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: KEGG:D03575 (CoCl2)
1,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor-1 (HIF-1) is a heterodimer composed of HIF-1alpha and HIF-1beta protein subunits. This transcription factor is essential for the activation of hypoxia-inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2 for 3 hours), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. To support the role of HIF-1 in protective preconditioning, we also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1alpha and HIF-1beta protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl2 or DFX 24 hours before hypoxia-ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle-injected littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning, which could be used in high-risk deliveries and other clinical situations.
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PMID:Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. 1097 34

HIF-1 is composed of HIF-1alpha and HIF-1beta protein subunits. HIF-1 is induced by hypoxia and binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2/3 hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. We also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1alpha and HIF-1beta protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.
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PMID:Hypoxia-inducible factor in brain. 1195 Jan 44

Acute systemic hypoxia induces delayed cardioprotection against ischemia (I)-reperfusion (R) injury via inducible nitric oxide synthase (iNOS)-dependent mechanism. Because CoCl2 is known to elicit hypoxia-like responses, we hypothesized that this chemical would mimic the delayed preconditioning effect in the heart. Adult male mice were pretreated with CoCl2 or saline. The hearts were isolated 24 h later and subjected to 20 min of global I and 30 min of R in Langendorff mode. Myocardial infarct size (% of risk area; mean +/- SE, n=6-8/group) was reduced in mice pretreated with 30 mg/kg CoCl2 (16.1 +/- 3.1% vs. 27.6 +/- 3.3% with saline control; P <0.05) without compromising postischemic cardiac function. Higher doses of CoCl2 failed to induce similar protection. Electrophoretic mobility gel shift assay demonstrated significant enhancement in DNA binding activity of hypoxia-inducible factor 1alpha (HIF-1alpha) and activator protein 1 (AP-1) in nuclear extracts from CoCl2-treated hearts. Activation of HIF-1alpha and AP-1 was evident at 30 min and sustained for the next 4 h after CoCl2 injection. In contrast, CoCl2-induced protection was independent of NF-kappaB activation because no DNA binding or p65 translocation was observed in nuclear extracts. Also, CoCl2-induced cardioprotection was preserved in p50 subunit NF-kappaB-knockout (KO) mice (11.1 +/- 3.0% vs. 25.1 +/- 5.0% in saline-treated p50-KO mice; P <0.05). The infarct-limiting effect of CoCl2 was absent in iNOS-KO mice (20.9 +/- 3.0%). We conclude that in vivo administration of CoCl2 preconditions the heart against I/R injury. The delayed protective effect of CoCl2 is achieved through a distinctive signaling mechanism involving HIF-1alpha, AP-1, and iNOS but independent of NF-kappaB activation.
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PMID:Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1alpha and AP-1 and iNOS signaling. 1528 66

Tumor hypoxia is a spatially and temporally heterogeneous phenomenon, which results from several tumor and host tissue-specific processes. To study the dynamics and spatial heterogeneity of hypoxia-inducible factor-1 (HIF-1)-specific transcriptional activity in tumors, we used repetitive noninvasive positron emission tomography (PET) imaging of hypoxia-induced HIF-1 transcriptional activity in tumors in living mice. This approach uses a novel retroviral vector bearing a HIF-1-inducible "sensor" reporter gene (HSV1-tk/GFP fusion) and a constitutively expressed "beacon" reporter gene (DsRed2/XPRT). C6 glioma cells transduced with this multireporter system revealed dose-dependent patterns in temporal dynamics of HIF-1 transcriptional activity induced by either CoCl2 or decreased atmospheric oxygen concentration. Multicellular spheroids of C6 reporter cells developed a hypoxic core when >350 microm in diameter. 18F-2'-fluoro-2'deoxy-1beta-D-arabionofuranosyl-5-ethyl-uracil (FEAU) PET revealed spatial heterogeneity of HIF-1 transcriptional activity in reporter xenografts in mice as a function of size or ischemia-reperfusion injury. With increasing tumor diameter (>3 mm), a marked increase in HIF-1 transcriptional activity was observed in the core regions of tumors. Even a moderate ischemia-reperfusion injury in small C6 tumors caused a rapid induction of HIF-1 transcriptional activity, which persisted for a long time because of the inability of C6 tumors to rapidly compensate acute changes in tumor microcirculation.
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PMID:Molecular imaging of temporal dynamics and spatial heterogeneity of hypoxia-inducible factor-1 signal transduction activity in tumors in living mice. 1534 93

Various types of preconditioning including the main hypoxia (hypoxic, circulatory, hematic/hypemic and tissue/histotoxic), agonists of adenosine A-receptors and openers of K(ATP)-channels induce a hypothermia. A-agonists act through A1-receptors, CoCl2 and NiCl2--via endogenous adenosine and activation by it A1-receptors. The developing hypothermia correlates with neuroprotective effect and is important, but not the only mechanism of tolerance increase to global ischemia. At the similar hypothermia the preconditioning effect excels more frequently an influence of external cooling.
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PMID:[The importance of hypothermia in the preconditioning increase of ischemic tolerance to global cerebral ischemia]. 1686 90

In order to explore the effect of high glucose concentration and high glucose concentration with hypoxia on the production of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF), human RPE cells were cultured in 5.56 mmol/L glucose (control group), 5.56 mmol/L glucose with 150 micro mol/L CoCl2 (hypoxic group), 25 mmol/L glucose (high glucose group) and 25 mmol/L glucose with 150 micro mol/L CoCl2 (combination group). RT-PCR was used to detect the expression of HIF-1alpha and VEGF mRNAs. Western blot analysis was used to measure the levels of HIF-1alpha and VEGF proteins. Although the small amount of HIF-1alpha protein was able to be detected in high glucose group but not in control group, there was no significant difference between the expression of HIF-1alpha mRNA of RPE cells in high glucose group and that of RPE cells in control group. As compared with RPE cells in control group, the mRNA expression and the protein synthesis of VEGF in high glucose group were up-regulated. As compared with RPE cells in hypoxic group, the expression of HIF-1alpha mRNA of RPE cells in combination group was not different, but the protein synthesis of HIF-1alpha, the mRNA expression and the protein synthesis of VEGF were more obviously up-regulated. In conclusion, high concentration glucose mainly influence the protein synthesis of HIF-1alpha of RPE cell, and HIF-1alpha protein is able to be accumulated in high concentration glucose. Under hypoxia, the HIF-1alpha protein induced by high concentration glucose is more stable, and the expression of VEGF is obviously increased. It is suggested that high concentration glucose may play a role in retinal neovascularization, especially at ischemia stage of diabetic retinopathy.
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PMID:Up-regulation of HIF-1alpha and VEGF expression by elevated glucose concentration and hypoxia in cultured human retinal pigment epithelial cells. 1712 Jul 49

Cerebral microvascular endothelial cells form the anatomical basis of the blood-brain barrier (BBB), and the tight junctions of the BBB are critical for maintaining brain homeostasis and low permeability. Ischemia/reperfusion is known to damage the tight junctions of BBB and lead to permeability changes. Here we investigated the protective role of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), against chemical hypoxia and hypoxia/reoxygenation (H/R)-induced BBB hyperpermeability using adult rat brain endothelial cell culture (ARBEC). YC-1 significantly decreased CoCl2- and H/R-induced hyperpermeability of fluorescein isothiocyanate (FITC)-dextran in cell culture inserts. It was found that the decrease and disorganization of tight junction protein zonular occludens-1 (ZO-1) in response to CoCl2, and H/R was antagonized by YC-1. The protection of YC-1 may result from the inhibition of HIF-1alpha accumulation and production of its downstream target vascular endothelial growth factor (VEGF). VEGF alone significantly increased FITC-dextran permeability and down-regulated mRNA and protein levels of ZO-1 in ARBECs. We further used animal model to examine the effect of YC-1 on BBB permeability after cerebral ischemia/reperfusion. It was found that YC-1 significantly protected the BBB against ischemia/reperfusion-induced injury. Taken together, these results indicate that YC-1 may inhibit HIF-1alpha accumulation and VEGF production, which in turn protect BBB from injury caused by hypoxia.
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PMID:Inhibition of hypoxia-induced increase of blood-brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. 1751 85

In bladder outlet obstruction (BOO), mechanical stress and ischemia/hypoxia are implicated in structural and functional alterations of the urinary bladder. Because mechanical stress and hypoxia may trigger endoplasmic reticulum (ER) stress, we examined involvement of ER stress in the damage of the bladder caused by BOO. An experimental model of BOO was established in rats by complete ligature of the urethra for 24 h, and bladders were subjected to northern blot analysis and assessment of apoptosis. Isolated urinary bladders and bladder-derived smooth muscle cells (BSMCs) were also exposed to mechanical strain and hypoxia and used for analyses. To examine involvement of ER stress in the damage of the bladder, the effects of a chemical chaperone 4-phenylbutyrate (4-PBA) were evaluated in vitro and in vivo. Outlet obstruction for 24 h induced expression of ER stress markers, GRP78 and CCAAT/enhancer-binding protein-homologous protein (CHOP), in the bladder. It was associated with induction of markers for mechanical stress (cyclooxygenases 2) and hypoxia (vascular endothelial growth factor and glyceraldehyde-3-phosphate dehydrogenase). When isolated bladders and BSMCs were subjected to mechanical strain, induction of GRP78 and CHOP was not observed. In contrast, when BSMCs were exposed to hypoxic stress caused by CoCl2 or thenoyltrifluoroacetone (TTFA), substantial upregulation of GRP78 and CHOP was observed, suggesting involvement of hypoxia in the induction of ER stress. In the bladder subjected to BOO, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells increased in the epithelial cells and BSMCs. Similarly, treatment with TTFA or CoCl2 induced apoptosis of BSMCs, and 4-PBA significantly attenuated ER stress and apoptosis triggered by these agents. Furthermore, in vivo administration with 4-PBA significantly reduced apoptosis in the bladder subjected to BOO. These results suggested that outlet obstruction caused ER stress via hypoxic stress in the bladder and that hypoxia-triggered ER stress may be involved in the induction of apoptosis in BOO.
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PMID:Involvement of hypoxia-triggered endoplasmic reticulum stress in outlet obstruction-induced apoptosis in the urinary bladder. 1834 81

In this study, we investigated the effects of ischemia/reperfusion and chemical hypoxia on the morphology, cell viability and expression of bystin and glial fibrillary acidic protein (GFAP) in primary cultured astrocytes which were prepared by the subculture method. The astrocytes in Hank's medium without glucose and serum (oxygen-glucose deprivation, ischemic cells) were first exposed to 1% O2 and then to 21% O2 (normoxia), or treated with different concentrations of CoCl2 or NaN3 for different periods. Relevant observations and measurements were then conducted. The findings showed that treatment with 1% O2 for 0.5 or 3 h could induce a characteristic 'reactive' morphology and a significant increase in cell viability and total protein amount. The western blot analysis showed that treatment with 1% O2 for 0.5 or 3 h also induced a significant increase in the expression of bystin and that the response of bystin to mild ischemia was much more sensitive than that of GFAP. Similar results were also found in the cells treated with mild chemical hypoxia. The data demonstrated for the first time that mild ischemia and hypoxia could activate astrocytes and that bystin is a much more sensitive marker in activated astrocytes induced by ischemia and hypoxia as compared to GFAP. The significant up-regulation of bystin suggests that bystin may play an important role in the activation of astrocytes as well as in the neuroprotective role of hypoxic and ischemic preconditioning.
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PMID:Expression of bystin in reactive astrocytes induced by ischemia/reperfusion and chemical hypoxia in vitro. 1892 47

Different types of hypoxia, including several new models, protect the brain against complete global ischemia. Hypoxic (stay in hermetic chamber without or with consumption of CO2 and H2O exhaled), circulatory (bleeding), hematic (injections of NaNO2, CoCl2, NiCl2) and tissue (histotoxic) hypoxia (K2-malonate injection) increases cerebral ischemic tolerance in early terms (in hours). Intracerebroventricular injections of NaNO2, CoCl2, NiCl2 and K2-malonate in nontoxic doses have weak effects. These substances act by peripheral mechanisms. Increased ischemic tolerance is accompanied by pronounced hypothermia which closely correlates with a neuroprotective effect. This shows using tolerant strategy.
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PMID:[Different types of hypoxic preconditioning protect the brain against complete global ischemia]. 1894 7


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