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

The A1/A2 adenosine agonist 5'-(N-ethylcarboxamido) adenosine (NECA) limits infarction when administered at reperfusion. The present study investigated whether p70S6 kinase is involved in this anti-infarct effect. Adult rat ventricular myocytes were isolated and incubated in tetramethylrhodamine ethyl ester (TMRE, 100 nM), which causes cells to fluoresce in proportion to their mitochondrial membrane potential. A reduction in TMRE fluorescence serves as an indicator of collapse of the mitochondrial transmembrane potential. Cells were subjected to H2O2 (200 microM), which like ischemia induces loss of mitochondrial membrane potential. Fluorescence was measured every 3 min and to facilitate quantification membrane potential was arbitrarily considered as collapsed when fluorescence reached less than 60% of the starting value. Adding NECA (1 mM) to the cells prolonged the time to fluorescence loss (48.0+/-3.2 min in the NECA group versus 29.5+/-2.2 min in untreated cells, P<0.001) and the mTOR/p70S6 kinase inhibitor rapamycin (5 nM) abolished this protection (31.3+/-3.4 min). Since cyclosporine A offered similar protection, mitochondrial permeability transition pore formation is a likely cause of the H2O2-induced loss of potential. The direct GSK-3beta inhibitor SB216763 (3 microM) also prolonged the time to fluorescence loss (49.2+/-2.1 min, P<0.001 versus control), and its protection could not be blocked by rapamycin (42.2+/-2.3 min, P<0.001 versus control). NECA treatment (100 nM) of intact isolated rabbit hearts at reperfusion after 30 min of regional ischemia decreased infarct size from 33.0+/-3.8% of the risk zone in control hearts to 11.8+/-2.0% (P<0.001), and rapamycin blocked this NECA-induced protection (38.3+/-3.7%). A comparable protective effect was seen for SB216763 (1 microM) with infarct size reduction to 13.5+/-2.3% (P<0.001). NECA treatment (200 nM) of intact rabbit hearts at reperfusion also resulted in phosphorylation of p70S6 kinase more than that seen in untreated hearts. This NECA-induced phosphorylation was blocked by rapamycin. These experiments reveal a critical role for p70S6 kinase in the signaling pathway of NECA's cardioprotection at reperfusion.
 ...
PMID:NECA at reperfusion limits infarction and inhibits formation of the mitochondrial permeability transition pore by activating p70S6 kinase. 1660 38

Pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of transcription factor nuclear factor kappa-B (NF-kappaB), has been reported to reduce inflammation and apoptosis. Because PDTC was recently found to protect in various models of adult brain ischemia with a wide therapeutic time window, we tested the effect of PDTC in a rodent model of neonatal hypoxia-ischemia (HI) brain injury. T2-weighed magnetic resonance imaging (T2-MRI) 7 days after the insult showed that a single PDTC (50 mg/kg) injection 2.5 h after the HI reduced the mean brain infarct size by 59%. PDTC reduced the HI-induced dephosphorylation of Akt and glycogen synthase kinase-3beta (GSK-3beta), expression of cleaved caspase-3, and nuclear translocation of NF-kappaB in the neonatal brain. PDTC targeted directly neurons, as PDTC reduced hypoxia-reoxygenation-induced cell death in pure hippocampal neuronal cultures. It is suggested that in addition to the previously indicated NF-kappaB inhibition as a protective mechanism of PDTC treatment, PDTC may reduce HI-induced brain injury at least partially by acting as an antioxidant, which reduces the Akt-GSK-3beta pathway of apoptotic cell death. The clinically approved PDTC and its analogues may be beneficial after HI insults with a reasonable time window.
 ...
PMID:Antioxidant pyrrolidine dithiocarbamate activates Akt-GSK signaling and is neuroprotective in neonatal hypoxia-ischemia. 1667 15

Uncontrolled calcium stress has been linked causally to a variety of neurodegenerative diseases, including ischemia, excitotoxicity and Alzheimer's disease. Thapsigargin, which increases [Ca2+]i, induces apoptotic cell death (chromatin condensation and DNA fragmentation) accompanied by caspase-3 activation in PC12 cells. We examined whether GSK-3 is involved in thapsigargin-induced cell death by using GSK-3 inhibitors in PC12 cells. Cells treated with 0.1 microM thapsigargin for 24h shrank. The injured cells underwent chromatin condensation and nuclear fragmentation, indicating apoptotic cell death. We assayed the effects of selective GSK-3 inhibitors, SB216763, azakenpaullone and alsteropaullone on thapsigargin-induced apoptosis. These inhibitors completely protected cells from thapsigargin-induced apoptosis. Alsterpaullone did not reduce the GRP78 protein expression induced by thapsigargin, suggesting that GSK-3 activation is not involved in induction of GRP78. In addition, GSK-3 inhibitors inhibited caspase-3 activation accompanied by thapsigargin-induced apoptosis. We showed in this report that thapsigargin-induced apoptosis is prevented by GSK-3 inhibitors, suggesting that thapsigargin induces caspase-dependent apoptosis mediated through GSK-3 activation in PC12 cells.
 ...
PMID:Thapsigargin-induced apoptosis was prevented by glycogen synthase kinase-3 inhibitors in PC12 cells. 1698 47

The mechanisms underlying the age-dependent reversal of female cardioprotection are poorly understood and complicated by findings that estrogen replacement is ineffective at reducing cardiovascular mortality in postmenopausal women. Although several protective signals have been identified in young animals, including PKC and Akt, how these signals are affected by age, estrogen deficiency, and ischemia-reperfusion (I/R) remains unknown. To determine the independent and combined effects of age and estrogen deficiency on I/R injury and downstream PKC-Akt signaling, adult and aged female F344 rats (n = 12/age) with ovaries intact or ovariectomy (Ovx) were subjected to I/R using Langendorff perfusion (31-min global-ischemia). Changes in cytosolic (s), nuclear (n), mitochondrial (m) PKC (delta, epsilon) levels, and changes in total Akt and mGSK-3beta phosphorylation after I/R were assessed by Western blot analysis. Senescence increased infarct size 50% in ovary-intact females (P < 0.05), whereas no differences in LV functional recovery or estradiol levels were observed. Ovx reduced functional recovery to a greater extent in aged compared with adult rats (P < 0.05). In aged (vs. adult), levels of m- and nPKC(-delta, -epsilon) were markedly decreased, whereas mGSK3beta levels were increased (P < 0.05). Ovx led to greater levels of sPKC(-delta, -epsilon) independent of age (P < 0.05). I/R reduced p-Akt(Ser473) levels by 57% and increased mGSK-3beta accumulation 1.77-fold (P < 0.05) in aged, ovary-intact females. These data suggest, for the first time, that estrogen alone cannot protect the aged female myocardium from I/R damage and that age- and estrogen-dependent alterations in PKC, Akt, and GSK-3beta signaling may contribute to loss of ischemic tolerance.
 ...
PMID:Estrogen deficiency decreases ischemic tolerance in the aged rat heart: Roles of PKCdelta, PKCepsilon, Akt, and GSK3beta. 1700 61

Brief periods of ischemia and reperfusion that precede sustained ischemia lead to a reduction in myocardial infarct size. This phenomenon, known as ischemic preconditioning, is mediated by signaling pathway(s) that are yet to be fully defined. 3'-Phosphoinositide-dependent kinase-1 (PDK1) has been implicated in numerous cellular processes. However, the involvement of PDK1 in preconditioning has yet to be elucidated. Studying PDK1 is not as straightforward as it is for the majority of kinases, due to the lack of a specific inhibitor of PDK1. Therefore, we have taken advantage of PDK1 hypomorphic mutant mice with reduced expression of PDK1 to study the role of PDK1 in preconditioning. Whole heart and single cell models of preconditioning demonstrated that the hearts and cardiac cells from PDK1 hypomorphic mice could not be preconditioned. The cardioprotective effect of PDK1 was not related to the effect that preconditioning has on sarcolemmal membrane action potential as revealed by di-8-ANEPPS, a sarcolemmal-potential sensitive dye, and laser confocal microscopy. In contrast, experiments with JC-1, a mitochondrial membrane potential-sensitive dye, has demonstrated that intact PDK1 levels were required for preconditioning-mediated regulation of mitochondrial membrane potential. Western blotting combined with functional experiments have shown that intact PDK1 levels were required for preconditioning-induced phosphorylation of protein kinase B (PKB), glycogen synthase kinase-3beta (GSK-3beta), and cardioprotection. We conclude that PDK1 mediates preconditioning in the heart by regulating activating PKB-GSK-3beta to regulate mitochondrial but not sarcolemmal membrane potential. 3'Phosphoinositide-dependent kinase-1 (PDK1) is essential for ischemic preconditioning of the myocardium.
 ...
PMID:3'Phosphoinositide-dependent kinase-1 is essential for ischemic preconditioning of the myocardium. 1707 84

Pyrrolidine dithiocarbamate (PDTC) is a clinically tolerated inhibitor of nuclear factor-kappaB (NF-kappaB), antioxidant and antiinflammatory agent, which provides protection in brain ischemia models. In neonatal hypoxia-ischemia model, PDTC activates Akt and reduces activation of glycogen synthase kinase 3beta (GSK-3beta). Because chronic inflammation, oxidative stress, and increased GSK-3beta activity are features of Alzheimer's disease (AD) pathology, we tested whether PDTC reduces brain pathology and improves cognitive function in a transgenic animal model of AD. A 7 month oral treatment with PDTC prevented the decline in cognition in AD mice without altering beta-amyloid burden or gliosis. Moreover, marked oxidative stress and activation of NF-kappaB were not part of the brain pathology. Instead, the phosphorylated form of GSK-3beta was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3beta. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric Abeta and reduced tau phosphorylation in the hippocampus of AD mice. Finally, astrocytic glutamate transporter GLT-1, known to be regulated by Akt pathway, was decreased in the transgenic AD mice but upregulated back to the wild-type levels by PDTC treatment. Thus, PDTC may improve spatial learning in AD by interfering with Akt-GSK pathway both in neurons and astrocytes. Because PDTC is capable of transferring external Cu2+ into a cell, and, in turn, Cu2+ is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu2+-activated Akt pathway.
 ...
PMID:Pyrrolidine dithiocarbamate activates Akt and improves spatial learning in APP/PS1 mice without affecting beta-amyloid burden. 1740 35

Both glycogen synthase kinase 3beta (GSK3beta) and the ATP-dependant potassium channel (K(ATP)) mediate opioid-induced cardioprotection (OIC). However, whether direct K(ATP) channel openers induce cardioprotection prior to reperfusion and their signaling cascade position with respect to GSK3beta inhibition is unknown. Therefore, we investigated the role of K(ATP) channel opening at reperfusion in OIC, and the interaction between the GSK signaling axis and K(ATP) channels in cardioprotection.Male Sprague-Dawley rats underwent 30 minutes ischemia with 2 hours of reperfusion and infarct size was determined. Rats given the nonselective opioid agonist, morphine (0.3 mg/kg), or the selective delta opioid agonist, BW373U86 (1.0 mg/kg), 5 minutes prior to reperfusion reduced infarct size (40.3+/-1.6*, 39.7+/-1.9* versus 60.0+/-1.1%, respectively, * P<0.001%). This protection was abrogated with prior administration of the putative sarcolemmal K(ATP) antagonist, HMR-1098 (6 mg/kg), or the putative mitochondrial K(ATP) antagonist, 5-HD (10 mg/kg). The putative sK(ATP) channel opener, P-1075 (1microg/kg) or the putative mK(ATP) channel opener, BMS-191095 (1 mg/kg) given 5 minutes prior to reperfusion also reduced infarct size (41.8+/-2.4*, 43.4+/-1.4*) and protection was abrogated by prior administration of the PI3k inhibitor wortmannin (60.0+/-1.7, 64.0+/-2.6%, respectively, * P<0.001). Cardioprotection afforded by the GSK inhibitor SB216763 (0.6 mg/kg) given 5 minutes prior to reperfusion was also partially blocked by either HMR or 5-HD and completely blocked when HMR and 5-HD were given in combination (40.8+/-1.6*, 50.4+/-1.6;; 49.4+/-1.7;, 61.6+/-1.6%, respectively, * or ; P<0.001). These data indicate that both the sK(ATP) and mK(ATP) channel are involved in acute OIC and the GSK signaling axis regulates cardioprotection via K(ATP) channel opening.
 ...
PMID:GSK3beta inhibition and K(ATP) channel opening mediate acute opioid-induced cardioprotection at reperfusion. 1745 Mar 14

Ischemic preconditioning renders the heart resistant to infarction from ischemia/reperfusion. Over the past two decades a great deal has been learned about preconditioning's mechanism. Adenosine, bradykinin, and opioids act in parallel to trigger the preconditioned state and do so by activating PKC. While adenosine couples directly to PKC through the phospholipases, bradykinin and opioids do so through a complex pathway that includes in order: phosphatidylinositol 3-kinase (PI3-kinase), Akt, nitric oxide synthase, guanylyl cyclase, PKG, opening of mitochondrial K(ATP) channels, and activation of PKC by redox signaling. There are even differences between the opioid and bradykinin coupling as the former activates PI3-kinase through transactivation of the epidermal growth factor receptor while the latter has an unknown coupling mechanism. Protection stems from inhibition of formation of mitochondrial permeability transition pores early in reperfusion through activation of the survival kinases, Akt and ERK. These kinases are activated as a result of PKC somehow promoting signaling from adenosine A(2) receptors early in reperfusion. The survival kinases are thought to inhibit pore formation by phosphorylating GSK-3beta. The reperfused heart requires the support of the protective signals for only about an hour after which the ischemic injury is repaired and the signals are no longer needed.
 ...
PMID:Signaling pathways in ischemic preconditioning. 1751 69

There is a close association between hyperglycemia and increased risk of mortality after acute myocardial infarction (AMI). However, whether acute hyperglycemia exacerbates myocardial ischemia/reperfusion (MI/R) injury remains unclear. We observed the effects of acute hyperglycemia on MI/R injury and on the cardioprotective effect of glucose-insulin-potassium (GIK). Male rats were subjected to 30 min of myocardial ischemia and 6 h of reperfusion. Rats were randomly received one of the following treatments (at 4 ml.kg(-1).h(-1) iv): Vehicle, GIK (GIK during reperfusion; glucose: 200g/l, insulin: 60 U/l, KCL: 60 mmol/l), HG (high glucose during ischemia; glucose:500 g/l), GIK + HG (HG during I and GIK during R) or GIK + wortmannin (GIK during R and wortmannin 15 min before R). Blood glucose, plasma insulin concentration and left ventricular pressure (LVP) were monitored throughout the experiments. Hyperglycemia during ischemia not only significantly increased myocardial apoptosis (23.6 +/- 1.7% vs. 18.8 +/- 1.4%, P < 0.05 vs. vehicle), increased infarct size (IS) (45.6 +/- 3.0% vs. 37.6 +/- 2.0%, P < 0.05 vs. vehicle), decreased Akt and GSK-3beta phosphorylations (0.5 +/- 0.2 and 0.6 +/- 0.1% fold of vehicle, respectively, P < 0.05 vs. vehicle) following MI/R, but almost completely blocked the cardioprotective effect afforded by GIK, as evidenced by significantly increased apoptotic index (19.1 +/- 2.0 vs. 10.3 +/- 1.2%, P < 0.01 vs. GIK), increased myocardial IS (39.2 +/- 2.8 vs. 27.2 +/- 2.1%, P < 0.01 vs. GIK), decreased Akt phosphorylation (1.1 +/- 0.1 vs. 1.7 +/- 0.2%, P < 0.01 vs. GIK) and GSK-3beta phosphorylation (1.4 +/- 0.2 vs. 2.3 +/- 0.2%, P < 0.05 vs. GIK). Hyperglycemia significantly exacerbates MI/R injury and blocks the cardioprotective effect afforded by GIK, which is, at least in part, due to hyperglycemia-induced decrease of myocardial Akt activation.
 ...
PMID:Acute hyperglycemia exacerbates myocardial ischemia/reperfusion injury and blunts cardioprotective effect of GIK. 1751 83

Injury due to ischemia and reperfusion (I/R) causes an inflammatory response due to oxidative damage, which triggers stress signaling processes that eventually result in cell apoptosis and death. There are a number of chemical mediators and pathways involved in the I/R response. Thus from a therapeutic point of view, it would be most efficient to focus on the most important active mediators of inflammation and apoptosis and manipulate these to improve cell function and survival. Over the last few years, the Akt pathway has become such a target due to its role as a signaling pathway where modulation of substrates prevents apoptosis. The involvement of Akt in the cell survival pathway is a complex process that requires an extensive machinery of intracellular events. The aim of this review is to organize these findings to better understand Akt's mechanism of protection and how it modulates specific substrates in the heart, liver, and brain affected by I/R. Akt functions as a survival kinase by phosphorylating a number of apoptosis-regulatory molecules such as BAD, forkhead transcription factors, caspase 9, and IkappaB kinase to influence NF-kappaB and GSK-3beta. Akt's broad scope places it at the center of multiple critical steps, allowing it to play a protective role in various organs affected by I/R injury. From a practical and clinical application point of view, the upregulation of Akt could potentially be used alone or in combination with other therapeutic strategies to treat I/R injury and thus to improve cell and organ function. The means by which Akt manipulation should occur is not well defined, and it is possible that pharmacologically, such as in the case of selectin inhibitors in our experience or through well-orchestrated gene therapy, this important molecule can be better upregulated and therefore can offer effective protection. The short- and long-term effects with Akt upregulation have not been well studied so far. Early concerns about cancer or cardiac damage potential are inconclusive. Thus, more experiments are required in this particular area of research.
 ...
PMID:Akt in ischemia and reperfusion. 1761 95


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