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 inhibitor of NF-kappaB (I-kappaB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-kappaB essential modulator (NEMO), and is involved in the activation of NF-kappaB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-kappaB or increased apoptosis after TNF-alpha stimulation whereas conditional NEMO knockout resulted in complete block of NF-kappaB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and could therefore emerge as a new pharmacological therapy for liver resection, hemorrhagic shock, or transplantation surgery.
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PMID:Activation and function of hepatocyte NF-kappaB in postischemic liver injury. 1577 10

Iloprost, a stable prostacyclin analogue, regulates expression of genes that are involved in inflammation and in cell growth and inhibits the in vitro production of cytokines. We evaluated the effect of an in vivo weekly iloprost treatment on TNF-alpha and IL6 monocyte production (evaluated by ELISA), on monocyte apoptosis (Annexin V/uptake of propidium iodide by flow cytometry) and on peripheral blood mononuclear cell (PBMC) TNF-alpha receptors (TNF-RI and TNF-RII) mRNA expression (RT-PCR) in 14 atherosclerotic critical limb ischemia patients. PBMC were stimulated with LPS for 24h. TNF-alpha production was significantly reduced by iloprost whereas IL6 production was not affected. Iloprost did not accelerate monocyte apoptosis. TNF-RI mRNA expression was not modified by iloprost, whereas TNF-RII mRNA expression was significantly reduced. Our data show that iloprost may have anti-inflammatory effects in addition to the well-known vasodilatatory and anti-aggregant ones.
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PMID:Iloprost treatment reduces TNF-alpha production and TNF-RII expression in critical limb ischemia patients without affecting IL6. 1609 91

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.
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PMID:Tumor necrosis factor alpha and glutathione interplay in chronic heart failure. 1623 78

The current study explored the concept that adult and pediatric populations differ in their response to major injury. Male C57BL/6 mice of a "young adult" (8-12 weeks) or "mature adult" (12-13 months) age were subjected to partial hepatic ischemia and reperfusion. Mature adult mice displayed significantly more liver injury than young adult mice as assessed histologically and by serum levels of alanine aminotransferase. Interestingly, there was far less neutrophil accumulation in the livers of mature adult mice. However, liver-recruited neutrophils from mature adult mice had a higher activation state than those from young adult mice. Activation of the inflammatory transcription factor, NF-kappaB, was suppressed in whole livers from mature adult mice. In isolated liver cells, Kupffer cells showed no difference in NF-kappaB activation, but hepatocytes from mature adult mice had delayed NF-kappaB activation in response to TNF. Furthermore, isolated hepatocytes from young adult mice produced abundant amounts of the chemokine, macrophage inflammatory protein-2, whereas hepatocytes from mature adult mice produced little, if any macrophage inflammatory protein-2. Mature adult mice had much lower hepatic expression of the cytoprotective protein, heat shock protein 70, than did young adult mice. In contrast, serum heat shock protein 70 levels, which has been linked to subsequent tissue injury, were higher in mature adult mice than in young adult mice. These data suggest that there are multiple alterations at the cellular and molecular levels that contribute to enhanced postischemic liver injury in mature adult mice.
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PMID:Age-dependent responses to hepatic ischemia/reperfusion injury. 1624 27

Many pathological processes involve the breakdown and remodeling of the extracellular matrix, which is mediated by the family of important enzymes known as matrix metalloproteinases (MMPs). One such process is warm ischemia/reperfusion (I/R) injury, the most important cause of dysfunction of liver allografts. We monitored protein expression of MMP-9 by Western blotting in rat liver after I/R. We also monitored changes in total MMP activity in the serum before and after I/R. Ischemia was induced by clamping the common hepatic artery and portal vein for 40 minutes and reperfusing for 90 minutes. Blood samples collected before ischemia and after reperfusion were analyzed for AST, hydroxyl radical, and tumor necrosis factor (TNFalpha). This protocol resulted in a high level of MMP-9 expression in liver tissue. Total MMP activity in serum was also significantly increased. Levels of AST, hydroxyl radicals, and TNF alpha were concomitantly increased. Ilomastat, an MMP inhibitor, attenuated the I/R-induced liver injury. After administration of the oxygen radical scavenger N-acetylcysteine (NAC), total MMP activity was suppressed, and liver injury was again attenuated. These results indicated that reperfusion liver injury induced an increase in MMP-9 protein expression and in serum MMP activity. The protective effects of an MMP inhibitor and NAC indicate that oxygen radical production is involved in MMP expression and liver injury associated with I/R.
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PMID:Oxygen radicals and matrix metalloproteinases mediate reperfusion liver injury. 1638 66

Focal cerebral ischemia causes apoptosis in neural cells during the postischemia period. TNF is critically involved in such neuronal apoptosis mediated by caspase pathways. A20 can inhibit TNF-induced apoptosis in many cell types. However, little work has been carried out in central nervous system. In the present study, gene transfer of A20 resulted in reduction of infarct volume and improvement of neurological deficit in ischemia rats. Results of flow cytometry, TUNEL and DNA fragmentation assay all indicated A20 could inhibit TNF-induced apoptosis both in primary rat hippocampal neurons and SH-SY5Y cells. Moreover, we found A20 targeted the TNF apoptotic pathway by inhibiting proteolytic cleavage of caspase 8 and 3 in SH-SY5Y cells. These data demonstrated A20 could effectively protect neurons from postischemic apoptosis and may function partly on death receptor caspase pathway. Gene transfer of A20 may be a promising approach to gene therapy for cerebral ischemia in the future.
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PMID:Neuroprotective effect of A20 on TNF-induced postischemic apoptosis. 1647 93

Coronary artery occlusion increased the TNF alpha level in the membrane fraction of the rat heart, almost maximally at 30 min. TNF alpha immunofluorescence labeled streak-like reticular structures inside of the cardiomyocyte but not vascular or interstitial cells in myocardial ischemia. Immuno-electron microscopy confirmed the localization of TNF alpha between myofibrils, mitochondria, or other membrane structures in the ischemic cardiomyocyte. Ischemic preconditioning (IP) is the protection of myocardium conferred by cycles of brief ischemia-reperfusion. The increases in TNF alpha production, as well as phosphorylation of p38 MAP kinase and S6 kinase after ischemia were inhibited by IP or p38 MAP kinase inhibitors (SB203580, FR167653). TNF alpha production appeared to be regulated possibly at the post-transcriptional step by ribosomal S6 phosphorylation given that IP did not suppress TNF alpha mRNA up-regulation and was independent of NFkappaB activation. Electron microscopy (EM) showed mitochondria damage in ischemic cardiomyocyte, which was inhibited either by IP or SB203580. This is the first demonstration of the TNF alpha up-regulation in membrane structures of ischemic cardiomyocyte through p38 MAP kinase-mediated post-transcriptional mechanism, in association with mitochondrial damage.
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PMID:Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF alpha production and mitochondria damage in brief myocardial ischemia. 1649 38

Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.
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PMID:Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. 1663 32

Vascular endothelial growth factor (VEGF) receptor-2 (KDR/flk-1) has a tyrosine kinase domain, and once activated, induces the autophosphorylation of the tyrosine residues, which is essential for angiogenesis. SHP-1, a cytoplasmic protein tyrosine phosphatase, plays a negative regulatory role in signal transduction pathways by dephosphorylation of the receptors to which it binds. Thus, therapeutic angiogenesis designed to inhibit expression of SHP-1 would be beneficial in hindlimb ischemia. In in vitro, the inhibition of SHP-1 by SHP-1 siRNA impaired the ability of TNF to block the tyrosine phosphorylation of KDR/flk-1 induced by VEGF and showed an increase in endothelial cell growth. In in vivo, SHP-1 mRNA, SHP-1 protein levels and VEGF were increased in a rat model of hindlimb ischemia. Upon injection to the ischemic adductor muscle, vector-based siRNA reduced SHP-1, increased phosphorylation of KDR/flk-1, and markedly increased capillary density. Our data demonstrated in vivo the potential use of siRNA targeting SHP-1 as therapy for peripheral ischemic diseases.
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PMID:SiRNA targeting SHP-1 accelerates angiogenesis in a rat model of hindlimb ischemia. 1672 44

Following ischemia-reperfusion, there is a sustained increase of TNF-alpha both locally in the heart as well as in circulating levels in blood. While TNF-alpha has been implicated in cardiomyocyte apoptosis which occurs in several cardiomyopathies, the molecular pathways by which TNF-alpha induces apoptosis in these cells are not fully elucidated. We investigated the role of the two families of cysteine proteases, caspases and calpains, which are known to participate in apoptotic cell death. The effect of the highly specific calpain inhibitor, Z-LLY-fmk, and the caspase pathways involved in TNF-alpha-mediated apoptosis of the HL-1 cardiomyocyte cell line were examined. Activation of the downstream caspase-3, and the cleavage of poly ADP-ribose polymerase (PARP) were observed in a time-dependent manner upon treatment with TNF-alpha. Caspase-12, but not caspase-9, was activated in response to TNF-stimulation, indicating that an endoplasmic reticulum (ER)/calcium-dependent pathway may be involved. In HL-1 cardiomyocytes, TNF-alpha-induced apoptosis appears to be mediated by calpain as apoptotic changes were abrogated in the presence of the highly specific calpain inhibitor, Z-LLY-fmk. In conclusion, our results suggest that TNF-alpha-mediated apoptosis in HL-1 cardiomyocytes follows the caspase-12 apoptotic pathway that involves calpain.
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PMID:TNF-alpha-mediated cardiomyocyte apoptosis involves caspase-12 and calpain. 1672 70


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