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)

Nitric oxide (NO), applied by inhalation or released from NO donors, has been used to reduce the expression of cell adhesion molecules (CAM) and ameliorate other consequences of ischemia/reperfusion (I/R) injury. In this study, we have assessed the time frames of pretreatment and of the duration of the preconditioned state using human umbilical vein endothelial cells (HUVECs) and the NO donor, SNAP, in combination with cysteine. The induction of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and E-selectin by the cytokines TNFalpha and IL-1beta, and by bacterial lipopolysaccharide (LPS) was reduced by SNAP/Cys preincubation (30 min, 1mM) to less than 10% of controls. This refractory state in respect to cytokine-induced CAM expression persisted for 6h after washout of the NO donor in the combination TNFalpha/VCAM, and a partial block was still observed after 8h. The effect was not mediated by the cGMP pathway, as was demonstrated by using the inhibitor of guanylyl cyclase, ODQ, and the cGMP analogue, 8-Br-cGMP. The TNFalpha-induced expression of CAM was exclusively dependent on the transcription factor NFkappaB since the inhibitor of NFkappaB activation, BAY 11-7082, completely blocked the induction. The TNFalpha-induced phosphorylation and degradation of the inhibitor of kappaB (IkappaBalpha) was suppressed for up to 8h after SNAP/Cys pretreatment. The inhibitory S-nitrosation of IkappaB kinase (IKKbeta), as assessed by the biotin-switch-procedure and immunoprecipitation, was only detectable immediately after SNAP/Cys incubation but not at later time points. In summary, a short preincubation of HUVEC with SNAP/Cys results in a persistent suppression of NFkappaB-dependent expression of CAM. The stabilization of IkappaBalpha over the same time span may be causally related to this effect.
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PMID:Nitric oxide donor-induced persistent inhibition of cell adhesion protein expression and NFkappaB activation in endothelial cells. 1650 56

The 70-kDa heat shock protein (Hsp70) is involved in protecting the brain from a variety of insults including stroke. Although the mechanism has been largely considered to be because of its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory responses. To explore how and whether Hsp70 regulate immune responses in brain ischemia, mice overexpressing Hsp70 (Hsp Tg) were subjected to 2 h middle cerebral artery occlusion, followed by 24 h reperfusion. Parallel experiments were performed using a brain inflammation model. Hsp Tg microglia cocultured with astrocytes were used to evaluate the direct effects of Hsp70 on cytotoxicity of microglia. Compared with wild-type (Wt) littermates, Hsp Tg mice showed decreased infarct size and improved neurological deficits. The number of activated microglia/macrophages were also reduced in ischemic brains of Hsp Tg mice. Similar observations were made in a model of brain inflammation that does not result in brain cell death. Overexpression of Hsp70 in microglia completely prevented microglia-induced cytotoxicity to astrocytes. Activation of the inflammatory transcription factor, nuclear factor-kappaB (NF-kappaB) was inhibited significantly in Hsp Tg mice and microglia. This was associated with decreased phosphorylation of NF-kappaB inhibitor protein, IkappaBalpha, and decreased expression of several NFkappaB-regulated genes. Co-immunoprecipitation studies revealed an interaction of Hsp70 with NF-kappaB and IkappaBalpha, but not with IkappaB kinase, IKKgamma, suggesting that Hsp70 binds to the NF-kappaB:IkappaB complex preventing IkappaB phosphorylation by IKK. The findings of the present work establish an anti-inflammatory role for Hsp70 in the context of brain ischemia as a novel mechanism of protection.
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PMID:Anti-inflammatory effects of the 70 kDa heat shock protein in experimental stroke. 1747 52

Leukotriene (LT) C4 (LTC4) synthesis enzymes including LTC4 synthase (LTC4S), microsomal glutathione S-transferase (MGST) 2 and MGST3 can all conjugate LTA4 and reduced glutathione (GSH) to form LTC4, which is related to hepatic ischemia/reperfusion (I/R) injury. The relationship between nitric oxide (NO) and cysteinyl LTs has been shown in previous studies. However, the mechanisms of NO action on gene expression of LTC4 synthesis enzymes are still largely unclear during hepatic I/R. Adult male Sprague-Dawley rats were divided into 5 groups: a sham group (control), an I/R group, and sodium nitroprusside (SNP, 2.5, 5 and 10 microg/kg/min)+I/R groups. Livers were subjected to 60 min of partial hepatic ischemia followed by 5 h of reperfusion, saline or SNP (2.5, 5 and 10 microg/kg/min) administered intravenously. The mRNA levels of LTC4 synthesis enzymes, inducible NO synthase (iNOS) and endothelial No synthase (eNOS) in rat liver tissue were examined by RT-PCR; the protein expressions of NF-kappaB p65, p50 and IkappaBalpha in liver cell lysates and nuclear extracts were detected by Western blot analysis, and serum NO2. levels were also evaluated. Serum NO2. levels, the protein expressions of NF-kappaB p65 and p50 in the nucleus extract, and hepatic mRNA expressions of LTC4S and iNOS were decreased while hepatic mRNA of eNOS was increased in the SNP (5 and 10 microg/kg/min)+I/R groups when compared with those in the I/R group. SNP (2.5 microg/kg/min) promoted the mRNA expressions of both MGST2 and MGST3, whereas SNP (10 microg/kg/min) increased MGST2 mRNA but decreased MGST3 mRNA compared to those in I/R group. Compared with control, the mRNA expression of MGST2 and MGST3 were elevated in SNP (2.5 microg/kg/min)+I/R group, MGST3 mRNA was significantly declined in the SNP (5 and 10 microg/kg/min)+I/R groups. Immunohistochemistry staining revealed that I/R liver exhibited strong cytoplasmic and nuclear staining for NF-kappaB p65, but the livers of the SNP (2.5 microg/kg/min)+I/R group presented slight cytoplasmic and nuclear staining. But IkappaBalpha protein in all groups remains unchanged. It was concluded that SNP downregulated LTC4S mRNA expression by inhibiting NF-kappaB activation independent of IkappaBalpha, but appeared to have a dual influence on the mRNA expressions of MGST2 and MGST3 by other signaling pathways during hepatic I/R injury.
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PMID:Sodium nitroprusside regulates mRNA expressions of LTC4 synthesis enzymes in hepatic ischemia/reperfusion injury rats via NF-kappaB signaling pathway. 1749 35

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappaB is dependent upon the phosphorylation of its inhibitor, IkappaBalpha, by the specific inhibitory kappaB kinase (IKK) subunit, IKKbeta. We hypothesized that specific antagonism of the NF-kappaB inflammatory pathway through IKKbeta inhibition reduces acute myocardial damage following IR injury. C57BL/6 mice underwent left anterior descending (LAD) artery ligation and release in an experimental model of acute IR. Bay 65-1942, an ATP-competitive inhibitor that selectively targets IKKbeta kinase activity, was administered intraperitoneally either prior to ischemia, at reperfusion, or 2 h after reperfusion. Compared with untreated animals, mice treated with IKKbeta inhibition had significant reduction in left ventricular infarct size. Cardiac function was also preserved following pretreatment with IKKbeta inhibition. These findings were further associated with decreased expression of phosphorylated IkappaBalpha and phosphorylated p65 in myocardial tissue. In addition, IKKbeta inhibition decreased serum levels of TNF-alpha and IL-6, two prototypical downstream effectors of NF-kappaB activity. These results demonstrate that specific IKKbeta inhibition can provide both acute and delayed cardioprotection and offers a clinically accessible target for preventing cardiac injury following IR.
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PMID:IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. 1782 58

We have previously reported that prostaglandin A(1) (PGA(1)) reduces infarct size in rodent models of focal ischemia. This study seeks to elucidate the possible molecular mechanisms underlying PGA(1)'s neuroprotective effects against ischemic injury. Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by intraluminal suture blockade. PGA(1) was injected intracerebroventricularly (icv) immediately after ischemic onset. Western blot analysis was employed to determine alterations in IkappaBalpha, pIKKalpha, and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Immunohistochemistry was used to confirm the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65 and the expression of PPAR-gamma. RT-PCR was used to detect levels of c-Myc mRNA. The contribution of PPAR-gamma to PGA(1)'s neuroprotection was evaluated by pretreatment with the PPAR-gamma irreversible antagonist GW9662. A brief increase in pIKKalpha levels and rapid reduction in IkappaBalpha were observed after ischemia. PGA(1) blocked ischemia-induced increases in pIKKalpha levels and reversed the decline in IkappaBalpha levels. Ischemia-induced nuclear translocation of NF-kappaB p65 was attenuated by PGA(1). PGA(1) also repressed the ischemia-induced increase in expression of NF-kappaB target gene c-Myc mRNA. Immunohistochemistry demonstrated an increase in PPAR-gamma immunoreactivity in the nucleus of striatal cells at 3 hr after pMCAO. Western blot analysis revealed that the expression of PPAR-gamma protein significantly increased at 12 hr and peaked at 24 hr. PGA(1) enhanced the ischemia-triggered induction of PPAR-gamma protein. Pretreatment with the irreversible PPAR-gamma antagonist GW9662 attenuated PGA(1)'s neuroprotection against ischemia. These findings suggest that PGA(1)-mediated neuroprotective effect against ischemia appears to be associated with blocking NF-kappaB activation and likely with up-regulating PPAR-gamma expression.
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PMID:Neuroprotective effects of prostaglandin A(1) in rat models of permanent focal cerebral ischemia are associated with nuclear factor-kappaB inhibition and peroxisome proliferator-activated receptor-gamma up-regulation. 1807 85

Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-kappaB during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-kappaB activation before I/R is unknown. Therefore, these experiments tested the hypothesis that APC-induced ROS results in activation of NF-kappaB before I/R, with consequent increased expression of antiapoptotic proteins such as Bcl-2 and decreased apoptosis. Experiments utilized an established perfused heart rat model of sevoflurane APC and I/R. The role of NF-kappaB was defined by a novel method of transient inhibition of the regulatory kinase IKK using the reversible inhibitor SC-514. In addition to functional measures of left ventricular developed and end-diastolic pressure, phosphorylation of IkappaBalpha and activation of NF-kappaB were measured along with cytosolic protein content of Bcl-2, release of cytochrome c, and degradation of caspase-3. APC resulted in ROS-dependent phosphorylation of IkappaBalpha and activation of NF-kappaB before I/R. APC also increased the expression of Bcl-2 before I/R. In addition to functional protection following I/R, APC resulted in lower release of cytochrome c and caspase-3 degradation. These protective effects of APC were abolished by transient inhibition of IkappaBalpha phosphorylation and NF-kappaB activation by SC-514 followed by washout. ROS-dependent activation of NF-kappaB by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-kappaB activation before I/R should protect hearts from I/R injury.
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PMID:Activation of NF-kappaB is a critical element in the antiapoptotic effect of anesthetic preconditioning. 1930 43

Ischaemia/reperfusion (I/R) is a major cause of heart failure. Recently cardiac stem cells (CSCs) were proposed as the most appropriate cell type for heart disease therapy. However, it is still unclear whether I/R can stimulate the CSCs homing to the injured myocardium. Male Sprague-Dawley rats were subjected to a 30-min ischaemia followed by reperfusion of different intervals. RT-PCR, western blotting and immunohistochemistry were performed to detect stem cell factor (SCF) expression at mRNA and protein levels respectively. Activation of nuclear factor-kappaB (NF-kappaB) was determined by electrophoretic mobility shift assay. To assess the homing of CSCs in vivo, BrdU-labelled CSCs were injected into AV-groove before induction of ischaemia and examined by immunofluorescent staining in the injured myocardium after I/R. From day 3 to day 6 after reperfusion, the accumulation of CSCs was significantly elevated in the injured area, which was matched with the increased SCF expression during I/R. Pretreatment of rats with NF-kappaB inhibitor, N-acetyl-L-cysteine (NAC) not only suppressed NF-kappaB activation induced by I/R but also attenuated SCF expression. Further analysis revealed that I/R induced phosphorylation of IkappaBalpha after 15 min of reperfusion, and the raised phosphor-IkappaBalpha returned to the basal level at 2 h of reperfusion. In simulated I/R(SI/R) in vitro, it enhanced NF-kappaB activation and SCF expression in cultured neonatal rat cardiomyocytes, which was markedly inhibited by NF-kappaB decoy oligodeoxynucleotide or NAC. Taken together, our results demonstrated that I/R induced CSCs homing to the injured myocardium by stimulating myocardial SCF expression via activation of NF-kappaB.
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PMID:Ischaemia/reperfusion induced cardiac stem cell homing to the injured myocardium by stimulating stem cell factor expression via NF-kappaB pathway. 1956 18

Reactive astrocytes have been implicated in neuronal loss following ischemic stroke. However, the molecular mechanisms associated with this process are yet to be fully elucidated. In this work, we tested the hypothesis that astroglial NF-kappaB, a key regulator of inflammatory responses, is a contributor to neuronal death following ischemic injury. We compared neuronal survival in the ganglion cell layer (GCL) after retinal ischemia-reperfusion in wild-type (WT) and in GFAP-IkappaBalpha-dn transgenic mice, where the NF-kappaB classical pathway is suppressed specifically in astrocytes. The GFAP-IkappaBalpha-dn mice showed significantly increased survival of neurons in the GCL following ischemic injury as compared with WT littermates. Neuroprotection was associated with significantly reduced expression of pro-inflammatory genes, encoding Tnf-alpha, Ccl2 (Mcp1), Cxcl10 (IP10), Icam1, Vcam1, several subunits of NADPH oxidase and NO-synthase in the retinas of GFAP-IkappaBalpha-dn mice. These data suggest that certain NF-kappaB-regulated pro-inflammatory and redox-active pathways are central to glial neurotoxicity induced by ischemic injury. The inhibition of these pathways in astrocytes may represent a feasible neuroprotective strategy for retinal ischemia and stroke.
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PMID:Inactivation of astroglial NF-kappa B promotes survival of retinal neurons following ischemic injury. 1961 77

TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kappaB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-kappaB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24h after cerebral I/R. NF-kappaB activity and phosphorylation of the inhibitor of kappa B (IkappaBalpha) increased in ischemic brains, but IRF3, inhibitor of kappaB kinase complex-epsilon (IKKepsilon), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-kappaB activity or p-IkappaBalpha induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-kappaB signaling and brain injury after acute cerebral I/R.
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PMID:The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice. 1982 64

Recent studies have found that liver X receptors (LXRs) agonists decrease brain inflammation and exert neuroprotective effect. The aim of this study was to examine the mechanisms of action of liver X receptor agonist GW3965 against brain injury following global cerebral ischemia in the rat. The 48 male SD (Sprague-Dawley) rats were randomly partitioned into three groups: sham, global ischemia (4-vessel occlusion for 15 min; 4VO) treated with vehicle and global ischemia treated with GW3965 (20 mg/kg, via i.p. injection at 10 min after reperfusion). The functional outcome was determined by neurological evaluation at 24 h post ischemia and by testing rats in T maze at 3 and 7 days after reperfusion. The rats' daily body weight, incidence of seizures and 72 h mortality were also determined. After Nissl staining and TUNEL in coronal brain sections, the numbers of intact and damaged cells were counted in the CA1 sector of the hippocampus. The expression of phosphorylated inhibitor of kappaB (p-IkappaBalpha), nuclear factor-kappaB (NF-kappaB) subunit p65, and cyclo-oxygenase-2 (COX-2) were analyzed with Western blot at 12 h after reperfusion. GW3965 tended to reduce 72 h mortality and the incidence of post-ischemic seizures. GW3965-treated rats showed an improved neuronal survivability in CA1 and a significant increase in the percentage of spontaneous alternations detected in T-maze on day 7 after ischemia. GW3965-induced neuroprotection was associated with a significant reduction in nuclear translocation of NF-kB p65 subunit and a decrease in the hippocampal expression of NF-kB target gene, COX-2. LXR receptor agonist protects against neuronal damage following global cerebral ischemia. The mechanism of neuroprotection may include blockade of NF-kappaB activation and the subsequent suppression of COX-2 in the post ischemic brain.
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PMID:Activation of liver X receptor reduces global ischemic brain injury by reduction of nuclear factor-kappaB. 2009 33


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