UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that endothelial nitric oxide (NO) synthase (eNOS)-derived NO is an important signaling molecule in ischemia-reperfusion (I-R) injury. Deficiency of eNOS-derived NO has been shown to exacerbate injury in hepatic and myocardial models of I-R. We hypothesized that transgenic overexpression of eNOS (eNOS-TG) would reduce hepatic I-R injury. We subjected two strains of eNOS-TG mice to 45 min of hepatic ischemia and 5 h of reperfusion. Both strains were protected from hepatic I-R injury compared with wild-type littermates. Because the mechanism for this protection is still unclear, additional studies were performed by using inhibitors and activators of both soluble guanylyl cyclase (sGC) and heme oxygenase-1 (HO-1) enzymes. Blocking sGC with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and HO-1 with zinc (III) deuteroporphyrin IX-2,4-bisethyleneglycol (ZnDPBG) in wild-type mice increased hepatic I-R injury, whereas pharmacologically activating these enzymes significantly attenuated I-R injury in wild-type mice. Interestingly, ODQ abolished the protective effects of eNOS overexpression, whereas ZnDPBG had no effect. These results suggest that hepatic protection in eNOS-TG mice may be mediated in part by NO signaling via the sGC-cGMP pathway and is independent of HO-1 signal transduction pathways.
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PMID:Genetic overexpression of eNOS attenuates hepatic ischemia-reperfusion injury. 1687 50

Omi/HtrA2 is a pro-apoptotic mitochondrial serine protease involved in both forms of apoptosis, caspase-dependent as well as caspase-independent cell death. However, the impact of Omi/HtrA2 in the apoptotic cell machinery that takes place in vivo under pathological conditions such as cerebral ischemia remains unknown. The present study was monitored in order to examine whether Omi/HtrA2 plays a decisive role in apoptosis observed after focal cerebral ischemia in rats. Male adult rats were subjected to 90min of focal cerebral ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, prior reperfusion. Focal cerebral ischemia/reperfusion induced a mitochondrial up-regulation of Omi/HtrA2 and significantly increased cytosolic accumulation of Omi/HtrA2. Furthermore, ischemia led to activation of caspase-3 and degradation X-linked inhibitor of apoptosis protein (XIAP). Treatment of animals prior ischemia with ucf-101, the specific inhibitor of Omi/HtrA2, was able to (1) reduce the number of TUNEL-positive cells, to (2) attenuate the XIAP-breakdown and to (3) reduce the infarct size. This study shows for the first time that focal cerebral ischemia in rats results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it participates in neuronal cell death. Blocking the proteolytic activity of Omi/HtrA2 with specific inhibitors, such as the ucf-101, could be a novel way to afford neuroprotection and minimize cellular damage in cerebral ischemia/reperfusion.
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PMID:The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion. 1697 42

Blocking either the Na(+) channel or the Na(+)/H(+) exchanger (NHE) has been shown to reduce Na(+) and Ca(2+) overload during myocardial ischemia and reperfusion, respectively, and to improve post-ischemic contractile recovery. The effect of combined blockade of both Na(+) influx routes on ionic homeostasis is unknown and was tested in this study. [Na(+)](i), pH(i) and energy-related phosphates were measured using simultaneous (23)Na- and (31)P-NMR spectroscopy in isolated rat hearts. Eniporide (3 muM) and/or lidocaine (200 muM) were administered during 5 min prior to 40 min of global ischemia and 40 min of drug free reperfusion to block the NHE and the Na(+) channel, respectively. Lidocaine reduced the rise in [Na(+)](i) during the first 10 min of ischemia, followed by a rise with a rate similar to the one found in untreated hearts. Eniporide reduced the ischemic Na(+) influx during the entire ischemic period. Administration of both drugs resulted in a summation of the effects found in the lidocaine and eniporide groups. Contractile recovery and infarct size were significantly improved in hearts treated with both drugs, although not significantly different from hearts treated with either one of them.
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PMID:Combined blockade of the Na+ channel and the Na+/H+ exchanger virtually prevents ischemic Na+ overload in rat hearts. 1710 5

Protein kinase A (PKA) activation has been implicated in early-phase ischemic preconditioning. We recently found that during ischemia PKA activation causes inactivation of cytochrome-c oxidase (CcO) and contributes to myocardial damage due to ischemia-reperfusion. It may be that beta-adrenergic stimulation during ischemia via endogenous catecholamine release activates PKA. Thus beta-adrenergic stimulation may mediate both myocardial protection and damage during ischemia. The present studies were designed to determine the role of the beta(1)-adrenergic receptor (beta(1)-AR) in myocardial ischemic damage and ischemic preconditioning. Langendorff-perfused rabbit hearts underwent 30-min ischemia by anterior coronary artery ligation followed by 2-h reperfusion. Occlusion-reperfusion damage was evaluated by delineating the nonperfused volume of myocardium at risk and volume of myocardial necrosis after 2-h reperfusion. In some hearts ischemic preconditioning was accomplished by two 5-min episodes of global low-flow ischemia separated by 10 min before coronary occlusion-reperfusion. Orthogonal electrocardiograms were recorded, and coronary flow was monitored by a drip count. Three hearts from each experimental group were used to determine mitochondrial CcO and aconitase activities. Two-hour reperfusion after occlusion caused an additional decrease in CcO activity vs. that after 30-min occlusion alone. Blocking the beta(1)-AR during occlusion-reperfusion reversed CcO activity depression and preserved myocardium at risk for necrosis. Similarly, mitochondrial aconitase activity exhibited a parallel response after occlusion-reperfusion as well as for the other interventions. Furthermore, classic ischemic preconditioning had no effect on CcO depression. However, blocking the beta(1)-AR during preconditioning eliminated the cardioprotection. If the beta(1)-AR was blocked after preconditioning, the myocardium was preserved. Interestingly, in both of the latter cases the depression in CcO activity was reversed. Thus the beta(1)-AR plays a dual role in myocardial ischemic damage. Our findings may lead to therapeutic strategies for preserving myocardium at risk for infarction, especially in coronary reperfusion intervention.
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PMID:beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning. 1723 52

Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.
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PMID:Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia. 1736 Jun 88

Attraction of mononuclear cells to sites of inflammation requires a close interplay of the inflammatory signal presented via chemokines and specific receptors on effector cells. First studies on acute renal transplant rejection demonstrated the involvement of CC-chemokines, such as RANTES, MIP-1alpha, MIP-1beta and MCP-1, as well as CXC-chemokines such as IL-8 and IP-10, correlating with expression of the corresponding chemokine receptors, CCR1, CCR5 and CCR2 as well as CXCR3. Since then, the pathophysiologic relevance has been extended to chronic allograft nephropathy and transplant glomerulopathy. Chemokine expression can be triggered by different stimuli, e.g. brain death, ischemia, HLA-mismatch and infection. Furthermore, anti-inflammatory chemokines have been identified. Chemokine receptor 7, e.g. enhances homing of lymphocytes to lymphatic tissues and the Duffy antigen receptor, DARC, a non-specific receptor that binds and inactivates different chemokines. While measurement of chemokine expression in clinical transplantation may facilitate the differential diagnosis of allograft dysfunction, knowledge of the chemokine network has also widened the understanding of transplant rejection and opened novel therapeutic approaches. Observations from humans with mutations of the chemokine network as well as transplantation of animals with targeted deletions in this system suggest that manipulations of chemokine signalling may improve the success rates of transplantation. Blocking chemokines unselectively with Met-RANTES or specifically with small molecule inhibitors of various chemokine receptors has lead to improved outcome in animal models. Currently, first human trials are under way to investigate drugs that stimulate lymphocyte homing. Inhibitors of CCR1 and CCR5 are being tested for other human diseases and may eventually be available in transplantation. Nonetheless, chemokine blockade my rather serve as an adjunct in the management of transplant recipients than a new "magic bullet".
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PMID:Chemokines and chemokine receptors in renal transplantation--from bench to bedside. 1744 76

Extracellular ATP is elevated by transient ischemia and is a potent signaling molecule in the central nervous system. ATP promotes neuron survival from serum starvation by activating P2Y purinergic receptors. ATP also activates IL-6 production and phosphorylation of Stat3 that promotes neuron survival. The transcription cofactor LMO4 is a positive mediator of IL-6/Stat3 signaling. Here, we found that LMO4 and the pro-survival factor cIAP2 (cellular inhibitor of apoptosis protein 2) are rapidly upregulated in neurons exposed to elevated extracellular ATP. Blocking LMO4 upregulation using siRNA in F11 cells blunted cIAP2 upregulation and abolished the early protective effect of ATP. Similar results were obtained using primary cortical neurons from LMO4 null mice, suggesting that LMO4 is required for ATP to protect neurons from hypoxia-induced apoptosis. Whereas increased Stat3 phosphorylation occurs after LMO4 and cIAP2 induction, the rapid upregulated phosphorylation of ERK and CREB may account for increased LMO4 and cIAP2 by ATP. ATP signaling through ERK and CREB activated LMO4 promoters and ERK activation increased LMO4 protein stability in F11 cells. Taken together, our studies reveal that LMO4 is a rapidly induced downstream effector of ATP signaling that promotes neuron survival from hypoxia.
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PMID:Extracellular ATP-dependent upregulation of the transcription cofactor LMO4 promotes neuron survival from hypoxia. 1752 92

Shock wave lithotripsy (SWL)-induced renal damage appears to be multifactorial. Recent data indicated that the mechanism of renal tissue damage secondary to SWL is similar to that of ischemia reperfusion injury. Nuclear factor-kappa B (NFkappaB) and its target genes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), have been demonstrated to play a very important role in a variety of cells or tissues ischemia reperfusion injuries. Thus in the present study, using an in vitro model MDCK cells, we investigated the role of NFkappaB and its target cytotoxic enzyme in shock wave-induced renal cellular damage. We also examined whether inhibition this pathway by pyrrolidine dithiocarbamate (PDTC) is contributed to alleviate SWL-caused cell damage. Suspensions of MDCK cells were placed in containers for shock wave exposure. Three groups of six containers each were examined: control group, no shock wave treatment and SWL group, which received 100 shocks at 18 kV; 3 SWL + PDTC group. PDTC were added to the suspensions before shock wave exposure. After shock wave 0, 2, 4, 6 and 8 h, respectively, the cell supernatants were detected for the level of MDA and release of LDH. At post-shock wave 8 h, cells were harvested to detect the nuclear translocation of NFkappaBp65 by immunofluorescence staining. Degradation of IkappaB-a (an inhibitor protein of NFkappaB) and expression of iNOS and COX-2 were also examined by western blotting. Our results indicated that shock wave initiated the apparent activation of NFkappaB, which in turn induced high expression of iNOS and COX-2. Blocking degradation of IkappaB-a by PDTC was contributed to decrease the expression of iNOS. And the level of MDA and the release of LDH were also significantly reduced by using PDTC. However, the degree of COX-2 expression does not differ significantly between SWL and SWL + PDTC groups. Activation of NFkappaB and subsequent expression of its target cytotoxic enzyme have been demonstrated to be a potential and crucial mechanism in SWL-induced renal cell damage. Blocking this pathway by PDTC is contributed to protect against cellular damage from shock wave.
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PMID:Pyrrolidine dithiocarbamate attenuate shock wave induced MDCK cells injury via inhibiting nuclear factor-kappa B activation. 1756 36

Platelet aggregation and secretion play a crucial role in acute coronary syndromes. In Galpha(q) knock-out mice (Galpha(q)(-/-)) platelet function is eliminated in terms of aggregation and secretion of cytokines. We investigated whether restricted platelet aggregation and secretion reduces myocardial infarct size in vivo. Thirty minute regional myocardial ischemia was followed by 24 h reperfusion (I/R) in vivo. Infarct size was determined by counterstaining. Left ventricular function was measured by ultrasound. Infarct size to area at risk ratio was significantly smaller in Galpha(q)(-/-) mice (5.6+/-1.6%) compared to wild-type (WT) mice (27.2+/-3.0%, p<0.01). Fractional shortening was improved in Galpha(q)(-/-) mice compared to WT (42.2+/-1.4% versus 30.5+/-1.4%, respectively, p<0.01). WT mice, transplanted with Galpha(q)(-/-) bone marrow showed a significant reduction in infarct size compared to control (7.8+/-2.2% versus 18.4+/-2.7%, respectively, p<0.01). Platelets of Galpha(q)(-/-) mice had an impaired aggregation and secretion phenotype. In the in vivo model of ischemia and reperfusion, beyond impaired platelet aggregation, platelet secretion plays an additional role in myocardial infarct extension. Blocking platelet aggregation in combination with secretion might be a promising supplementary therapeutic strategy in acute myocardial infarction.
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PMID:Impaired platelet function reduces myocardial infarct size in Galphaq knock-out mice in vivo. 1802 99

Recent studies suggest that besides the L-type calcium channel, two calcium channels on the endoplasmic reticulum (ER), the inositol 1,4,5-trisphosphate receptor (InsP3R) and ryanodine receptor (RyR), may play a role in the apoptotic process of renal tubular cells induced by ischemia/reperfusion (I/R) injury. We used antimycin A to induce cell I/R injury in vitro and found an elevation of the cytosolic calcium concentration and consequently apoptosis. Blocking either the L-type calcium channel with nicardipine or the InsP3R with TMB-8 can inhibit cytochrome c release, activate caspase 3 and decrease the apoptotic cell number. However, blocking the RyR with dantrolene had no effect. We further found that Ca(2+) influx through the L-type channel is needed for the opening of the InsP3R which activates a cascade of Ca(2+) release from the ER store. To test these blockers in vivo, in a rat renal I/R model, pretreatment with nicardipine and TMB-8, but not dantrolene, can protect renal function. Taken together, our results suggest that after I/R injury, Ca(2+) influx through the L-type calcium channel triggers the Ca(2+) release from the InsP3R and finally induces apoptosis. The InsP3R could be a new target for the treatment of renal I/R injury.
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PMID:Ischemia/reperfusion induce renal tubule apoptosis by inositol 1,4,5-trisphosphate receptor and L-type Ca2+ channel opening. 1818 15

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