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

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

Heat shock protein 72 (HSP72) is a stress-inducible protein capable of protecting a variety of cells from toxins, thermal stress, and ischemic injury. The cytoprotective role and mechanism of action of HSP72 in renal cell ischemic injury remain unclear. To study this, HSP72 was introduced (liposomal transfer) or induced (thermal stress, 43 degrees Cx1 hour) in renal tubular cells (LLC-PK1) with Western blot confirmation. Cells were subjected to simulated ischemia 24 hours after liposomal HSP72 transfer or thermal stress, and the effect of HSP72 on nuclear factor-kappaB (NF-kappaB) activation (electrophoretic mobility shift assay and immunohistochemistry), IkappaBalpha production (Western blot), postischemic tumor necrosis factor-alpha (TNF-alpha) production (RT-PCR), and apoptosis (TUNEL assay) were determined. In separate experiments, the role of TNF-alpha in apoptosis was determined (anti-TNF-alpha neutralizing antibody). Results demonstrated that both liposomal transfer of HSP72 and thermal induction of HSP72 prevented NF-kappaB activation and translocation, TNF-alpha gene transcription, and subsequent ischemia-induced renal tubular cell apoptosis. Furthermore, TNF-alpha neutralization also inhibited ischemia-induced renal tubular cell apoptosis. These results indicate that liposomal delivery of HSP72 inhibits ischemia-induced renal tubular cell apoptosis by preventing NF-kappaB activation and subsequent TNF-alpha production. Further elucidation of the mechanisms of HSP-induced cytoprotection may result in therapeutic strategies that limit or prevent ischemia-induced renal damage.
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PMID:Liposomal delivery of heat shock protein 72 into renal tubular cells blocks nuclear factor-kappaB activation, tumor necrosis factor-alpha production, and subsequent ischemia-induced apoptosis. 1259 41

Gut ischemia-reperfusion (I/R) injury is a serious complication of shock. Previously we demonstrated that the administration of alpha-melanocyte-stimulating hormone (MSH) immediately before mesenteric I/R protected against postischemic gut injury. In this report, we tested the therapeutic efficacy of alpha-MSH on gut I/R (60 min ischemia, 6 h reperfusion) injury when given at different time points of reperfusion. Rats underwent sham surgery or were treated with saline or with alpha-MSH that was given 1, 2, or 4 h after superior mesenteric artery clamping. Vehicle-treated I/R rats exhibited severe mucosal injury and increased NF-kappaB DNA binding activity, myeloperoxidase (MPO) activity, and interleukin-6 and heme oxygenase-1 (HO-1) expression. In contrast, rats given alpha-MSH at 1 h of reperfusion, but not 2 h or 4 h, exhibited much less mucosal injury. Rats given alpha-MSH at 1 h or 2 h of reperfusion, but not 4 h, exhibited less MPO activity, NF-kappaB DNA binding activity, and interleukin-6 protein and even higher levels of heme oxygenase-1 than vehicle-treated rats. In addition, we found that combined use of alpha-MSH, a known inhibitor of IkappaBalpha tyrosine phosphorylation, with BAY 11-7085, an inhibitor of IkappaBalpha Ser 32,36 phosphorylation, abrogates gut MPO induction and tissue injury at early and late time points of reperfusion. Thus, alpha-MSH, an endogenous peptide with a favorable side-effect profile, is effective in treating experimental gut I/R injury when given early after the initial ischemia and may represent a candidate therapy for gut I/R in humans in whom recognition and treatment are often delayed.
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PMID:Delayed administration of alpha-melanocyte-stimulating hormone or combined therapy with BAY 11-7085 protects against gut ischemia-reperfusion injury. 1456 Jan 13

IkappaB proteins play an important role in regulating NF-kappaB induction following a diverse range of environmental injuries. Studies evaluating IkappaBbeta knock-in mice (AKBI), in which the IkappaBalpha gene is replaced by the IkappaBbeta cDNA, have uncovered divergent properties of IkappaBalpha and IkappaBbeta that influence their ability to activate hepatic NF-kappaB and subsequent downstream proinflammatory processes in a stimulus-specific manner. While AKBI mice demonstrated identical levels of hepatic NF-kappaB activation in response to endotoxin, a significantly reduced level of hepatic NF-kappaB activation was observed in AKBI mice after liver ischemia/reperfusion (I/R) injury. This reduced level of NF-kappaB activation in AKBI mice after liver I/R also correlated with decreased induction of serum TNF-alpha, reduced hepatic inflammation, and increased survival. In contrast, no differences in any of these indicators were observed between AKBI mice and WT littermates after a lethal injection of LPS. Molecular studies suggest that the specificity of IkappaBalpha, but not IkappaBbeta, to properly regulate NF-kappaB induction during the acute phase of I/R injury is due to injury context-specific activation of c-Src and subsequent tyrosine phosphorylation of IkappaBalpha on Tyr42. These results demonstrate that IkappaBalpha and IkappaBbeta play unique injury context-specific roles in activating NF-kappaB-mediated proinflammatory responses and suggest that strategies aimed at inhibiting IkappaBalpha gene expression may be of potential therapeutic benefit in hepatic I/R injury.
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PMID:IkappaBalpha and IkappaBbeta possess injury context-specific functions that uniquely influence hepatic NF-kappaB induction and inflammation. 1499 Oct 73

While moderate hypothermia is protective against ischemic cardiac and brain injury, it is associated with much higher mortality in patients with sepsis. We previously showed that in vitro exposure to moderate hypothermia (32 degrees C) delays the induction and prolongs the duration of TNF-alpha and IL-1beta secretion by lipopolysaccharide (LPS)-stimulated human mononuclear phagocytes. In the present study, we extended these observations by showing that moderate hypothermia exerts effects on TNF-alpha and IL-1beta generation in the human THP-1 monocyte cell line that are similar to those that we previously found in primary cultured monocytes; that hypothermia causes comparable changes in cytokine generation stimulated by zymosan, toxic shock syndrome toxin-1, and LPS; and that hypothermia causes similar changes in TNF-alpha and IL-1beta mRNA accumulation. TNF-alpha mRNA half-life, determined after transcriptional arrest with actinomycin D, was not significantly prolonged by lowering incubation temperature from 37 to 32 degrees C, suggesting that hypothermia modifies TNF-alpha gene transcription. This finding was further supported by reporter gene studies showing a threefold increase in activity of the human TNF-alpha promoter at 32 vs. 37 degrees C. Electrophoretic mobility shift assay revealed that hypothermia prolonged NF-kappaBeta activation, identifying a potential role for this transcription factor in mediating the effects of hypothermia on TNF-alpha and IL-1beta production. Delayed reexpression of the inhibitor IkappaBalpha, shown by Northern blotting and immunoblotting, may account in part for the prolonged NF-kappaBeta activation at 32 degrees C. Augmentation of NF-kappaBeta-dependent gene expression during prolonged exposure to hypothermia may be a common mechanism leading to increased lethality in sepsis, late-onset systemic inflammatory response syndrome after accidental hypothermia, and neuroprotection after ischemia.
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PMID:Hypothermia prolongs activation of NF-kappaB and augments generation of inflammatory cytokines. 1507 Aug 15

Neonatal necrotizing enterocolitis (NEC), which is a disease with a poor prognosis, is considered to be caused by the coincidence of intestinal ischemia-reperfusion injury and systemic inflammation due to the colonization of pathogenic bacteria. Interleukin (IL)-8, a proinflammatory cytokine, plays an important role in the pathophysiology of NEC. It was recently reported that IL-1beta activates the IL-8 gene by regulating the transcriptional nuclear factor kappaB (NF-kappaB) signaling pathways in intestinal cells. The protective role of maternal milk in NEC pathogenesis has been reported in both human and animal studies. In this study, we show that human breast milk dramatically suppressed the IL-1beta-induced activation of the IL-8 gene promoter by inhibiting the activation pathway of NF-kappaB. Moreover, we also show that human breast milk induced the production of IkappaBalpha. These results suggest that human breast milk could be protective and therapeutic in neonates with NEC by inhibiting the activation pathway of NF-kappaB.
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PMID:Human breast milk suppresses the transcriptional regulation of IL-1beta-induced NF-kappaB signaling in human intestinal cells. 1522 9

Epithelial injury and repair are central consequences of ischemia and reperfusion of the gut. Intestinal mucosal wounds are repaired in part by epithelial restitution. However, the signaling mechanisms regulating restitution remain poorly understood, and few therapies to enhance restitution have been described. Previously we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH) protected against postischemic gut injury in the rat. In this report, we tested the effects and mechanisms of alpha-MSH on wound restitution of rat small intestine (IEC-6) cells subjected to H2O2 stress with or without scrape wounding. H2O2 treatment resulted in tyrosine phosphorylation of Syk kinase and its downstream target IkappaBalpha, with subsequent NF-kappaB activation. Alpha-MSH and the Syk kinase inhibitor piceatannol blocked these processes. In scrape-wounded cells, H2O2 inhibited wound restitution, and this was partially restored by cotreatment with alpha-MSH or piceatannol. In contrast, overexpression of NF-kappaB p65 or Syk kinase, but not a dominant-negative mutant of Syk kinase, aggravated H2O2 inhibition of wound restitution, and inhibitors of c-Src tyrosine kinase or phosphatidylinositol-3 kinase were without effect. The results indicate an important role for Syk tyrosine kinase and the NF-kappaB pathway in the response to oxidant stress and the impairment of epithelial restitution in IEC-6 cells. The data also disclose that the beneficial effects of alpha-MSH on gut ischemia/reperfusion injury may relate to its acceleration of epithelial restitution.
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PMID:Alpha-melanocyte stimulating hormone protects against H2O2-induced inhibition of wound restitution in IEC-6 cells via a Syk kinase- and NF-kappabeta-dependent mechanism. 1548 38

Ischemia-reperfusion (IR) of the testis results in testicular oxidative stress and germ cell-specific apoptosis. Nuclear factor kappa B (NF-kappaB) is a nuclear transcription factor involved in the control of a number of cellular processes, and its activation is part of the cellular stress response to a variety of factors including cytokine stimulation, irradiation, and IR. The present study investigates NF-kappaB activation after IR of the murine testis and potential downstream target genes of that activation. Mice were subjected to a period of testicular ischemia followed by 0-4 hours of reperfusion. Activation of NF-kappaB was assessed by 1) Western blot analysis of the NF-kappaB inhibitory protein, IkappaBalpha; 2) immunohistochemistry for IkappaBalpha; and 3) TranSignal NF-kappaB target gene array (107 genes) analysis. Results demonstrate that IkappaBalpha is phosphorylated on serine 32 reaching a peak by 2 hours after IR of the testis. A decrease in total IkappaBalpha was also noted at 2 hours after IR, consistent with the rapid degradation of the phosphorylated protein. Phosphorylation and degradation of IkappaBalpha is indicative of NF-kappaB activation. Immunolocalization revealed IkappaBalpha specifically in Sertoli cells of the murine testis. Results of the TranSignal target gene array revealed that the expression of 9 genes was consistently changed 2 hours after IR of the testis, 3 of which increased in expression and 6 of which were down-regulated. Most notably, high-mobility group nucleosomal binding domain 1 increased in expression while platelet-derived growth factor B and Wilms tumor homolog decreased. These results suggest that testicular IR releases the suppression of NF-kappaB by IkappaBalpha in Sertoli cells. Activation of the NF-kappaB pathway in the testis resulted in an alteration of expression of potential NF-kappaB target genes, some increased while others decreased. The specific roles of these genes in the testicular response to IR remains to be determined.
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PMID:Activation of the nuclear factor kappa B pathway following ischemia-reperfusion of the murine testis. 1561 77

The role of NF-kappaB in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-kappaB signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-kappaB activation by preventing phosphorylation at specific serine residues of the inhibitory kappaB (IkappaB) protein isoform IkappaBalpha. However, these models are unable to completely block NF-kappaB because of a second signaling pathway that regulates NF-kappaB function via Tyr42 phosphorylation of IkappaBalpha. We report the development of transgenic (3M) mouse lines that express the mutant IkappaBalpha(S32A,S36A,Y42F) in a cardiac-specific manner. NF-kappaB activation in cardiomyopathic TNF-1.6 mice is completely blocked by the 3M transgene but only partially blocked (70-80%) by the previously described double-mutant 2M [IkappaBalpha(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-kappaB activation in TNF-alpha-induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF-alpha and ischemia-reperfusion (I/R), NF-kappaB activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-kappaB activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, which conclusively demonstrates that NF-kappaB is involved in I/R injury. In summary, we have engineered novel transgenic mice that allow us to distinguish two major proximal pathways for NF-kappaB activation. Our results demonstrate that the serine and tyrosine phosphorylation pathways are differentially activated during different pathophysiological processes (cardiomyopathy and I/R injury) and that NF-kappaB contributes to infarct development after I/R.
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PMID:Cardiac-specific blockade of NF-kappaB in cardiac pathophysiology: differences between acute and chronic stimuli in vivo. 1569 59

Activation of transcription factor nuclear factor-kappaB (NF-kappaB) can result in enhanced de novo synthesis of both proteins that confer protection and those that cause death. The present study was undertaken to clarify in primary neuronal cultures the consequences of the oxidative stress-induced activation of NF-kappaB and mediation of death or survival signals. The neuronal cultures were exposed to chemical ischemia (iodoacetic acid), followed by reperfusion (I/R insult). This insult injured the neurons, as manifested in a 7- to 10-fold increase in LDH release, and decreased the cellular content of IkappaBalpha by 55-65 %, indicating NF-kappaB activation. The antioxidants LY231617, melatonin, and sodium salicylate and the antioxidant and inhibitor of NF-kappaB activation pyrrolidine dithiocarbamate, protected the neurons against the insult and prevented the decrease in cellular IkappaBalpha content. In contrast, inhibition of NF-kappaB translocation by SN50 in both uninsulted and insulted neuronal cultures resulted in a 2.9- and 2.4-fold increase in LDH release, respectively. The results indicate that the insult-induced oxidative stress activates transcription factor NF-kappaB associated with induction of protection and suggest that constitutive activation of NF-kappaB under physiological conditions acts to protect the neurons against physiological injury.
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PMID:Oxidative stress activates transcription factor NF-kB-mediated protective signaling in primary rat neuronal cultures. 1596 83

Microvascular changes in the brain are significant causes of cerebral edema and ischemia injury. A number of studies suggest that angiotensin (Ang) II may be involved in the initiation and regulation of processes occurring in brain ischemia. We recently reported that Ang II injures brain microvascular endothelial cells (BMEC) partially via stimulating intercellular adhesion molecule-1 (ICAM-1) expression. However, the signaling cascade leading to Ang II-induced ICAM-1 expression in BMEC was unclear. The present study tested the hypothesis that Ang II induces ICAM-1 expression via an AT1 receptor/nuclear factor-kappaB (NF-kappaB) pathway in BMEC. Ang II directly stimulated the expression of ICAM-1 mRNA and protein in primary cultured BMEC. Ang II treatment also resulted in the degradation of IkappaBalpha and increase of NF-kappaB p65 subunit in the nucleus as well as the DNA binding activity of nuclear NF-kappaB. These effects were abolished by pretreatment with the selective AT1 receptor antagonists, losartan and compound EXP-2528, or losartan plus the AT2 receptor antagonist PD123319, but not by PD123319 alone. Moreover, there were no significant differences between the losartan and losartan plus PD123319 groups. These findings indicate that Ang II-induced ICAM-1 upregulation in brain microvascular endothelial cells may be mediated via an AT1 receptor/NF-kappaB pathway.
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PMID:Angiotensin II stimulates intercellular adhesion molecule-1 via an AT1 receptor/nuclear factor-kappaB pathway in brain microvascular endothelial cells. 1634 50


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