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)

A growing body of evidence, primarily from animal models of cerebral ischemia and preliminary human studies, indicates that inflammatory mechanisms contribute to secondary neuronal injury after acute cerebral ischemia. Ischemia followed by reperfusion rapidly leads to the expression of inflammatory cytokines, particularly tumor necrosis factor-alpha and interleukin-1beta, which stimulate a complex cascade of events involving local endothelial cells, neurons, astrocytes, and perivascular cells. A secondary response includes the release of other cytokines, an increase in components of the coagulation system, an upregulation of cell adhesion molecule expression, and changes in the expression of components of the immune response. The net effect of these events is transformation of the local endothelium to a prothrombotic/proinflammatory state and induction of leukocyte migration to the site of injury. A number of studies have shown that leukocyte migration occurs within hours of reperfusion. Leukocytes accumulate in the injured region, where they cause tissue injury by several mechanisms, including occlusion of microvasculature, generation of oxygen free radicals, release of cytotoxic enzymes, alteration of vasomotor reactivity, and increase in cytokine and chemoattractant release. Monoclonal antibodies against leukocyte adhesion molecules have been shown to reduce infarct volume in animal models of ischemia-reperfusion. However, this treatment failed to show benefit in the Enlimomab Acute Stroke Trial. A number of factors may complicate the use of antibody directed adhesion molecule blockade in acute stroke and will be discussed in this article. Overall, an increased understanding of inflammatory and immunologic mechanisms still offers great potential for reducing acute stroke injury.
 ...
PMID:The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy. 974 39

The blood-brain barrier (BBB) plays a crucial role in protecting the central nervous system (CNS) from any changes in homeostasis brought about by pathological conditions. Cerebrovascular permeability is an important factor in the development of cerebral edema following stroke [M. Plateel, E. Teissier, R. Cecchelli, Hypoxia, dramatically increases the nonspecific transport of blood-borne proteins to the brain. J. Neurochem. 68 (1997) 874-877] and any changes in its function can have detrimental neurological consequences. Recently, research has shown that an in vitro model of the BBB is sensitive to short exposures of hypoxia/aglycemia and that changes in endothelial cell calcium flux may be responsible for structural and functional variations in the BBB during ischemic stress [T.J. Abbruscato, T.P. Davis, Combination of hypoxia/aglycemia compromises in vitro BBB. J. Pharmacol. Exp. Ther. 289 (1999) 668-675]. Present experiments investigated bovine brain microvessel endothelial cell (BBMEC) expression of a Ca(2+)-dependent cell-cell adhesion molecule, E-cadherin, which has been shown to be important for blood-brain barrier function [D. Pal, K.L. Audus, T.J. Siahaan, Modulation of cellular adhesion in bovine brain microvessel endothelial cells by a decapeptide. Brain Research 747 (1997) 103-113]. Since it is believed that astrocyte-endothelial cell interaction is crucial for maintenance of in vivo BBB characteristics, we have attempted to optimize our isolation and culturing techniques to produce a reliable, in vitro model of the BBB that is suitable to study pathological conditions. Immunofluoresence experiments showed positive staining for E-cadherin, yet failed to show any change in cellular distribution of E-cadherin upon hypoxic/aglycemic exposure. In addition, culturing BBMECs with C6 conditioned medium (CM) had no effect on the localization of E-cadherin. Western blotting experiments showed that BBMECs express E-cadherin and this protein is decreased in a time dependent manner after various hypoxic/aglycemic exposures when endothelial cells are cultured alone or with C6 astrogliomas grown on a separate culture surface. When C6 astrocytes are grown directly opposed to endothelial cells, with a porous membrane between, we observed a slight attenuation in the decreased BBMEC expression of E-Cadherin after hypoxia/aglycemia exposure. This work has shown that the mammalian brain endothelial/astrocyte co-culture system is a useful model for studies of pathological conditions where BBB characteristics are maintained.
 ...
PMID:Protein expression of brain endothelial cell E-cadherin after hypoxia/aglycemia: influence of astrocyte contact. 1052 24

Stroke is a major cause of morbidity and mortality in sickle cell (SS) disease. Genetic risk factors have been postulated to contribute to this clinical outcome. The human genome project has substantially increased the catalog of variations in genes, many of which could modify the risk for manifestations of disease outcome in a monogenic disease, namely SS. VCAM1 is a cell adhesion molecule postulated to play a critical role in the pathogenesis of SS disease. We identified a total of 33 single nucleotide polymorphisms (SNPs) by sequencing the entire coding region, 2134 bp upstream of the 5' end of the published cDNA, 217 bp downstream of the 3' end of the cDNA, and selected intronic regions of the VCAM1 locus. Allelic frequencies for selected SNPs were determined in a healthy population. We subsequently analyzed 4 nonsynonymous coding, 2 synonymous coding, and 4 common promoter SNPs in a genetic association study of clinically apparent stroke in SS disease conducted in a cohort derived from a single institution in Jamaica (51 symptomatic cases and 51 matched controls). Of the 10 candidate SNPs analyzed in this pilot study, the variant allele of the nonsynonymous SNP, VCAM1 G1238C, may be associated with protection from stroke (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15-0.83, P =.04). Further study is required to confirm the importance of this variant in VCAM1 as a clinically useful modifier of outcome in SS disease.
 ...
PMID:Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. 1239 16

The F11 receptor (F11R) is a cell adhesion molecule (CAM), member of the immunoglobulin superfamily found on the surface of human platelets, and determined to play a role in platelet aggregation, secretion, adhesion and spreading. The same molecule is present also at tight junctions of endothelial cells (EC) where it is known as JAM and acts as a CAM through homophilic interactions. The role of F11R/JAM in the interaction of platelets with endothelial cells was investigated in the current studies. We report here that washed human platelets adhere specifically to a matrix made of immobilized, recombinant sF11R. Furthermore, platelets adhere to cytokine- (TNF-alpha, INF-gamma) stimulated human umbilical vein endothelial cells (HUVEC), and approximately 40-60% of the adhesive force is exerted by homophilic interactions between the F11R of platelets and EC. This is evidenced by the inhibition of platelet adhesion to endothelial cells by recombinant soluble form of the F11R, and by two F11R peptides with amino acid sequences of the N-terminal region, and in the 1(st) Ig fold of the F11R, respectively. This study suggests a role for F11R in the adhesion of platelets to cytokine-inflamed endothelial cells and thus in thrombosis and atherosclerosis induced in non-denuded blood vessels by inflammatory processes. Agents that block the F11R-mediated adhesion of platelets to EC may be of therapeutic value in controlling thrombosis and preventing heart attacks and stroke.
 ...
PMID:F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in inflammatory thrombosis. 1242 4

Cytokine-mediated inflammatory cell recruitment into the brain is a critical step in the response to diverse insults, including infection, trauma, and stroke. Hence, continous intra-cerebroventricular infusion of interleukin (IL)-1beta leads to an impressive cell invasion into the cerebrospinal fluid, as well as the brain parenchyma. Neither tumor necrosis factor-alpha nor IL-6 induced any significant cell invasion at all. However, the diverse immune cells (granulocytes, monocytes/macrophages) showed a different time course of invasion. Moreover, there was an association between the number of infiltrating immune cells and the infused IL-1 concentration. By analyzing intra-brain immune events, we demonstrated a time- and dose-dependent induction of intercellular adhesion molecule (ICAM)-1, whereas there were no differences for P-selectin, vascular cell adhesion molecule (VCAM)-1, and monocyte-chemotractant protein (MCP)-1, comparing vehicle and IL-1-infused animals. In conclusion, we assume IL-1beta to be a key cytokine for the granulocyte and monocyte recruitment into the central nervous system after various insults. However, granulocytes anticipate monocyte invasion.
 ...
PMID:Differences in immune cell invasion into the cerebrospinal fluid and brain parenchyma during cerebral infusion of interleukin-1beta. 1252 76

Vascular cell adhesion molecule-1 (VCAM-1) has been implicated as being important in the pathophysiology of acute pain episodes (APE) and acute chest syndrome (ACS) of sickle cell disease (SCD). The frequency of these episodes is reduced by chronic transfusion therapy. The impact of chronic transfusion therapy on VCAM-1 expression is unknown. Soluble VCAM-1 (sVCAM-1) levels were measured in plasma using an ELISA assay (R&D Systems) in 61 patients with SCD (age range 1.5-20 years) and 12 normal controls (2.5-14 years). SCD patients included 20 with ACS, 14 with APE, 12 at well-child visits, and 15 receiving chronic transfusion therapy. Asymptomatic SCD patients had higher sVCAM-1 levels compared to normal subjects (P < 0.001). Levels of sVCAM-1 were further elevated during ACS (P < 0.001) and APE (P = 0.072) and returned to the asymptomatic range on resolution. Levels were significantly lower in transfused patients (P = 0.003) compared to asymptomatic SCD patients. Our findings of increased VCAM-1 expression during ACS and perhaps APE offer a rationale for therapeutic use of cytokine and other VCAM-1 modulators. The reduction of sVCAM-1 levels observed in our transfused SCD patients offers insight into the mechanism of the protective effect of transfusion against ACS and APE and possibly stroke.
 ...
PMID:Elevated plasma sVCAM-1 levels in children with sickle cell disease: impact of chronic transfusion therapy. 1511 98

Several observational studies have shown that estrogen replacement therapy decreases cardiovascular mortality and morbidity in postmenopausal women. However, The Women's Health Initiative (WHI) study has found that women receiving estrogen plus progestin had a significantly higher risk of breast cancer, coronary heart disease, stroke, and pulmonary embolus. In the present study, we examined whether estrogen prevents mechanisms that relate to plaque formation by inhibiting monocyte adhesion to endothelial cells. ECV304 cells, an endothelial cell line that normally expresses minimal estrogen receptor (ER)alpha, were transfected with an ERalpha expression plasmid. Treatment with tumor necrosis factor (TNF)-alpha increased expression of vascular cell adhesion molecule (VCAM)-1 mRNA, activation of nuclear factor-kappaB (NF-kappaB), and U937 cell adhesion in ECV304 cells. These effects of TNF-alpha were not significantly inhibited by pretreatment of native ECV304 cells with 17beta-estradiol (E(2)). In ECV304 cells overexpressing ERalpha, E(2) significantly inhibited the effects of TNF-alpha on NF-kappaB activation, VCAM-1 expression, and U937 cell adhesion. These findings suggest E(2) suppresses inflammatory cell adhesion to vascular endothelial cells that possess functional estrogen receptors. The mechanism of suppression may involve inhibition of NF-kappaB-mediated up-regulation of VCAM-1 expression induced by atherogenic stimuli. E(2) may prevent plaque formation, as first stage of atheroscrelosis through inhibiting adhesion monocytes to endothelial cell. Actions of estrogen replacement therapy can be assessed in terms of densities of functional ERalpha.
 ...
PMID:Suppression by 17beta-estradiol of monocyte adhesion to vascular endothelial cells is mediated by estrogen receptors. 1515 69

The F11 receptor (F11R) (a.k.a. Junctional Adhesion Molecule, JAM) was first identified in human platelets as a 32/35 kDa protein duplex that serves as receptor for a functional monoclonal antibody that activates platelets. We have sequenced and cloned the F11R and determined that it is a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules. The signaling pathways involved in F11R-induced platelet activation were examined in this investigation. The binding of M.Ab.F11 to the platelet F11R resulted in granule secretion and aggregation. These processes were found to be dependent on the crosslinking of F11R with the Fc gammaRII by M.Ab.F11. This crosslinking induced actin filament assembly with the conversion of discoidal platelets to activated shapes, leading to the formation of platelet aggregates. We demonstrate that platelet secretion and aggregation through the F11R involves actin filament assembly that is dependent on phosphoinositide-3 kinase activation, and inhibitable by wortmannin. Furthermore, such activation results in an increase in the level of free intracellular calcium, phosphorylation of the 32 and 35 kDa forms of the F11R, F11R dimerization coincident with a decrease in monomeric F11R, and association of the F11R with the integrin GPIIIa and with CD9. On the other hand, F11R-mediated events resulting from the binding of platelets to an immobilized surface of M.Ab.F11 lead to platelet adhesion and spreading through the development of filopodia and lammelipodia. These adhesive processes are induced directly by interaction of M.Ab.F11 with the platelet F11R and are not dependent on the Fc gammaRII. We also report here that the stimulation of the F11R in the presence of nonaggregating (subthreshold) concentrations of the physiological agonists thrombin and collagen, results in supersensitivity of platelets to natural agonists by a F11R-mediated process independent of the Fc gammaRII. The delineation of the two separate F11R-mediated pathways is anticipated to reveal significant information on the role of this cell adhesion molecule in platelet adhesion, aggregation and secretion, and F11R-dependent potentiation of agonist-induced platelet aggregation. The participation of F11R in the formation and growth of platelet aggregates and plaques in cardiovascular disorders, resulting in enhanced platelet adhesiveness and hyperaggregability, may serve in the generation of novel therapies in the treatment of inflammatory thrombosis, heart attack and stroke, and other cardiovascular disorders.
 ...
PMID:Signaling pathways of the F11 receptor (F11R; a.k.a. JAM-1, JAM-A) in human platelets: F11R dimerization, phosphorylation and complex formation with the integrin GPIIIa. 1534 81

Cerebral ischemia triggers an inflammatory process involving the infiltration of leukocytes to the parenchyma. Circulating leukocytes adhere to the vascular wall through adhesion molecules. Here we quantified the in vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in the brain, heart and lungs from 6 to 48 h after transient middle cerebral artery (MCA) occlusion in rats, by intravenous injection of a tracer radiolabelled anti-VCAM-1 antibody. The vascular localization of VCAM-1 was verified by immunohistochemistry after in vivo injection of the antibody. Vascular cell adhesion molecule-1 was strongly induced (4-fold at 24 h) in the microvasculature of the ischemic area, and, to a lesser extent, in the contralateral hemisphere and in a remote organ, the heart, but not in the lungs, indicating that the inflammatory process propagates beyond the injured brain. We injected intravenously either blocking doses of anti-VCAM-1 antibodies or control antibodies after MCA occlusion in rats and mice. We evaluated the neurological score in rats, and infarct volume at 2 days in rats and at 4 days in mice. Anti-VCAM-1 did not protect against ischemic damage either in rats or in mice. Vascular cell adhesion molecule-1 blockade significantly decreased the number of ED1 (labeling monocytes /macrophages/reactive microglia)-positive cells in the ischemic rat brain. However, it did not reduce the numbers of infiltrating neutrophils and lymphocytes, and total leukocytes (CD45 positive), which showed a trend to increase. The results show vascular upregulation of VCAM-1 after transient focal ischemia, but no benefits of blocking VCAM-1, suggesting that this is not a therapeutical strategy for stroke treatment.
 ...
PMID:Anti-VCAM-1 antibodies did not protect against ischemic damage either in rats or in mice. 1607 86

Chunghyuldan (CHD), a combinatorial drug that has antihyperlipidemic and anti-inflammatory activities, has been shown to improve arterial stiffness and inhibit stroke recurrence in clinical study. To understand the molecular basis of CHD's clinical effects, we explored its effect on cell proliferation and expression of nitric oxide synthase (NOS) and vascular cell adhesion molecule (VCAM-1) in human umbilical vein endothelial cells (HUVECs). Cell number counting and [3H]thymidine incorporation assay demonstrated that nontoxic doses of CHD have an inhibitory effect on DNA synthesis and suppress cell cycle progression of HUVECs. CHD treatment led to a marked induction of NO production through up-regulation of NOS mRNA expression in a dose- and time-dependent manner, whereas it suppressed VCAM-1 expression. CHD inhibition of VCAM-1 expression was totally blocked by pretreatment with the NO synthesis inhibitor L-NMMA, whereas pretreatment with the NO donor DETA-NO further decreased VCAM-1 level in CHD-treated HUVECs, indicating that VCAM-1 regulation by CHD is mediated through increased NO synthesis by CHD. In addition, TNF-alpha-mediated VCAM-1 activation was substantially impeded by CHD treatment. Collectively, our data suggest that anti-inflammatory or anti-hyperlipidemic effects of CHD might be associated with its ability to activate NO production and suppress VCAM-1 expression in human endothelial cells.
 ...
PMID:Chunghyuldan activates NOS mRNA expression and suppresses VCAM-1 mRNA expression in human endothelial cells. 1646 9


1 2 3 Next >>