of Mg2+ when Na(+)-K+ ATPase is inhibited). Histopathology of brain revealed areas of degeneration in the rats administered DEHP. There was significant inhibition of membrane Na(+)-K+ ATPase in brain, liver and RBC. Intracellular Ca2+ increased in the RBC while intracellular Mg2+ decreased. However activity of hepatic HMG CoA reductase decreased. Activity of Na(+)-K+ ATPase and HMG CoA reductase, however returned to normal levels within 7 days of stopping administration of DEHP. The inhibition of membrane Na(+)-K+ ATPase activity by DEHP may indicate the possibility of predisposing recipients of transfusion of blood or hemodialysis to the various disorders mentioned above. However since this effect is reversed when DEHP administration is stopped, it may not be a serious problem in the case of a few transfusion; but in patients receiving repeated blood transfusion as in thalassemia patients or patients undergoing hemodialysis, possibility of this risk has to be considered. This inhibition is a direct effect of DEHP or its metabolites, since activity of HMG CoA reductase, (an enzyme which catalyses a major rate limiting step in the isoprenoid pathway by which digoxin, the physiological inhibitor of Na(+)-K+ ATPase is synthesized) showed a decrease.
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PMID:Inhibition of membrane Na(+)-K+ Atpase of the brain, liver and RBC in rats administered di(2-ethyl hexyl) phthalate (DEHP) a plasticizer used in polyvinyl chloride (PVC) blood storage bags. 1524 77

Within 2 min of stroke onset, neurons and glia in brain regions most deprived of blood (the ischemic core) undergo a sudden and profound loss of membrane potential caused by failure of the Na+/K+ ATPase pump. This anoxic depolarization (AD) represents a collapse in membrane ion selectivity that causes acute neuronal injury because neurons simply cannot survive the energy demands of repolarization while deprived of oxygen and glucose. In vivo and in live brain slices, the AD resists blockade by antagonists of neurotransmitter receptors (including glutamate) or by ion channel blockers. Our neuroprotective strategy is to identify AD blockers that minimally affect neuronal function. If the conductance underlying AD is not normally active, its selective blockade should not alter neuronal excitability. Imaging changes in light transmittance in live neocortical and hippocampal slices reveal AD onset, propagation, and subsequent dendritic damage. Here we identify several sigma-1 receptor ligands that block the AD in slices that are pretreated with 10-30 microM of ligand. Blockade prevents subsequent cell swelling, dendritic damage, and loss of evoked field potentials recorded in layers II/III of neocortex and in the CA1 region of hippocampus. Even when AD onset is merely delayed, electrophysiological recovery is markedly improved. With ligand treatment, evoked axonal conduction and synaptic transmission remain intact. The large nonselective conductance that drives AD is still unidentified but represents a prime upstream target for suppressing acute neuronal damage arising during the first critical minutes of stroke. Sigma receptor ligands provide insight to better define the properties of the channel responsible for anoxic depolarization. Video clips of anoxic depolarization and spreading depression can be viewed at http://anatomy.queensu.ca/faculty/andrew.cfm.
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PMID:Blocking the anoxic depolarization protects without functional compromise following simulated stroke in cortical brain slices. 1545 3

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