Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proto-oncogene (c-fos, c-jun) and nuclear factor-kappa B (NF-kappaB) expression, as well as DNA synthesis, in aortic and cerebral vascular smooth muscle cells (VSMCs) were upregulated by a decrease in extracellular magnesium ions ([Mg2+]o). Upregulation of these transcriptional factors was inversely proportional to the [Mg2+]o and occurred over the pathophysiologic range of serum Mg2+ found in patients presenting with hypertension, ischemic heart disease, and stroke. Removal of extracellular Ca2+ ([Ca2+]o), use of nifedipine or protein kinase C (PKC) inhibitors prevented the upregulation of the proto-oncogenes and DNA synthesis in VSMCs. These data show that [Mg2+]o may be an important, heretofore, overlooked natural modulator of proto-oncogene and NF-kappaB expression in VSMCs and that Ca2+ and PKC may play critical roles in induction of c-fos and c-jun in VSMCs induced by a decrease in [Mg2+]o. These results point to a role for low serum Mg2+ in potential development of hypertension, atherogenesis, vascular disease, and stroke.
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PMID:Expression of the nuclear factor-kappaB and proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle cells: possible links to hypertension, atherogenesis, and stroke. 1294 25

Pathological conditions such as ischaemic stroke and inflammatory disorders cause c-fos activation in the brain. This activation contributes to the initiation of the brain's inflammatory response, orchestrated by activated glial cells. The inflammatory signalling cascades leading to c-fos activation in glial cells are not well characterized. Thus, we have attempted a detailed analysis of the cis-acting elements, transcription factors and upstream kinase pathways involved in the activation of c-fos by lipopolysaccharide (LPS) in primary rat cortical glial cells. We found that (1) LPS-induced c-fos mRNA levels were sensitive to p38 mitogen-activated protein kinase (MAPK) inhibitors but not to mitogen-activated/extracellular signal-regulated kinase (ERK) or calcium-calmodulin-dependent kinase inhibitors, (2) LPS activated both serum response element (SRE) and cyclic AMP/calcium response element (CRE)-driven luciferase reporters in transient transfection assays, (3) LPS induced the phosphorylation of Elk1 CRE-binding protein (CREB)/activated transcription factor-1 (ATF-1) and the activation of GAL4-Elk1 and GAL4-CREB chimeric proteins, and (4) mutation of both SRE and CRE elements was necessary and sufficient to completely abolish LPS induction of a rat c-fos proximal promoter-luciferase reporter. Thus, c-fos activation by LPS in glial cells occurs via the SRE or CRE in an independent manner, and involves the Elk1 or CREB/ATF-1 transcription factors. Elk1-mediated transactivation was dependent on p38 MAPK, suggesting a crucial role of these factors in mediating inflammatory responses in the CNS.
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PMID:Activation of c-fos by lipopolysaccharide in glial cells via p38 mitogen-activated protein kinase-dependent activation of serum or cyclic AMP/calcium response element. 1568 94

Sympathetic hyper-innervation and increased levels of nerve growth factor (NGF), an essential neurotrophic factor for sympathetic neurons, have been observed in the vascular tissues of spontaneously hypertensive rats (SHRs). Such observations have suggested that the pathogenesis of hypertension might involve a qualitative or quantitative abnormality in the NGF protein, resulting from a significant mutation in the gene's promoter or coding region. In the present study, we analyzed the nucleotide sequences of the cis-element of the NGF gene in SHRs, stroke-prone SHRs (SHRSPs), and normotensive Wistar-Kyoto (WKY) rats. The present analyses revealed some differences in the 3-kb promoter region, coding exon, and 3' untranslated region (3'UTR) for the NGF gene among those strains. However, the observed differences did not lead to changes in promoter activity or to amino acid substitution; nor did they represent a link between the 3'UTR mutation of SHRSPs and elevated blood pressure in an F2 generation produced by crossbreeding SHRSPs with WKY rats. These results suggest that the NGF gene locus is not involved in hypertension in SHR/ SHRSP strains. The present study also revealed two differences between SHRs and WKY rats, as found in cultured vascular smooth muscle cells and in mRNA prepared from each strain. First, SHRs had higher expression levels of c-fos and c-jun genes, which encode the component of the AP-1 transcription factor that activates NGF gene transcription. Second, NGF mRNAs prepared from SHRs had a longer 3'UTR than those prepared from WKY rats. Although it remains to be determined whether these events play a role in the hypertension of SHR/SHRSP strains, the present results emphasize the importance of actively searching for aberrant trans-acting factor(s) leading to the enhanced expression of the NGF gene and NGF protein in SHR/SHRSP strains.
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PMID:No involvement of the nerve growth factor gene locus in hypertension in spontaneously hypertensive rats. 1602 43

Neuregulins are a family of growth factor domain proteins that are structurally related to the epidermal growth factor. Accumulating evidence has shown that neuregulins have cyto- and neuroprotective properties in various cell types. In particular, the neuregulin-1 Beta (NRG1-Beta) isoform is well documented for its antiinflammatory properties in rat brain after acute stroke episodes. Pentachlorophenol (PCP) is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Previous investigations from our laboratory have demonstrated that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG2) cells, primary catfish hepatocytes and AML 12 mouse hepatocytes. We have also shown that in HepG2 cells, PCP has the ability to induce stress genes that may play a role in the molecular events leading to toxicity and tumorigenesis. In the present study, we hypothesize that NRG1-Beta will exert its cytoprotective effects in PCP-treated AML 12 mouse hepatocytes by its ability to suppress the toxic effects of PCP. To test this hypothesis, we performed the MTT-cell respiration assay to assess cell viability, and Western-blot analysis to assess stress-related proteins as a consequence of PCP exposure. Data obtained from 48 h-viability studies demonstrated a biphasic response; showing a dose-dependent increase in cell viability within the range of 0 to 3.87 microg/mL, and a gradual decrease within the concentration range of 7.75 to 31.0 microg/mL in concomitant treatments of NRG1-Beta+PCP and PCP. Cell viability percentages indicated that NRG1-Beta+PCPtreated cells were not significantly impaired, while PCP-treated cells were appreciably affected; suggesting that NRG1-Beta has the ability to suppress the toxic effects of PCP. Western Blot analysis demonstrated the potential of PCP to induce oxidative stress and inflammatory response (c-fos), growth arrest and DNA damage (GADD153), proteotoxic effects (HSP70), cell cycle arrest as consequence of DNA damage (p53), mitogenic response (cyclin- D1), and apoptosis (caspase-3). NRG1-Beta exposure attenuated stress-related protein expression in PCP-treated AML 12 mouse hepatocytes. Here we provide clear evidence that NRG1-Beta exerts cytoprotective effects in AML 12 mouse hepatocytes exposed to PCP.
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PMID:Neuregulin 1-Beta cytoprotective role in AML 12 mouse hepatocytes exposed to pentachlorophenol. 1682 72

Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders like atherosclerosis and restenosis after angioplasty. In the present study, the possible anti-proliferative effect of a synthetic 1,4-naphthoquinone derivative, 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304) was investigated on rat aortic VSMCs. NQ304 was shown to potently inhibit 5% fetal bovine serum (FBS)-induced the growth of VSMCs. Pre-treatment of VSMCs with NQ304 (1-10 microM) for 24 h resulted in significant cell number decreases, i.e., inhibition percentages were 44.75+/-10.77, 73.85+/-6.38 and 89.77+/-6.52% at NQ304 concentrations of 1, 5 and 10 microM, respectively. NQ304 was also found to significantly inhibit 5% FBS-induced DNA synthesis in a concentration-dependent manner. Furthermore, NQ304 elevated p21(cip1) and p27(kip1) mRNA levels and caused G0/G1 phase arrest in cell cycle progression. However, no evidence of NQ304-induced apoptotic or necrotic cell death was obtained, as determined by flow cytometry analysis and DNA fragmentation assays. To investigate the mechanism underlying the anti-proliferative effect of NQ304, we examined the effects of NQ304 on c-fos mRNA expression, activator protein-1 (AP-1) binding activity and extracellular signal-regulated kinase1/2 (ERK1/2) and Akt activation. Pre-treatment of VSMCs with NQ304 (1-10 microM) was found to significantly inhibit the 5% FBS-induced phosphorylations of ERK1/2 and Akt, the activation of AP-1 and the expression of c-fos. These data suggest that the anti-proliferative and cell cycle arresting effects of NQ304 on serum-induced VSMCs may be mediated by AP-1 activation downregulation via the suppression of phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 signaling pathways, and it may contribute to the prevention of atherosclerosis through inhibition of VSMC proliferation.
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PMID:Potent inhibition of serum-stimulated responses in vascular smooth muscle cell proliferation by 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone, a newly synthesized 1,4-naphthoquinone derivative. 1720 71

The assessment of target organ damage is important in defining the optimal treatment of hypertension and blood pressure-related cardiovascular disease. The aims of the present study were (1) to investigate candidate biomarkers of target organ damage, osteopontin (OPN) and plasminogen activator inhibitor-1 (PAI-1), in models of malignant hypertension with well characterized end-organ pathology; and (2) to evaluate the effects of chronic treatment with a p38 MAPK inhibitor. Gene expression, plasma concentrations, and renal immunohistochemical localization of OPN and PAI-1 were measured in stroke-prone spontaneously hypertensive rats on a salt-fat diet (SFD SHR-SP) and in spontaneously hypertensive rats receiving N(omega)-nitro-L-arginine methyl ester (L-NAME SHR). Plasma concentrations of OPN and PAI-1 increased significantly in SFD SHR-SP and L-NAME SHR as compared with controls, (2.5-4.5-fold for OPN and 2.0-9.0-fold for PAI-1). The plasma levels of OPN and PAI-1 were significantly correlated with the urinary excretion of albumin (p < 0.0001). Elevations in urinary albumin, plasma OPN and PAI-1 were abolished by chronic treatment (4-8 weeks) with a specific p38 MAPK inhibitor, SB-239063AN. OPN immunoreactivity was localized predominantly in the apical portion of tubule epithelium, while PAI-1 immunoreactivity was robust in glomeruli, tubules and renal artery endothelium. Treatment with the p38 MAPK inhibitor significantly reduced OPN and PAI-1 protein expression in target organs. Kidney gene expression was increased for OPN (4.9- and 7.9-fold) and PAI-1 (2.8- and 11.5-fold) in SFD SHR-SP and L-NAME SHR, respectively. In-silico pathway analysis revealed that activation of p38 MAPK was linked to OPN and PAI-1 via SPI, c-fos and c-jun; suggesting that these pathways may play an important role in p38 MAPK-dependent hypertensive renal dysfunction. The results suggest that enhanced OPN and PAI-1 expression reflects end-organ damage in hypertension and that suppression correlates with end-organ protection regardless of overt antihypertensive action.
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PMID:P38 MAPK inhibitors suppress biomarkers of hypertension end-organ damage, osteopontin and plasminogen activator inhibitor-1. 1743 56

To assess the effects of acetylsalicylic acid (ASA) on glutamate and interleukin-6 (IL-6) release in the striatum of rats suffering from cerebral ischemia, we used the microdialysis technique with probes implanted 2 h prior to stroke onset. A total of 36 rats were randomly assigned to either temporary (90 min, n=18) or permanent (n=18) middle cerebral artery occlusion (MCAO). Animals received either a bolus of 40 mg/kg ASA or saline as control 30 min after stroke onset. Permanent MCAO led to large infarct volumes with no differences between treatment with ASA (239.8+/-4.1 mm3) and saline (230.1+/-3.9 mm3, p=0.15). In contrast, ASA therapy in temporary ischemia (87.2+/-6.2 mm3) reduced infarct size significantly compared to placebo (155.6+/-4.8 mm3, p<0.0001). Only in temporary ischemia, ASA application reduced glutamate significantly at the time points 90, 120, and 150 min after MCAO. Pooled post-ischemic microdialysate concentrations of IL-6 in temporary MCAO were significantly higher after ASA treatment (215+/-81 pg/mL, p=0.0297) than in saline-treated rats (80+/-13 pg/mL). In the permanent MCAO group, no difference in IL-6 between the ASA (125+/-21 pg/mL) and saline group (68+/-34 pg/mL) was noted. No differences were seen for c-fos positive neurons in the penumbra and hippocampus between all groups. These results suggest that the neuroprotective effect of ASA is reflected by glutamate attenuation and IL-6 induction even if given after stroke onset, but only if reperfusion is achieved.
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PMID:Neuroprotection and glutamate attenuation by acetylsalicylic acid in temporary but not in permanent cerebral ischemia. 1818 32

Macrophages as inflammatory cells are involved in the pathogenesis of atherosclerosis that today is recognized as an inflammatory disease. Activation of coagulation leads to the late complication of atherosclerosis, namely atherothrombosis with its clinical manifestations stroke, unstable angina, myocardial infarction, and sudden cardiac death. Thus inflammation and coagulation play fundamental roles in the pathogenesis of atherosclerosis. We show that the coagulation enzyme thrombin up-regulates oncostatin M (OSM), a pleiotropic cytokine implicated in the pathophysiology of vascular disease, in human monocyte-derived macrophages (MDMs) up to 16.8-fold. A similar effect was seen in human peripheral blood monocytes and human plaque macrophages. In MDMs, the effect of thrombin on OSM was abolished by PPACK and mimicked by a PAR-1-specific peptide. Thrombin induced phosphorylation of ERK1/2 and p38 in MDMs. The ERK1/2 inhibitor PD98059 blocked the effect of thrombin on OSM production in MDMs, whereas the p38 inhibitor SB202190 had no effect. Thrombin induced translocation of c-fos and c-jun to the nucleus of MDMs. Using OSM promoter-luciferase reporter constructs transfected into MDMs, we show that a functional AP-1 site is required for promoter activation by thrombin. We present another link between coagulation and inflammation, which could impact on the pathogenesis of atherosclerosis.
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PMID:Thrombin induces the expression of oncostatin M via AP-1 activation in human macrophages: a link between coagulation and inflammation. 1965

Chronic administration of cerebrocurin and cerebrolysin to Mongolian jirds with acute cerebral stroke model led to a decrease in the mitochondrial dysfunction on the 4th day, which was manifested by their ability to inhibit the mitochondrial permeability transition pore opening, normalize the energy metabolism, and enhance c-fos gene expression. In addition, cerebrocurin restored the morphofunctional state of neurons and favored the cell loss mechanism switching from necrosis to apoptosis. With respect to all characteristics under consideration, the effect of cerebrocurin exceeded with statistical confidence that of cerebrolysin.
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PMID:[Neuroprotective effect of cerebrocurin in a model of acute cerebral stroke]. 2036 93

The adult brain responds to diverse pathologies such as stroke with increased generation of neurons in the dentate gyrus of the hippocampus. However, only little is known regarding the functional integration of newborn neurons into pre-existing neuronal circuits. In this study, we investigated whether newborn neurons generated after experimental stroke are recruited for different behavioral tasks. Adult mice received photochemical cortical infarcts in the sensorimotor cortex and proliferating cells were labeled using the proliferation marker, bromodeoxyuridine. Eight weeks after stroke induction, the animals were trained to perform either a spatiotemporal task or a sensorimotor task. Immediate early gene expression (c-fos, Zif268) in newborn neurons was analyzed directly after the last session. Using this approach, we demonstrate that post-stroke generated neurons are recruited within the hippocampal networks. The sensorimotor task activates significantly more newborn neurons compared to the spatiotemporal task. Further experiments employing the two well-established stimulators of neurogenesis, enriched environment and voluntary wheel running, both significantly increase post-stroke neurogenesis in the dentate gyrus but do not affect the percentage of recruited neurons compared to controls. Significantly, the spatiotemporal task leads to a higher portion of activated newborn neurons in the granule cell layer, suggesting a specific spatial activation pattern of new neurons in the dentate gyrus.
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PMID:Functional recruitment of newborn hippocampal neurons after experimental stroke. 2236 83


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