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)

Transforming growth factor-alpha (TGF-alpha) is a ligand for the epidermal growth factor (EGF) receptor (EGFR), and is more abundant than EGF in the brain. The authors studied whether administration of exogenous TGF-alpha into the brain can protect neurons against ischemia in a model of permanent middle cerebral artery (MCA) occlusion in the rat, and whether any effect of TGF-alpha was mediated by EGFR by administering 4,5-dianilinophthalimide (DAPH), a protein-tyrosine kinase inhibitor with high selectivity for EGFR. Rats received either TGF-alpha (10 or 25 ng), DAPH (100 ng), DAPH plus TGF-alpha (25 ng), or vehicle in the ipsilateral first ventricle. Drugs were administered twice: 30 minutes before and 30 minutes after MCA occlusion, and infarct volume was evaluated 24 hours later. Transforming growth factor-alpha at the dose of 25 ng caused a statistically significant reduction of infarct volume (60%) in relation to ischemic rats administered vehicle. This reduction was no longer seen when TGF-alpha was administered in combination with DAPH. The present results show that TGF-alpha can protect neurons from ischemic damage, and that this effect is mediated by EGFR. It is suggested that activation of EGFR-mediated intracellular signalling pathways contributes to the survival of neural cells susceptible to ischemic injury.
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PMID:Transforming growth factor-alpha acting at the epidermal growth factor receptor reduces infarct volume after permanent middle cerebral artery occlusion in rats. 1002 66

The functions of the epidermal growth factor (EGF) family members in the adult brain are not known. This study investigated the changes in the expression of members of the EGF family following global ischemia employing in situ hybridization and immunohistochemical techniques to elucidate their roles in pathological conditions. EGF mRNA was not detected in either the control or the postischemic rat brain. Although transforming growth factor-alpha (TGF-alpha) mRNA was widely expressed in the normal brain, its expression did not change appreciably following ischemia. By contrast, heparin-binding EGF-like growth factor (HB-EGF) mRNA expression was rapidly increased in the CA3 sector and the dentate gyrus of the hippocampus, cortex, thalamus, and cerebellar granule and Purkinje cell layers. EGF receptor mRNA, which was widely expressed, also showed an increase in the CA3 sector and dentate gyrus. Conversely, HB-EGF mRNA did not show any increase prior to ischemic neuronal injury in the CA1 sector, the region most vulnerable to ischemia. Immunohistochemical detection of HB-EGF in the postischemic brain suggested a slight increase of immunostaining in the dentate gyrus of the hippocampus and the cortex. These findings showed that the gene encoding HB-EGF is stress-inducible, indicating the likelihood that HB-EGF is a neuroprotective factor in cerebral ischemia.
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PMID:The gene for heparin-binding epidermal growth factor-like growth factor is stress-inducible: its role in cerebral ischemia. 1007 83

For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion; (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells; and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.
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PMID:Bcl-2 genes and growth factors in the pathology of ischaemic acute renal failure. 1036 Dec 61

The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. This study analyzes the temporal and spatial relationship between expression of pro- and anti-apoptotic members of the Bcl-2 gene family (Bcl-2, Bcl-X(L), Bax) and epidermal growth factor (EGF), insulin-like growth factor- (IGF-1), and transforming growth factor-beta (TGF-beta), growth factors that are thought to be reparative in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other cellular damage including necrosis and loss of cellular adhesion. Locality and level of expression of the Bcl-2 and growth factor proteins were determined using immunohistochemistry. Apoptosis peaked between 4 and 14 d postischemia in both proximal and distal tubules. Mitosis peaked at 2 d in proximal tubules and 4 to 14 d in the distal tubules. A spatio-temporal relationship was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl-2, Bcl-X(L) was low in epithelium of distal tubules, Bax had low-to-moderate expression in the proximal tubule and had low expression in the distal tubule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-beta had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-X(L) and Bax. Proximal tubules showed a marked increase in Bax expression and a moderate increase in Bcl-X(L). Twenty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proximal tubules, suggestive of paracrine action in these tubules. TGF-beta expression was moderately increased in regenerating proximal tubules, but no relationship was seen with the pattern of expression of the Bcl-2 genes. An explanation of these results is that the distal tubule is adaptively resistant to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 genes, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine action), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).
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PMID:Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. 1070 69

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is found in cerebral neurons, and its expression is increased after hypoxic or ischemic injury, which also stimulates neurogenesis. To investigate the possible role of HB-EGF in hypoxic-ischemic induction of neurogenesis, we measured its expression, effects, and target receptors in embryonic murine cerebral cortical cultures and in adult rat brain. Hypoxia increased HB-EGF expression by approximately 50% in cortical cultures, where expression was associated with mature and immature neurons. HB-EGF (5-100 ng/ml) stimulated by approximately 80% the incorporation of bromodeoxyuridine (BrdU) into cultured cells that expressed the HB-EGF receptors epidermal growth factor receptor (EGFR)/avian erythroblastic leukemia viral oncogene homolog 1 (ErbB1) and N-arginine dibasic convertase (NRDc). Intracerebroventricular administration of HB-EGF in adult rats increased BrdU labeling in the subventricular zone and in the subgranular zone of dentate gyrus, where EGFR/ErbB1 and NRDc were also expressed and where ischemia-induced neurogenesis is observed. We conclude that HB-EGF stimulates neurogenesis in proliferative zones of the adult brain that are also affected in ischemia and that it does so by interacting with EGFR/ErbB1 and possibly NRDc. Therefore, HB-EGF may help to trigger proliferation of neuronal precursors in brain after hypoxic or ischemic injury.
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PMID:Heparin-binding epidermal growth factor-like growth factor: hypoxia-inducible expression in vitro and stimulation of neurogenesis in vitro and in vivo. 1209 88

The applications of neural progenitor cells in clinical therapy for neural degeneration, such as Parkinson's disease, Huntington's disease, and cerebral infarction, have long been explored widely. It had been suggested that these cells may block the apoptosis of ischemia-induced neuronal damage and may themselves resist neurotoxic factors. In the present study, neural progenitor cells derived from the cortex of rodent embryos were cultured with the mitogenic agent epidermal growth factor. It was observed that these progenitor cells could self-renew and differentiate into a number of types of neurons and glial cells. By using sodium nitroprusside, glutamate, and N-methyl-D-aspartate, these neural progenitor cells were shown to have a higher resistance to neurotoxicity induced by these drugs compared with primary neuronal cells. However, the release of nitric oxide in response to glutamate by these neural progenitor cells was similar to the released by primary neuronal cells. Also, when the glutamate-stimulated increase in intracellular free Ca(2+) concentration was measured, stimulation of the glutamate receptors could not induce a significant influx of Ca(2+) into these progenitor cells until they differentiated. Our results suggest that the resistance of neural progenitor cells to neurotoxicity may be partially due to a lack of response to glutamate. In addition, some progenitor-generated neurotrophic factors may contribute to the resistance of these cells to nitric oxide-induced neurotoxicity.
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PMID:Neural progenitor cells resist excitatory amino acid-induced neurotoxicity. 1250 90

EGF promotes proliferation and migration of stem/progenitor cells in the normal adult brain. The effect of epidermal growth factor on neurogenesis in ischemic brain is unknown, however. Here we show that intraventricular administration of EGF and albumin augments 100-fold neuronal replacement in the injured adult mouse striatum after cerebral ischemia. Newly born immature neurons migrate into the ischemic lesion and differentiate into mature parvalbumin-expressing neurons, replacing more than 20% of the interneurons lost by 13 weeks after ischemia and representing 2% of the total BrdU-labeled cells. These data suggest that administration of EGF and albumin could be used to manipulate endogenous neurogenesis in the injured brain and to promote brain self-repair.
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PMID:EGF amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia. 1269 32

Expression of endogenous heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a proven intestinal cytoprotective molecule, was examined in intestinal epithelial cells (IEC) in vitro, and in intestine undergoing ischemia/reperfusion (I/R) injury in vivo. In vitro, cells were exposed to anoxia for 90 min followed by reoxygenation for 1-3 h (A/R). In vivo, total midgut I/R injury was produced in rats by occlusion of the superior mesenteric artery for 30 or 90 min followed by reperfusion for 4 h. In situ hybridization and immunohistochemistry were used to study HB-EGF mRNA expression and protein production. In vitro, normal IEC had no detectable HB-EGF mRNA or protein expression. After anoxia, cells expressed HB-EGF mRNA and protein, with expression reaching a peak 2-3 h after reoxygenation. In vivo, only very low levels of HB-EGF mRNA and no detectable protein were found in normal intestine. Four hours after I/R, HB-EGF protein was detected in villous epithelia subjected to 30 min but not 90 min of ischemia, whereas HB-EGF mRNA was highly expressed after both ischemic intervals. Endogenous HB-EGF is immediately upregulated in IEC after A/R injury and in intestine after I/R injury. Thus, HB-EGF acts as an immediate early gene under these conditions.
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PMID:Upregulation of endogenous heparin-binding EGF-like growth factor (HB-EGF) expression after intestinal ischemia/reperfusion injury. 1274 88

Production of reactive oxygen species (ROS) during islet purification by enzymatic digestion as well as during warm and cold ischemia causes islet cell damage. Recent reports have shown that activated Akt, the downstream protein after phosphatidylinositol (PI) 3-kinase, is involved in cell survival by phosphorylating several proteins that mediate apoptosis. We analyzed the role of PI3-kinase/Akt pathway activation using insulin or epidermal growth factor (EGF) on islet beta cell survival during oxidative stress. Canine islets and murine beta cell line (BTC) were cultured in the presence of hydrogen peroxide (H(2)O(2)) for 12 to 20 hours. Viability and cell death were measured by MTT assay. Maximum cell damage was observed with as little as 100 micromol/L of H(2)O(2). Pretreatment with 100 ng/mL of insulin significantly decreased cell damage. Meanwhile, the protective effect of insulin was partially blocked with an inhibitor of PI3-kinase, LY294002, suggesting the utilization of PI3-kinase/Akt signaling pathway for the observed cytoprotective effect. Similar to insulin, EGF also protected beta cells from oxidative stress. Our results suggest that PI3-kinase/Akt activation by insulin or EGF is beneficial for islet beta cell protection.
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PMID:Epidermal growth factor and insulin inhibit cell death in pancreatic beta cells by activation of PI3-kinase/AKT signaling pathway under oxidative stress. 1519 3

Necrotizing enterocolitis (NEC) is the most common surgical emergency in the neonatal intensive care unit and remains a major cause of death in neonates. Although the pathophysiology of NEC has not been completely elucidated, progress has been made in the characterization of the molecular events which may take place during an episode of ischemia. This possible initiating event is followed by a complex cascade of inflammatory mediators active in NEC: epidermal growth factor, platelet-activating factor, and, nitric oxide. Additionally, unique characteristics of the premature gut are thought to be crucial to the development of NEC. The diagnosis of NEC continues to be based on clinical and radiographic features. Several new laboratory tests are under investigation for the purposes of earlier diagnosis, but none have prevailed at this time. Both exploratory laparotomy, with intestinal resection and peritoneal drainage are widely practiced. Mortality rates remain high and have improved little over the last couple of decades. Therefore, prevention remains crucial in order to decrease the incidence of NEC. Cautious feeding regimens, the use of maternal breast milk, passive immunization, and the use of probiotics have all been suggested but not proven as possible preventive methods. Although many advances have been made, significant opportunity remains to improve our understanding of the disease process and to develop better strategies for prevention and treatment.
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PMID:Current issues in the management of necrotizing enterocolitis. 1528 1


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