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)

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

Cilostazol was developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). The anti-platelet and vasodilator properties of cilostazol have been extensively characterized and considered to contribute to the variety of clinical effects such as intermittent claudication and recurrent stroke. In this review, the novel action mechanism (s) of cilostazol are overviewed with the focus on the action of cilostazol in in vitro and in vivo studies as a maxi-K channel opener targeting anti-apoptotic signaling pathways. Under treatment with cilostazol (10 mg/kg intravenously or 30 mg/kg orally), a significant reduction in cerebral infarct area was evident in rats subjected to ischemia/reperfusion. Increase in cyclic AMP and decrease in TNF-alpha levels were identified in the ipsilateral cortex under treatment with cilostazol accompanied by decreased Bax formation and cytochrome c release with increased Bcl-2 production in the penumbral area as well as in the in vitro human umbilical endothelial cells. Cilostazol suppressed TNF-alpha-induced decrease in viability of SK-N-SH (human neuroblastoma) cells and HCN-1A (human cortical neuron) cells in association with decrease in PTEN phosphorylation and increase in Akt/CREB phosphorylation with suppression of DNA fragmentation, all of which were antagonized by iberiotoxin, a maxi-K(+) channel blocker. Further, cilostazol prevented TNF-alpha-induced PTEN phosphorylation and apoptotic cell death via increased CK2 phosphorylation in the SK-N-SH cells. Cilostazol increased K(+) current in SK-N-SH cells by opening the maxi-K channels. Thus, it was suggested that the action of cilostazol to promote cell survival was ascribed to the maxi-K channel opening-coupled upregulation of CK2 phosphorylation and downregulation of PTEN phosphorylation with resultant increased phosphorylation of Akt and CREB. These in vitro data were confirmed in the in vivo results of rats subjected to focal transient ischemic damage.
 ...
PMID:Cilostazol: therapeutic potential against focal cerebral ischemic damage. 1647 48

Strokes due to transmural vasculitis associated with coccidioidal meningitis result in significant morbidity and mortality. The immunological and inflammatory processes responsible are poorly understood. To determine the inflammatory mediators, i.e. cytokines, chemokines, iNOS, matrix metalloproteinase-9 (MMP-9), that possibly contribute to vasculitis, temporal mRNA expression in brain basilar artery samples and MMP-9 protein in the CSF of male NZW rabbits infected intracisternally with 6.5 x 10(4) arthroconidia of Coccidioides immitis were assessed. Five infected and 3 sham-injected rabbits at each time point were euthanized 4, 9, 14 and 20 days post infection. All infected rabbits had neurological abnormalities and severe vasculitis in the basilar arteries on days 9-20. In basilar arteries of infected animals versus controls, mRNAs encoding for IL-6, iNOS, IFN-gamma, IL-2, MCP-1, IL-1beta, IL-10, TNF-alpha, CCR-1, MMP-9, TGF-beta, as well as MMP-9 protein in CSF, were found to be significantly up-regulated. Thus, this study identified inflammatory mediators associated with CNS vasculitis and meningitis due to C. immitis infection. Assessment of the individual contribution of each mediator to vasculitis may offer novel approaches to the treatment of coccidioidal CNS infection. This study also provides unique methodology for immunology studies in a rabbit model.
 ...
PMID:Temporal expression of inflammatory mediators in brain basilar artery vasculitis and cerebrospinal fluid of rabbits with coccidioidal meningitis. 1648 45

We hypothesized that exercise preconditioning strengthens brain microvascular integrity against ischemia/reperfusion injury through the tumor necrosis factor (TNF)-integrin signaling pathway. Adult male Sprague Dawley rats (n = 24) were studied in: (1) exercise (the animals run on a treadmill 30 min each day) for 3 weeks, (2) non-exercise. Six animals from each group (n = 12) were subjected to stroke, the remaining animals served as controls (n = 6 x 2). Brain infarction and edema were determined by Nissl staining. Cerebral integrin expression was detected by immunochemistry and stereological methods. In addition, we used flow cytometry to address the causal role of TNF-alpha in inducing the expression of integrins in the human umbilical vein endothelial cells under TNF-alpha or vascular endothelial growth factor (VEGF) pretreatment. Exercise reduces brain infarction and brain edema in stroke. Expressions of integrin subunit alpha(1), alpha(6), beta(1), and beta(4) were increased after exercise. Exercise preconditioning reversed stroke-reduced integrin expression. An in vitro study revealed a causal link between the gradual upregulation of TNF-alpha (rather than VEGF) and cellular expression of integrins. These results demonstrated an increase in cerebral expression of integrins and a decrease in brain injury from stroke after exercise preconditioning. The study suggests that upregulation of integrins during exercise enhances neurovascular integrity after stroke. The changes in integrins might be altered by TNF-alpha.
 ...
PMID:Exercise preconditioning upregulates cerebral integrins and enhances cerebrovascular integrity in ischemic rats. 1670 37

Mild hypothermia is one of the most robust neuroprotectant studied in the laboratory to date. The reasons for this protective effect are likely multifactorial, but work from our laboratory and others have shown that this protection is associated with remarkable suppression of the inflammatory response that accompanies brain ischemia. Consistently, laboratories have shown that small decreases in brain temperature to 30-34 degrees C result in reduced inflammatory cell infiltrate, less microglial activation, and reduction of a variety of inflammatory mediators such as nitric oxide, inflammatory cytokines and superoxide. Nuclear factor-kappaB (NFkappaB) is a transcription factor that is activated after cerebral ischemia. NFkappaB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. Our laboratory has shown that hypothermia decreases NFkappaB translocation and binding activity, by affecting NFkappaB regulatory proteins. Mild hypothermia appears to suppress phosphorylation of NFkappaB's inhibitory protein (IkappaB-alpha) by decreasing expression and activity of IkappaB kinase-gamma (IKK). As a consequence, hypothermia suppressed gene expression of two NFkappaB target genes, inducible nitric oxide synthase and TNF-alpha. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFkappaB inhibition due to decreased activity of IKK.
 ...
PMID:Influence of hypothermia on post-ischemic inflammation: role of nuclear factor kappa B (NFkappaB). 1675 Aug 72

Carbon monoxide-releasing molecules are emerging as a new class of pharmacological agents that regulate important cellular function by liberating CO in biological systems. Here, we examined the role of carbon monoxide-releasing molecule 3 (CORM-3) in modulating neuroinflammatory responses in BV-2 microglial cells, considering its practical application as a novel therapeutic alternative in the treatment of stroke. BV-2 microglia cells were incubated for 24 h in normoxic conditions with thrombin alone or in combination with interferon-gamma to simulate the inflammatory response. Cells were also subjected to 12 h of hypoxia and reoxygenated for 24 h in the presence of thrombin and interferon-gamma. In both set of experiments, the anti-inflammatory action of CORM-3 was evaluated by assessing its effect on nitric oxide production (nitrite levels) and tumor necrosis factor (TNF)-alpha release. CORM-3 (75 microM) did not show any cytotoxicity and markedly attenuated the inflammatory response to thrombin and interferon-gamma in normoxia and to a lesser extent in hypoxia as evidenced by a reduction in nitrite levels and TNF-alpha production. Inactive CORM-3, which does not liberate CO and is used as a negative control, failed to prevent the increase in inflammatory mediators. Blockade of endogenous CO production by tin protoporphyrin-IX did not change the anti-inflammatory activity of CORM-3, suggesting that CO liberated from the compound is responsible for the observed effects. In addition, inhibition of the mitogen-activated protein kinases phosphatidyl inositol 3 kinase and extracellular signal-regulated kinase amplified the anti-inflammatory effect of CORM-3. These results suggest that the anti-inflammatory activity of CORM-3 could be exploited to mitigate microglia activity in stroke and other neuroinflammatory diseases.
 ...
PMID:Modulation of thrombin-induced neuroinflammation in BV-2 microglia by carbon monoxide-releasing molecule 3. 1677 36

There is growing evidence that patients with rheumatoid arthritis (RA) are at higher risk of cardiovascular diseases (CVD) including myocardial infarction and stroke. Recent analysis indicate that CVD is the most common cause of death in RA; however research on traditional risk factors such as smoking, hypertension or elevated cholesterol level has shown mixed results. There are many convincing suggestions that RA-specific factors associated with systemic inflammation may play a critical role in endothelial cell damage and accelerated development of atherosclerosis. Since atherosclerosis is currently recognized as a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis--the interplay between inflammatory mediators including cytokines (TNF-alpha, IL-1, IL-6), C-reactive protein, blood coagulation factors and vessel wall cells attracts much attention. Their pivotal role in the pathogenesis of both diseases, RA and atherosclerosis has been presented and discussed in our review.
 ...
PMID:[Atherosclerosis and rheumatoid arthritis]. 1678 83

An approach combining reperfusion mediated by thrombolytics with pharmacological neuroprotection aimed at inhibiting the physiopathological disorders responsible for ischemia-reperfusion damage, could provide an optimal treatment of ischemic stroke. We investigate, in a rat embolic stroke model, the combination of rtPA with citicoline as compared to either alone as monotherapy, and whether the neuroprotector should be provided before or after thrombolysis to achieve a greater reduction of ischemic brain damage. One hundred and nine rats have been studied: four were sham-operated and the rest embolized in the right internal carotid artery with an autologous clot and divided among 5 groups: 1) control; 2) iv rtPA 5 mg/kg 30 min post-embolization 3) citicoline 250 mg/kg ip x3 doses, 10 min, 24 h and 48 h post-embolization; 4) citicoline combined with rtPA following the same pattern; 5) rtPA combined with citicoline, with a first dose 10 min after thrombolysis. Mortality, neurological score, volume of ischemic lesion and neuronal death (TUNEL) after 72 h and plasma levels of IL-6 and TNF-alpha, were considered to assess ischemic brain damage. Compared with controls, the use of citicoline after thrombolysis produced the greatest reduction of mortality caused by the ischemic lesion (p<0.01), infarct volume (p=0.027), number of TUNEL positive cells in striatum (p=0.014) and plasma levels of TNF-alpha at 3 h (p=0.027) and 72 h (p=0.011). rtPA induced reperfusion provided a slight non-significant reduction of infarct volume and neuronal death, but it reduced mortality due to brain damage (p<0.01) although an increase in the risk of fatal bleeding was noted. CiT as monotherapy only produced a significant reduction of neuronal death in striatum (p=0.014). The combination of CiT before rtPA did not add any benefit to rtPA alone. The superiority of the combined treatment with rtPA followed by citicoline suggests that early reperfusion should be followed by effective neuroprotection to inhibit ischemia-reperfusion injury and better protect the tissue at risk.
 ...
PMID:Effect of combined therapy with thrombolysis and citicoline in a rat model of embolic stroke. 1676 88

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1beta, TNF-alpha or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1beta, TNF-alpha or even IL-18, in patients with poststroke depression.
 ...
PMID:The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines. 1689 92

Cerebral stroke induces proliferation of subventricular zone (SVZ) neural progenitor cells in adult rodent brain. Tumor necrosis factor-alpha-converting enzyme (TACE) proteolysis sheds the nonamyloidogenic soluble ectodomain of the amyloid precursor protein (APP) and is a convertase for tumor necrosis factor-alpha (TNFalpha). The resulting soluble peptides of APP and TNFalpha are mitogenic for neural progenitor cells of the SVZ. Therefore, we hypothesized a role for TACE proteolysis in stroke-induced neurogenesis. Using laser-capture microdissection, we found TACE transcription was increased in SVZ cells of ischemic brain. Immunohistochemistry revealed TACE protein was upregulated in SVZ neuroblasts. Intraventricular infusion of tumor necrosis factor-alpha protease inhibitor-2 (TAPI-2) decreased bromodeoxyuridine incorporation in SVZ cells of rats subjected to middle cerebral artery occlusion. Furthermore, primary culture SVZ neurospheres from ischemic brain overexpress TACE and its substrates APP and TNF-alpha. These cells proliferated more rapidly, possessed increased TACE protease-dependent alpha-secretase activity, and released more soluble APP and TNFalpha compared with nonischemic control. In addition, TAPI-2 reduced SVZ neuroblast migration out of SVZ explants in vitro. These findings indicate TACE proteolysis as a promoter of stroke-induced SVZ progenitor cell neurogenesis, and suggest this protease activity may represent an attractive therapeutic target for stroke recovery.
 ...
PMID:Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-alpha-converting enzyme protease activity. 1692 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>