Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

A major consequence of brain hypoxia and hypoglycemia, which induces the detrimental effects of stroke, is impaired ATP supply. However, it is not yet clear to which degree reduced cellular ATP production affects Ca(2+) homeostasis and Ca(2+) signaling of glia cells. Here we studied in cultured hippocampal astrocytes the influence of inhibition of cellular energy supply on Ca(2+) load of intracellular stores. Inhibition of glycolysis in the presence of substrates for mitochondrial respiration resulted in an average drop of intracellular ATP levels by 35%. Inhibition of oxidative phosphorylation reduced intracellular ATP on average by 16%. With inhibition of both glycolysis and mitochondrial ATP production, intracellular ATP level was drastically reduced (84%). In astrocytes in Ca(2+)-free buffer, cytosolic [Ca(2+)](i) was dramatically increased due to inhibition of glycolysis, even in the presence of mitochondrial substrates. However, only a minor increase of [Ca(2+)](i) was observed with inhibitors of mitochondrial ATP synthesis. Remarkably, the moderate reduction of ATP levels found with inhibitors of glycolysis caused a severe loss of Ca(2+) from cyclopiazonic acid (CPA)-sensitive Ca(2+) stores. Consequently, inhibition of glycolysis reduced P2Y receptor- or thrombin receptor-evoked Ca(2+) responses on average by 95%, whereas a reduction of only 26% was found with mitochondrial inhibitors. In conclusion, glycolysis is the most important source of ATP for the maintenance of Ca(2+) load in stores that are required for transmitter-induced signaling. These results are consistent with the concept that a local ATP source in the vicinity of endoplasmic reticulum Ca(2+) pumps is required.
...
PMID:Requirement of glycolytic and mitochondrial energy supply for loading of Ca(2+) stores and InsP(3)-mediated Ca(2+) signaling in rat hippocampus astrocytes. 1093 27

Organellar Hsp-70 is required for post-translational translocation into the endoplasmic reticulum and mitochondria. The functional role played by Hsp-70 is unknown. However, two operating principles have been suggested. The power stroke model proposes that Hsp-70 undergoes a conformational change, which pulls the precursor protein through the translocation pore, whereas, in the Brownian ratchet model, the role of Hsp-70 is simply to block backsliding through the pore. A mathematical analysis of both mechanisms is presented and reveals that qualitative differences between the models occur in the behavior of the mean velocity and effective diffusion coefficient as a function of Hsp-70 concentration. An experimental method is proposed for measuring these two quantities that only relies on current experimental techniques.
...
PMID:Models of post-translational protein translocation. 1105 5

This report summarizes recent findings in the field of basic and translational apoptosis research which were presented at the 1st Conference on 'Mechanisms of Cell Death and Disease: Advances in Therapeutic Intervention' organized by the European School of Hematology and the University of Texas MD Anderson Cancer Center, 13-17 May, in Dublin, Ireland, and puts them in the context of the literature. Recent discoveries have significantly advanced the understanding of biochemical and genetic requirements of distinct apoptosis pathways (ie mitochondrial, death-receptor and endoplasmic reticulum-mediated apoptosis) and their dysregulation in disease. Progress has been made especially in the elucidation of the mechanisms of action of the Bcl-2 family members, in detail the formation of channels and their regulation in the mitochondrial membranes, conformational changes in Bax and Bak, and crosstalk of death receptor-triggered apoptosis to the mitochondria by activation of Bax via Bid. In addition, novel insights have been gained about the regulation of caspases and novel caspase signaling pathways, such as activation of caspase-12 by the endoplasmic reticulum stress response. Therapeutic applications of apoptosis manipulation include (1) the inhibition of caspases in acute and chronic neurodegenerative diseases, ie stroke, Alzheimer's or Huntington's disease by drugs and (2) sensitization of cancer cells for drug/radiation-induced apoptosis by modulation of survival signals and viral transfer of apoptosis promoting genes.
...
PMID:Dissecting the pathways to death. 1118 90

A quantitative analysis of experimental data for posttranslational translocation into the endoplasmic reticulum is performed. This analysis reveals that translocation involves a single rate-limiting step, which is postulated to be the release of the signal sequence from the translocation channel. Next, the Brownian ratchet and power stroke models of translocation are compared against the data. The data sets are simultaneously fit using a least-squares criterion, and both models are found to accurately reproduce the experimental results. A likelihood-ratio test reveals that the optimal fit of the Brownian ratchet model, which contains one fewer free parameter, does not differ significantly from that of the power stroke model. Therefore, the data considered here cannot be used to reject this import mechanism. The models are further analyzed using the estimated parameters to make experimentally testable predictions.
...
PMID:The brownian ratchet and power stroke models for posttranslational protein translocation into the endoplasmic reticulum. 1186 41

Ubiquitylated protein aggregates are characteristic features of neurodegenerative disorders that are also found in acute pathological states of the brain such as stroke. Many of the proteins connected to neurodegenerative diseases play a role in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3 ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's disease. Here we show that transient focal cerebral ischemia of 1-h duration induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9. After 3 h of reperfusion, when parkin protein levels were already reduced to <40% of control, ATP levels were almost completely recovered from ischemia and we did not observe DNA fragmentation, suggesting that parkin depletion preceded development of neuronal cell death. Up-regulation of the expression of parkin has been shown to protect cells from injury induced by endoplasmic reticulum (ER) dysfunction, and this form of cellular stress is also triggered by transient cerebral ischemia. However, in contrast to observations in neuroblastoma cells, we saw no up-regulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction. Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.
...
PMID:Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease? 1241 19

Estrogenic compounds have been shown to protect neurons from a variety of toxic stimuli in vitro and in vivo and depletion of estrogen at menopause has been associated with increased risk of neurodegenerative diseases. Genistein is an isoflavone soy derivative that binds to estrogen receptors with selective estrogen receptor modulator (SERM) properties. Recent FDA recommendations of soy intake for cholesterol reduction have prompted investigation into the potentially estrogenic role of dietary soy phytochemicals in the brain. In this study, we have shown that 50nM genistein significantly reduces neuronal apoptosis in an estrogen receptor-dependent manner. The importance of apoptosis in the brain has been recognized with regard to organization of the developing brain as well as degeneration in response to disease or stroke; however, the effects of estrogenic compounds on neuronal apoptosis have not been thoroughly examined. We developed a model of apoptotic toxicity in primary cortical neurons by using the endoplasmic reticulum (ER) calcium-ATPase inhibitor, thapsigargin, to test potential anti-apoptotic effects of 17beta-estradiol and genistein. Estrogen receptor beta, but not estrogen receptor alpha, was detected in our primary neuron cultures. Thapsigargin-induced apoptosis was confirmed by loss of mitochondrial function, DNA laddering, nuclear condensation and fragmentation, and caspase activation. Both 17beta-estradiol and genistein reduced the number of apoptotic neurons and reduced the number of neurons containing active caspase-3. This effect was blocked by co-addition of ICI 182780. Our results demonstrate that genistein and 17beta-estradiol have comparable anti-apoptotic properties in primary cortical neurons and that these properties are mediated through estrogen receptors.
...
PMID:17beta-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin. 1244 Nov 88

The mode of neuronal death caused by cerebral ischemia and reperfusion appears on the continuum between the poles of catastrophic necrosis and apoptosis: ischemic neurons exhibit many biochemical hallmarks of apoptosis but remain cytologically necrotic. The position on this continuum may be modulated by the severity of the ischemic insult. The ischemia-induced neuronal death is an active process (energy dependent) and is the result of activation of cascades of detrimental biochemical events that include perturbion of calcium homeostasis leading to increased excitotoxicity, malfunction of endoplasmic reticulum and mitochondria, elevation of oxidative stress causing DNA damage, alteration in proapoptotic gene expression, and activation of the effector cysteine proteases (caspases) and endonucleases leading to the final degradation of the genome. In spite of strong evidence showing that brain infarction can be reduced by inhibiting any one of the above biochemical events, such as targeting excitotoxicity, up-regulation of an antiapoptotic gene, or inhibition of a down-stream effector caspase, it is becoming clear that targeting a single gene or factor is not sufficient for stroke therapeutics. An effective neuroprotective therapy is likely to be a cocktail aimed at all of the above detrimental events evoked by cerebral ischemia and the success of such therapeutic intervention relies upon the complete elucidation of pathways and mechanisms of the cerebral ischemia-induced active neuronal death.
...
PMID:Molecular mechanisms of cerebral ischemia-induced neuronal death. 1245 47

The endoplasmic reticulum (ER) is emerging as a contributory component of cell death after ischemia. Since caspase-12 has been localized to the ER and is a novel signal for apoptosis, we examined the message levels and protein expression of caspase-12 after cerebral ischemia in vivo. Animals underwent permanent middle cerebral artery occlusion (MCAO) and were sacrificed 24 h after ischemia. Protein analysis revealed a significant increase in caspase-12 and a corresponding up-regulation of caspase-12 mRNA in the ischemia group compared with that in the sham group. Immunohistochemical analysis revealed diffuse positive immunostaining of caspase-12 throughout the striatum and cerebral cortex in animals that underwent ischemia, with more intense caspase-12 immunostaining in the striatum than in the cortex after ischemia. These results demonstrate that cerebral ischemia initiates an ER-based stress response that results in the transcriptional up-regulation and corresponding increased expression of caspase-12 protein, and may provide a new area for therapeutic intervention to ameliorate outcomes following stroke.
...
PMID:Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat. 1259 25

Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of antiexcitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer's, Parkinson's, and Huntington's disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.
...
PMID:Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. 1272 91

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.
...
PMID:Detailed in vitro pharmacological analysis of FK506-induced neuroprotection. 1287 56


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---