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

Between 60% and 100% of epidermal growth factor (EGF) binding activity was recovered from membranes of the A431 human epidermoid carcinoma cell line treated with solutions containing the nonionic detergent Triton X-100. Approximately half of the recovered binding activity was sedimented at low centrifugal force and hence was operationally insoluble in nonionic detergent solution. Receptors in both the detergent-soluble and -insoluble fractions displayed similar affinities for 125I-EGF, and the values were in good agreement with those obtained for receptors in untreated membranes. The receptors in both fractions also formed identical direct linkage complexes with 125I-EGF in similar yield, providing no evidence for partitioning of different molecular species of EGF receptors in the detergent-soluble membrane fraction of Sepharose 6-B revealed heterogeneity of 125I-EGF binding activity; the smallest and most monodisperse peak of activity resolved by this technique was eluted at a Strokes radius of 95 A. Operationally soluble 125I-EGF binding activity also behaved heterogeneously during velocity sedimentation; more than half the activity sedimented more rapidly than the apparently monidisperse, 7S form. An average of less than half the nonionic detergent-solubilized activity recovered from 10 independent membrane preparations behaved as an apparently monodisperse entity. Since a maximum of 60% of 125I-EGF binding activity was operationally soluble, less than 25% of the total EGF binding activity was recovered in an apparently monodisperse form. The remaining 75% of the EGF receptors displayed a marked tendency to exist as aggregates in nonionic detergent solutions.
 ...
PMID:Properties of receptors for epidermal growth factor in detergent solution: evidence for heterogeneous aggregated states. 626 35

1. We examined the proliferative rates of cultured astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHRSR). Wistar-Kyoto rats (WKY) were used as a control for SHRSP and SHRSR. 2. In the presence of 10% fetal bovine serum (FBS), the doubling time for astrocytes from SHRSP and SHRSR was significantly shorter than WKY. 3. When quiescent astrocytes derived from SHRSP or SHRSR were released from serum-deprivation, the DNA synthesis was stimulated 13.3-fold and 12.5-fold, respectively, whereas only a 7.76-fold increase was observed in WKY astrocytes. 4. Further we studied the effects of two growth factors, epidermal growth factor (EGF) and fibroblast growth factor (FGF) on astrocytes proliferation. EGF induced greater DNA synthesis in SHRSP and SHRSR astrocytes compared with WKY astrocytes, although FGF had little or no effect. 5. Total cholesterol levels in SHRSP astrocytes and SHRSR astrocytes were significantly lower than that of WKY astrocytes, which was consistent with our previous observations in cultured vascular smooth muscle cells. 6. There was no difference in morphology among the cultured astrocytes from the three strains. 7. The abnormality of growth rate and cell membranes composition of astrocytes might be closely related to the genetic phenotypes (acute death of neurons and oedema of astrocytes) of SHRSP or SHRSR.
 ...
PMID:Demonstration of hereditarily accelerated proliferation in astrocytes derived from spontaneously hypertensive rats. 854 70

Our previous study in vivo suggested that vascular smooth muscle cells (VSMCs) in stroke-prone spontaneously hypertensive rats (SHRSP) were vulnerable when plasma components were deficient. Therefore, we cultured VSMCs isolated from normotensive and hypertensive rats to clarify the weakness of VSMCs isolated from hypertensive rats and maintained in plasma-deficient conditions by employing ultrastructural and biochemical analyses. VSMCs, obtained from normotensive rats and cultured without fetal bovine serum (FBS) for 1 week, were intact and well differentiated; without FBS for 2 weeks retained their original structures except for several degenerative changes. VSMCs, obtained from hypertensive rats and cultured without FBS for 2 weeks, were extensively damaged and lost their cell organelles. Apoptotic bodies were frequently observed. We also cultured VSMCs in medium containing a variety of growth factors. VSMCs obtained from normotensive rats and cultured with epidermal growth factor or insulin-like growth factor-1 for 2 weeks were almost intact, as were VSMCs from hypertensive rats, although some degenerative changes of cell organelles were observed. VSMCs from hypertensive rats, maintained with platelet-derived growth factor-BB or basic fibroblast growth factor, were generally in poor condition. Thus VSMCs from hypertensive rats have hereditary weaknesses in cell survival including apoptosis and require specific growth factors for their maintenance.
 ...
PMID:Ultrastructural analysis of survival in cultured smooth muscle cells isolated from stroke-prone spontaneously hypertensive rats: effect of growth factors. 876 57

Cerebral ischemia induces a massive efflux of glutamate causing delayed neuronal death in stroke-prone spontaneously hypertensive rats (SHRSP) but not in Wistar Kyoto rats (WKY). It is obvious that L-N-nitroarginine (L-NNA; NO synthase (NOS) inhibitor), benzamide (poly(ADP-ribose) synthetase inhibitor), and growth factors are involved in reducing neuronal cell death due to toxic conditions, especially phosphatidylinositol 3 (PI3)-kinase activity; however, no studies have clarified whether genetic vulnerability to neurotoxic states is present in cortical neurons isolated from SHRSP. For this purpose, we prepared cortical neurons from WKY and SHRSP (15 weeks of gestation) to test the genetic vulnerability involved in the pathogenesis of stroke as well as apoptosis of cortical neurons isolated from SHRSP. We also examined the mechanisms necessary to reduce apoptosis under neurotoxic states using ultrastructural and biochemical techniques. Cortical neurons from SHRSP were in fact found to be more vulnerable than neurons from WKY and resulted in apoptosis when treated with nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, especially insulin-like growth factor (IGF), rescued neurons from NO- and NMDA-mediated neurotoxicity, particularly those from SHRSP. Conversely, benzamide and L-NNA reduced NMDA-mediated neurotoxicity but not NO-mediated toxicity. The ability to protect neurons from neurotoxicity was as follows: IGF-->nerve growth factor epidermal growth factor-->L-NNA-->benzamide. In addition, it was demonstrated that wortmannin, a PI3-kinase inhibitor, lessened the protective effects of these growth factors against NO-mediated toxicity. The data thus indicate that genetic factors related to neuronal vulnerability to apoptosis are involved in the pathogenesis of stroke lesions in SHRSP. PI3-kinase activity, which is stimulated by growth factors, is closely related to protective effects against NO- and NMDA-mediated toxicity in cortical neurons, especially those isolated from SHRSP. Moreover, the genetic vulnerability observed in SHRSP neurons is possibly linked to the inadequate activation of signaling pathways in the downstream of protein tyrosine kinases.
 ...
PMID:Insulin-like growth factors prevent apoptosis in cortical neurons isolated from stroke-prone spontaneously hypertensive rats. 916 79

The anticoagulant transmembrane glycoprotein thrombomodulin (TM) is expressed at the luminal surface of vascular endothelial cells. Recently, we showed that TM antigen and TM mRNA are expressed in brain microvessels in several species and that brain capillaries have the capability to activate protein C. The activation of protein C in brain microcirculation was greatly impaired by major stroke risk factors in rats due to downregulation of TM. In this study, a partial sequence of TM was determined from TM mRNA from brain capillaries examined in brain capillaries of the rat, a species that provides a useful model to investigate stroke mechanisms in relation to brain hemostasis. The predicted deduced amino acid sequences for rat TM were compared with other TM sequences. Particularly high homology (77-100%) among functional domains of the protein, i.e., the epidermal growth factor repeats (EGFRs) 1-6 and the transmembrane region, was observed between mice and rats. Somewhat less degree of homology was observed for bovine and human EGFRs 1-6, while the homology of the transmembrane region was 92-96%. All cysteine residues were conserved among the TM sequences, and specific amino acids previously suggested to be essential for activation of protein C by thrombin TM were highly conserved. We conclude that the highly conserved mRNA and protein sequences may reflect a similar anticoagulant role of TM in brain endothelial and systemic vascular endothelial cells across different species.
 ...
PMID:Rat brain capillary thrombomodulin: structure and function. 985 12

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.
 ...
PMID:Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. 1085 11

Remodeling of the cerebral vasculature contributes to the pathogenesis of cerebral ischemia. Remodeling is caused by increased smooth muscle proliferation and may be due to an increase in the responsiveness of vascular cells to epidermal growth factor (EGF). Aldosterone is a risk factor for stroke, and the literature suggests it may play a role in increasing the expression of the receptor for EGF (EGFR). We hypothesized that mRNA for the EGF-stimulated pathway would be elevated in the vasculature of stroke-prone spontaneously hypertensive rats (SHRSP) and that this and experimental ischemic cerebral infract size would be reduced by aldosterone inhibition with spironolactone. We found that spironolactone treatment reduced the size of cerebral infarcts after middle cerebral artery occlusion in SHRSP (51.69 +/- 3.60 vs. 22.00 +/- 6.69% of hemisphere-infarcted SHRSP vs. SHRSP + spironolactone P < 0.05). Expression of EGF and EGFR mRNA was higher in cerebral vessels and aorta from adult SHRSP compared with Wistar-Kyoto rats. Only the expression of EGFR mRNA was elevated in the young SHRSP. Spironolactone reduced the EGFR mRNA expression in the aorta (1.09 +/- 0.25 vs. 0.56 +/- 0.11 phosphorimage units SHRSP vs. SHRSP + spironolactone P < 0.05) but had no effect on EGF mRNA. In vitro incubation of aorta with aldosterone +/- spironolactone produced similar results, suggesting a direct effect of aldosterone. Thus spironolactone may reduce the size of cerebral infarcts via a reduction in the expression of the EGFR mRNA, leading to reduced remodeling.
 ...
PMID:Spironolactone reduces cerebral infarct size and EGF-receptor mRNA in stroke-prone rats. 1150 12

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.
 ...
PMID:NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. 1170 20

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a type of hereditary stroke and dementia. More than 90% of patients with CADASIL have mutations in the Notch3 gene. All mutations either create or destroy a cysteine residue in the epidermal growth factor-like repeats. In addition, five polymorphisms, which lead to amino acid substitutions, have been identified within the Notch3 coding sequence. However, whether these polymorphisms affect Notch signalling or are involved in cerebrovascular diseases is unknown. In the present study, we investigated a possible association between a T6746C polymorphism in the Notch3 coding region and the occurrence of symptomatic ischaemic cerebrovascular disease (CVD) was investigated. Two hundred and thirty five patients with CVD, as confirmed by brain CT or MRI, and 315 age and sex matched control subjects were analyzed for genotype frequencies of the T6746C polymorphism in Notch3. The genotype distributions were: patients with CVD, C/C 14.0%, C/T 45.5%, and T/T 40.4%; controls, C/C, 14.3%; C/T, 47.9%; T/T, 37.8%. The Japanese population has a higher C allele frequency of the T6746C polymorphism than European populations. There was no significant difference between the T6746C polymorphism in patients with CVD and controls (chi(2)=0.414, p=0.813). This was confirmed by the results of multiple logistic regression analysis including established risk factors (chi(2) =4.65, p=0.311). In conclusion, the results indicate that T6746C polymorphism in the intracellular domain of the Notch3 gene is not associated with an increased risk for CVD.
 ...
PMID:Notch3 gene polymorphism and ischaemic cerebrovascular disease. 1186 1

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the notch3 epidermal growth factor-like repeats. A Colombian kindred carries a novel C455R mutation located in the predicted ligand-binding domain. Stroke occurred in the patients at an unusually early age (median age: 31 years) in comparison to the more frequent onset in the fourth decade of life in other CADASIL populations, including a second Colombian kindred with an R1031C mutation.
 ...
PMID:C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke. 1213 71


1 2 3 4 5 6 7 Next >>