Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 14-3-3 protein family comprises critical regulatory molecules involved in signaling during cell division, proliferation, and apoptosis. Despite extensive study, the functions of the 14-3-3 proteins in brain remain unclear. 14-3-3gamma, a subtype of the 14-3-3 family of proteins, was thought to be brain- and neuron-specific. Using RNA arbitrarily primed PCR, we identified an upregulated cDNA fragment of the 14-3-3gamma gene in primary cultures of astrocytes. Using Northern blot analysis, we confirmed this fragment was brain-specific. In cultures of astrocytes, 14-3-3gamma genes and proteins were differentially expressed at different ages and the proteins were distributed only in the cytoplasm. These results indicated that 14-3-3gamma was not neuron-specific but also expressed in astrocytes. The function of this protein in brain is unclear. Northern and Western blot analyses demonstrated that 14-3-3gamma mRNA and protein were upregulated in cultured astrocytes in an anaerobic chamber-induced ischemia model. The induction of 14-3-3gamma proteins was neither suppressed by an MAP kinase inhibitor (U0126) nor a PI-3 kinase inhibitor (LY294002). These data indicated that induction of 14-3-3gamma might not involve PI-3 and MAP kinase-dependent pathways. Using coimmunoprecipitation, we demonstrated that endogenous 14-3-3gamma bound to c-Raf-1 and p-Raf 259. As Raf is one of the critical serine/threonine kinases controlling cell growth, differentiation, and death, the binding of 14-3-3gamma to Raf indicates the critical role of this protein in ischemia-induced apoptosis and the changes in signal transduction in astrocytes in culture.
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PMID:14-3-3gamma is upregulated by in vitro ischemia and binds to protein kinase Raf in primary cultures of astrocytes. 1273 Sep 52

The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.
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PMID:The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects. 1453 Sep 74

c-Jun N-terminal protein kinase (JNK) activation and subsequent c-Jun phosphorylation which stimulates its transcriptional activity have been well studied in cerebral ischemia. To determine whether mitogen-activated protein kinase kinase 7 (MKK7) play a role in JNK activation in response to the stress of global cerebral ischemia, we tested the activation of such a kinase by using phospho-Ser and phospho-Thr antibodies. Immunoprecipitation and Western blot analysis revealed that MKK7 was expressed at similar levels in all conditions, whereas phospho-MKK7 was highly augmented from 1 to 5 days and reached its peak at 3 days after 15 min of ischemia. Consistent with the active phase, the interaction of MLK3, ASK1 and phospho-JNK with MKK7 was increased compared with sham control, as shown by coimmunoprecipitation experiments. Moreover, MKK7 activation was markedly reduced by pretreatment of the free radical scavenging thiol antioxidant N-acetylcysteine (NAC). Together with previous studies, the late activation of MKK7 in hippocampal CA1 region may contribute to delayed cell death, and the protective effects of antioxidant against ischemia-induced injury may be partially mediated by the down-regulation of JNK signal pathway.
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PMID:Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. 1457 11

The solute carrier family 1 (SLC1) is composed of five high affinity glutamate transporters, which exhibit the properties of the previously described system XAG-, as well as two Na+-dependent neutral amino acid transporters with characteristics of the so-called "ASC" (alanine, serine and cysteine). The SLC1 family members are structurally similar, with almost identical hydropathy profiles and predicted membrane topologies. The transporters have eight transmembrane domains and a structure reminiscent of a pore loop between the seventh and eighth domains [Neuron 21 (1998) 623]. However, each of these transporters exhibits distinct functional properties. Glutamate transporters mediate transport of L-Glu, L-Asp and D-Asp, accompanied by the cotransport of 3 Na+ and one 1 H+, and the countertransport of 1 K+, whereas ASC transporters mediate Na+-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. Given the high concentrating capacity provided by the unique ion coupling pattern of glutamate transporters, they play crucial roles in protecting neurons against glutamate excitotoxicity in the central nervous system (CNS). The regulation and manipulation of their function is a critical issue in the pathogenesis and treatment of CNS disorders involving glutamate excitotoxicity. Loss of function of the glial glutamate transporter GLT1 (SLC1A2) has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), resulting in damage of adjacent motor neurons. The importance of glial glutamate transporters in protecting neurons from extracellular glutamate was further demonstrated in studies of the slc1A2 glutamate transporter knockout mouse. The findings suggest that therapeutic upregulation of GLT1 may be beneficial in a variety of pathological conditions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) but not the glial glutamate transporters may be of therapeutic interest, allowing blockage of glutamate exit from neurons due to "reversed glutamate transport" of EAAC1, which will occur during pathological conditions, such as during ischemia after a stroke.
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PMID:The glutamate and neutral amino acid transporter family: physiological and pharmacological implications. 1461 54

Grape seed proanthocyanidin extract (GSPE), a polyphenolic compound with antioxidant properties, may protect against cardiac ischemia and reperfusion injury. However, its potential toxicity at higher doses is unknown. The authors tested the effects of GSPE on reactive oxygen species (ROS) generation, cell survival, lactate dehydrogenase (LDH) release, and caspase- 3 activity using chick cardiomyocytes incubated with GSPE at 5, 10, 50, 100, or 500 micrograms/mL in medium for 8 h. Exposure to increasing concentrations of GSPE (100 or 500 micrograms/mL) resulted in an increase in ROS generation and cell death as measured by propidium iodide uptake and LDH release. Caspase-3 activity was significantly increased fourfold in cells exposed to GSPE 500 micrograms/ mL compared to controls; this was abolished by the selective caspase-3 inhibitor Ac-Asp-Gln-Thr-Asp-H (50 microM), which also significantly reduced the cell death resulting from GSPE (500 micrograms/mL). The antioxidant N-acetylcysteine (NAC, 100 microM) reduced cell death induced by GSPE (500 micrograms/mL) but failed to attenuate caspase-3 activation. Collectively, the authors conclude that higher doses of GSPE could cause apoptotic cell injury via effector caspase-3 activation and subsequent induction of ROS generation. Consumers may take higher doses of dietary supplements in the belief that natural herbs have no major side effects. This study demonstrates that dosages of GSPE should be optimized to avoid potential harmful pro-oxidant effects.
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PMID:Grape seed proanthocyanidins induce pro-oxidant toxicity in cardiomyocytes. 1473 30

The search for an effective treatment for global ischemia following cardiac arrest has proved to be very difficult. However, studies by Uchino et al. show that the immunosuppressant cyclosporin A (CsA), when administered in such a way that the drug can bypass the blood brain barrier (BBB), dramatically reduces ischemic damage in rat forebrain preparations. An alternative immunosuppressant, FK506, is apparently less efficacious. Both CsA and FK506 are specific inhibitors of immunophilins, (CsA inhibits cyclophilins, FK506 inhibits FKBPs), and of calcineurin, a type 2B Ser/Thr phosphatase that is abundant in the central nervous system. The superiority of CsA may be partly attributable to its selective amelioration of mitochondrial damage, as assayed in vivo and in vitro. Our results suggest that pathways involving calcineurin and cyclophilins, particularly mitochondrial cyclophilin D, play pivotal roles in the development of ischemic brain damage. The present findings may inform the search for new drugs in the treatment of global ischemic damage to the brain, and in other organs.
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PMID:Calcineurin and cyclophilin D are differential targets of neuroprotection by immunosuppressants CsA and FK506 in ischemic brain damage. 1475 16

Mitogen-activated protein kinases are serine-threonine protein kinases that are involved in several processes important to cardiac surgery such as vascular permeability, cytokine production, vasomotor function, and reperfusion injury. Mitogen-activated protein kinases are expressed in multiple cell types including cardiomyocytes, vascular endothelial cells, and vascular smooth muscle cells. Mitogen-activated protein kinases function in cellular signal transduction cascades and are activated by a diverse range of stimuli including ischemia, shear stress, and vasoactive agents. Three major mitogen-activated protein kinase families were identified as the extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases, and p38 kinases. Extensive investigation has established roles for extracellular signal-regulated kinases, c-Jun NH(2)-terminal protein kinases, and p38 kinases in cardiovascular signal transduction pathways. Activity of these signal cascades may contribute to the increased pulmonary vascular permeability and myocardial reperfusion injury observed after cardiac surgery with cardioplegia and cardiopulmonary bypass. Recent findings from our laboratory suggest that alterations in the activity of myocardial extracellular signal-regulated kinase pathways occur as a result of cardioplegia-cardiopulmonary bypass in humans. In addition, these differences in extracellular signal-regulated kinase activity were shown to mediate coronary microcirculatory dysfunction associated with cardioplegia-cardiopulmonary bypass. The resulting deficit in coronary microcirculatory regulation may potentially lead to detrimental effects on organ perfusion and function. As mitogen-activated protein kinase pathways are further characterized, our potential to develop methods to prevent morbidity associated with cardiac surgery and cardiopulmonary bypass may be greatly improved.
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PMID:Mitogen-activated protein kinase pathways and cardiac surgery. 1500 10

Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase's substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations such as when the membrane undergoes mechanical deformation (ie, cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminates in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function. The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Given their roles in such a wide variety of disease states, protein kinases are rapidly becoming extremely attractive targets for drug discovery, probably second only to heterotrimeric G protein-coupled receptors (eg, angiotensin II). Here, we will review the reasons for this explosion in interest in inhibitors of protein kinases and will describe the process of identifying novel drugs directed against kinases. We will specifically focus on disease states for which drug development has proceeded to the point of clinical or advanced preclinical studies.
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PMID:Inhibitors of protein kinase signaling pathways: emerging therapies for cardiovascular disease. 1502 94

Cell cycle regulators such as cyclin-dependent kinases (Cdks) and their inhibitors (Ckis) have been reported to be involved in neuronal cell death (NCD) induced by a variety of insults such as ischemia, UV-irradiation, nerve growth factor (NGF)-withdrawal, and anticancer therapeutics. But their precise interactive regulation has still to be unveiled. In the present study, we focused on cell cycle regulators such as Cdk4, p21(WAF1) and p53 to clarify their regulatory mechanisms, using NCD induced by doxorubicin (D-NCD) in mouse cerebellar granule neurons as a model. Doxorubicin induced NCD in a dose-dependent manner, a typical feature of apoptosis as determined by TUNEL assay. Doxorubicin increased the protein expression of p53 in time- and dose-dependent manners. The protein expression of p21(WAF1), a Cki of Cdk4, was stimulated by doxorubicin at low concentrations, but it disappeared at high concentrations. Doxorubicin activated the kinase activity of Cdk4 without the enhancement of Cdk4 protein. 3-Amino-9-thio(10H)-acridone (3-ATA), the specific inhibitor of Cdk4, prevented D-NCD in a dose-dependent manner. Wortmannin, an inhibitor of ATM (ataxia telangiectasia, mutated) that has high homology with the phosphatidyl-inositol-3-kinase (PI3K) family and has protein kinase activity for the induction of p53 with specificity for serine and threonine residues, inhibited the activation of Cdk4 without the induction of p53 in D-NCD. These data suggest that (1) Cdk4 is one of the essential components for inducing NCD, that (2) p53 may prevent D-NCD through the induction of p21(WAF1) at low concentrations of doxorubicin, and that (3) Cdk4 might be activated by the same signal-molecules, like ATM, that are necessary for the activation of p53 in D-NCD.
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PMID:Roles of cyclin-dependent kinase 4 and p53 in neuronal cell death induced by doxorubicin on cerebellar granule neurons in mouse. 1524 44

The early detection and appropriate treatment of brain ischemia is of paramount importance. The interstitial concentrations of neurotransmitter amino acids are often used as an index of neuronal injury. However, monitoring of non-neurotransmitter amino acids may be equally important. We have studied the behavior of 10 amino acids during K(+)-induced spreading depression (application of 70 mM KCl during 40 min) and global forebrain ischemia (two-vessel occlusion with hypotension during 20 min). The concentrations of glutamate, aspartate, taurine, GABA, glycine, and alanine, measured in the rat striatum by microdialysis, increased during both ischemia and spreading depression, whereas glutamine concentrations decreased in both cases. Only ischemia, but not spreading depression, led to enhanced release of serine, threonine, and asparagine. We thus conclude that an elevation in the interstitial concentrations of non-neurotransmitter amino acids is specific to deep ischemic injury to nervous tissue. We propose the monitoring of serine, asparagine, and threonine, together with excitatory amino acids, as an index of the degree of ischemic brain injury.
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PMID:Interstitial concentrations of amino acids in the rat striatum during global forebrain ischemia and potassium-evoked spreading depression. 1526 Jan 29


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