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)

The present studies were initiated to investigate whether p53 transactivated target genes are induced in a rat model of focal cerebral ischemia. Therefore, we applied in situ hybridization, immunocytochemistry and western blotting to study the temporal and spatial expression of p53 and its transcriptional targets Bax, p21 and cyclin G1 following permanent middle cerebral artery occlusion in the rat. Cyclin G1 immunoreactivity was constitutively expressed in the nuclei of cells in the choroid plexus and ependymal cell layer and in the cytoplasm of cell bodies and dendrites of pyramidal neurons of the cerebral cortex. Cyclin G1 messenger RNA and protein levels transiently increased to 150% of contralateral levels in neurons of the ipsilateral frontal and parietal cortex and striatum 3 h following middle cerebral artery occlusion. A low level of constitutively expressed p21 messenger RNA and protein was found in nuclei of cells in the choroid plexus, oligodendrocytes and neurons. p21 messenger RNA and protein levels gradually increased to 250% and 140% of contralateral levels in areas bordering the infarct core up to 6 h following middle cerebral artery occlusion. In contrast, p53 and Bax messenger RNA and protein levels, and protein levels of p27, cyclin-dependent kinase 5, p35 and cyclin E decreased in the infarct core and border areas with time after middle cerebral artery occlusion. The selective up-regulation of cyclin G1 and p21 in neurons in the border zone of a focal ischemic infarct indicates their involvement in an adaptive response to ischemic injury. The possible participation of cyclin G1 and p21 in a signal transduction pathway associated with ischemia-induced cellular stress is discussed.
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PMID:Cell cycle-related gene expression in the adult rat brain: selective induction of cyclin G1 and p21WAF1/CIP1 in neurons following focal cerebral ischemia. 957 98

After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number ( approximately 1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.
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PMID:Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death. 1143 80

Formation of new blood vessels in the adult animal (i.e., angiogenesis) is an important event for tissue repair and for tumor growth and metastasis. Angiogenesis involves the migration and proliferation of endothelial cells. We have investigated the role of the growth suppressor p27(Kip1) (p27) on endothelial cell function in vitro and angiogenesis in vivo. We have generated Ad-TetON, a replication-deficient adenovirus that constitutively expresses the reverse tet-responsive transcriptional activator, and Ad-TRE-p27, which drives expression of p27 under the control of the tet response element. Western blot analysis demonstrated doxycycline-dependent overexpression of p27 in human umbilical vein endothelial cells (HUVECs) coinfected with Ad-TetON and Ad-TRE-p27, which resulted in a marked inhibition of DNA replication and cell migration in vitro. Inducible overexpression of p27 in cultured HUVECs inhibited the formation of tubelike structures and, when applied in a murine model of hind limb ischemia, reduced hind limb blood flow recovery and capillary density. These findings thus underscore a novel role of p27 in regulating endothelial cell migration in vitro and angiogenesis in vivo, suggesting a novel anti-angiogenic therapy based on inducible p27 overexpression.
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PMID:Overexpression of p27(Kip1) by doxycycline-regulated adenoviral vectors inhibits endothelial cell proliferation and migration and impairs angiogenesis. 1153 67

The RING (really interesting new gene) finger proteins containing a characteristic C3HC4 or C3H2C3 motif appear to act as E3 ubiquitin ligase and play important roles in many processes, including cell-cycle progression, oncogenesis, signal transduction, and development. This review is focused on SAG/ROC/Rbx/Hrt (sensitive to apoptosis gene/regulator of cullins/RING box protein), an evolutionarily conserved RING finger family of proteins that were cloned recently by several independent laboratories through differential display, yeast two-hybrid screening, or biochemical purification. SAG/ROC2/Rbx2/Hrt2 is expressed in multiple mouse adult tissues, as well as early embryos. In humans, both SAG and ROC1 are ubiquitously expressed at a very high level in heart, skeletal muscle, and testis. Expression of both SAG and ROC1 is induced by mitogenic stimulation. SAG is also induced by a redox agent in cultured cells, as well as in in vivo mouse brain upon ischemia/reperfusion. Structurally, SAG consists of four exons and three introns with at least one splicing variant and two pseudogenes. The SAG gene promoter is enriched with multiple transcription factor binding sites. Biochemically, SAG binds to RNA, has metal-ion binding/free radical scavenging activity, and is redox-sensitive. Most importantly, like ROC1, SAG/ROC2 binds to cullins and acts as an essential component of E3 ubiquitin ligase. Biologically, SAG is a growth-essential gene in yeast. In mammalian cells, SAG protects apoptosis mainly through inhibition of cytochrome c release/caspase activation, and promotes growth under serum deprivation at least in part by inhibiting p27 accumulation. Blocking SAG expression via antisense transfection inhibits tumor cell growth. Thus, SAG appears to be a valid drug target for anticancer therapy.
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PMID:SAG/ROC/Rbx/Hrt, a zinc RING finger gene family: molecular cloning, biochemical properties, and biological functions. 1155 50

Inhibition of poly (ADP-ribose) polymerase 1 (PARP-1) improved hemodynamics and organ function in various shock models induced by sepsis or ischemia/reperfusion. PARP-1, however, is also referred to play a pivotal role for the maintenance of genomic integrity. Therefore, we investigated the effect of the PARP-1 blocker INO-1001 on hemodynamics, kidney function, and DNA damage and repair during porcine thoracic aortic cross-clamping. The animals underwent 45 min of aortic cross-clamping after receiving vehicle (n=9) or i.v. INO-1001 (n=9; total dose, 4 mg.kg, administered both before clamping and during reperfusion), data were recorded before clamping, before declamping, and 2 and 4 h after declamping. During reperfusion, continuous i.v. norepinephrine was incrementally adjusted to maintain blood pressure greater than or equal to 80% of the pre-clamping level. The plasma INO-1001 levels analyzed with high-pressure liquid chromatography were 1 to 1.4 micromol/L and 0.4 to 0.6 micromol/L before and after clamping, respectively. Although INO-1001-treated animals required less norepinephrine support, kidney function was comparable in the 2 groups. There was no intergroup difference either in the time course of DNA damage and repair (comet assay) as assessed both in vivo in whole blood before surgery, before clamping, before declamping, 2 h after declamping, and ex vivo in isolated lymphocytes (Ficoll gradient) sampled immediately before clamping and analyzed before, immediately, and 1 and 2 h after exposure to 4 bar 100% O2 for 2 h. There was no difference either in the expression of the cyclin-dependent kinase inhibitor gene, p27, in the kidney (immunohistochemistry). The reduced norepinephrine requirements during reperfusion suggest a positive inotropic effect of INO-1001, as demonstrated by other authors. In our model, INO-1001 proved to be safe with respect to DNA repair.
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PMID:The parp-1 inhibitor ino-1001 facilitates hemodynamic stabilization without affecting DNA repair in porcine thoracic aortic cross-clamping-induced ischemia/reperfusion. 1672 Dec 72

Cell cycle inhibition of neural stem and progenitor cells is critical for maintaining the stability of central nervous system in adults, but it may represent a significant hurdle for neural regeneration after injury. We have previously demonstrated that the cyclin-dependent kinase inhibitor (CKI) p21(cip1/waf1) (p21) maintains the quiescence of neural stem-like cells under cerebral ischemia, as similarly shown for the hematopoietic stem cells. Here, we report the distinct role of another CKI member, p27(kip1) (p27) in neural progenitor cells (NPCs) from adult brain (subventricular zone and hippocampal subgranular zone) under both homeostatic and ischemic conditions. The basal level of NPC proliferation in the p27-/- mice was higher than that in p27+/+ mice. Upon ischemia, the overall proliferation of NPCs continued to be higher in p27-/- mice than that in p27+/+ mice. Moreover, the increase of NPC proliferation in p27-/- mice remained until 2 weeks after ischemia, whereas it resumed back to the basal level in p27+/+ mice. As a result, newly generated neuronal cells in the granular layer of p27-/- brain were more abundant compared with p27+/+ controls. These new data demonstrate that p27 functions as a distinct inhibitor for NPC proliferation under homeostatic as well as ischemic conditions.
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PMID:p27Kip1 constrains proliferation of neural progenitor cells in adult brain under homeostatic and ischemic conditions. 1935 20

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to promote apoptosis in cancer cells. However, the role of EGCG in endothelial cells following ischemia/reperfusion (I/R) injury remains unclear. In the present study, we investigated the mechanisms by which EGCG enhances I/R-induced cell growth inhibition and apoptosis in human umbilical vein endothelial cells (HUVECs). Our results showed that EGCG treatment caused cell proliferation inhibition during I/R injury, and this effect was associated with increased p27 and p21 levels and reduced cyclin D1 level. Moreover, treatment of cells with EGCG resulted in increase of caspase-3 and Bax and decrease of Bcl-2, enhancing I/R-induced apoptosis. Interestingly, EGCG decreased I/R-induced phosphorylation of AKT and its downstream substrates Foxo1 and Foxo3a and ERK1/2. In contrast, EGCG increased JNK1/2 and c-Jun phosphorylation. Furthermore, both wortamannin (PI3K inhibitor) and U0126 (MEK1/2 inhibitor) markedly enhanced EGCG-induced apoptosis during I/R, whereas SP600125 (JNK inhibitor) attenuated the action of EGCG. Taken together, our study for the first time suggest that EGCG is able to enhance growth arrest and apoptosis of HUVECs during I/R injury, at least in part, through inhibition of AKT and ERK1/2 and activation of JNK1/2 signaling pathways.
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PMID:Epigallocatechin-3-gallate enhances ischemia/reperfusion-induced apoptosis in human umbilical vein endothelial cells via AKT and MAPK pathways. 1966 89

Transplantation of bone marrow stromal cells (BMSCs) improves animal neurological functional recovery after stroke. But the mechanism remains unclear. As cell cycle machinery plays an important role in stroke, we investigated the dynamic changes of cell cycle elements in a rat model of middle cerebral artery occlusion. We found the cell cycle markers, cdk4 along with its activator cyclin D1, and proliferating cell nuclear antigen (PCNA), increased after brain ischemia-reperfusion. Phosphorylation of the retinoblastoma protein (pRb, on ser-795), the cyclin D/cdk4 complex mutual target, was upregulated accordingly. However, intravenously administrated BMSCs facilitated cyclin D1, cdk4, and PCNA decrease in the ischemic cortex. Meanwhile, phospho-pRb (ser-795) was completely inhibited. On the contrary, endogenous cdk inhibitor p27 reduced before but enhanced after BMSCs treatment. These findings suggested BMSCs might modulate cell cycle progression in injured brain via downregulation of the cyclin D1/cdk4/pRb pathway as well as upregulation of p27 level. These results provide another way by which BMSCs may contribute to the recovery from stroke.
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PMID:Dynamic changes of cell cycle elements in the ischemic brain after bone marrow stromal cells transplantation in rats. 1979 67

Chronic limb ischemia, a complication commonly observed in conjunction with cardiovascular disease, is characterized by insufficient neovascularization despite the up-regulation of pro-angiogenic mediators. One hypothesis is that ischemia induces inhibitory signals that circumvent the normal capillary growth response. FoxO transcription factors exert anti-proliferative and pro-apoptotic effects on many cell types. We studied the regulation of FoxO1 protein in ischemic rat skeletal muscle following iliac artery ligation and in cultured endothelial cells. We found that FoxO1 expression was increased in capillaries within ischemic muscles compared with those from rats that underwent a sham operation. This finding correlated with increased expression of p27(Kip1) and reduced expression of Cyclin D1. Phosphorylated Akt was reduced concurrently with the increase in FoxO1 protein. In skeletal muscle endothelial cells, nutrient stress as well as lack of shear stress stabilized FoxO1 protein, whereas shear stress induced FoxO1 degradation. Endogenous FoxO1 co-precipitated with the E3 ubiquitin ligase murine double minute-2 (Mdm2) in endothelial cells, and this interaction varied in direct relation to the extent of Akt and Mdm2 phosphorylation. Moreover, ischemic muscles had a decreased level of Mdm2 phosphorylation and a reduced interaction between Mdm2 and FoxO1. Our results provide novel evidence that the Akt-Mdm2 pathway acts to regulate endothelial cell FoxO1 expression and illustrate a potential mechanism underlying the pathophysiological up-regulation of FoxO1 under ischemic conditions.
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PMID:Identification of a mechanism underlying regulation of the anti-angiogenic forkhead transcription factor FoxO1 in cultured endothelial cells and ischemic muscle. 2128 24

The wood frog (Rana sylvatica) is one of only a few vertebrate species that can survive extensive freezing of its body fluids during the winter. The mechanisms of natural freeze tolerance include metabolic rate depression to conserve energy and the implementation of cryoprotective strategies, especially the synthesis of huge amounts of glucose as a cryoprotectant. Liver is the main source of glucose production/export (and other cryoprotective actions) and plays a central role in freezing survival of the whole animal. Freezing is a multi-component stress that includes anoxia/ischemia due to the cessation of blood flow and dehydration of cells caused by ice accumulation in extracellular spaces. To help endure these stresses, cells need to suppress and reprioritize ATP-expensive cell functions. One of these is cell growth and proliferation, and we hypothesized that cell cycle arrest would be key to freezing survival. The present study examines the responses by key cell cycle components to freezing, anoxia and dehydration stresses in wood frog liver. Immunoblotting was used to investigate protein expression of Cdc 2, Cdks (2, 4, 6), and cyclins (A, B1, D1, E) as well as the phosphorylation states of Cdks (Thr14/Tyr15), the phosphatases Cdc25a (Ser76) and Cdc25c (Ser216) and the CIP/KIP Cdk inhibitors p21 (Thr145) and p27 (Thr187). Responses to 24 h freezing, 24 h anoxia and 40% dehydration as well as recovery from these stresses were analyzed. The results showed very similar responses by cell cycle components to anoxia or dehydration and were consistent with cell cycle suppression under stress and reversal during recovery. Freezing showed elements of cell cycle suppression, including reduced protein levels of Cdks and cyclins A and B1, but also showed unique responses by cyclin D1, Cdc25 phosphatases and p21/p27. These may be linked with alternative actions by these proteins that contribute to cryoprotection; e.g., an alternative action of cyclin D1 as a transcription factor may contribute to the upregulation of glucose-6-phosphatase, a key enzyme needed for the export of glucose cryoprotectant.
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PMID:Cell cycle regulation in the freeze tolerant wood frog, Rana sylvatica. 2251 May 73


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