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)

Interleukin-1 (IL-1) is induced immediately after insults to the brain, and elevated levels of IL-1 have been strongly implicated in the neurodegeneration that accompanies stroke, Alzheimer's disease, and multiple sclerosis. In animal models, antagonizing IL-1 has been shown to reduce cell death; however, the basis for this protection has not been elucidated. Here we analyzed the response to penetrating brain injury in mice lacking the type 1 IL-1 receptor (IL-1R1) to determine which cellular and molecular mediators of tissue damage require IL-1 signaling. At the cellular level, fewer amoeboid microglia/macrophages appeared adjacent to the injured brain tissue in IL-1R1 null mice, and those microglia present at early postinjury intervals retained their resting morphology. Astrogliosis also was mildly abrogated. At the molecular level, cyclooxygenase-2 (Cox-2) and IL-6 expression were depressed and delayed. Interestingly, basal levels of Cox-2, IL-1, and IL-6 were significantly lower in the IL-1R1 null mice. In addition, stimulation of vascular cell adhesion molecule-1 mRNA was depressed in the IL-1R1 null mice, and correspondingly, there was reduced diapedesis of peripheral macrophages in the IL-1R1 null brain after injury. This observation correlated with a reduced number of Cox-2+ amoeboid phagocytes adjacent to the injury. In contrast, several molecular aspects of the injury response were normal, including expression of tumor necrosis factor-alpha and the production of nerve growth factor. Because antagonizing IL-1 protects neural cells in experimental models of stroke and multiple sclerosis, our data suggest that cell preservation is achieved by abrogating microglial/macrophage activation and the subsequent self-propagating cycle of inflammation.
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PMID:The type 1 interleukin-1 receptor is essential for the efficient activation of microglia and the induction of multiple proinflammatory mediators in response to brain injury. 1212 68

We sought to assess the anti-inflammatory properties of unfractionated heparin (UFH) in patients with ischemic stroke treated within 24 h from the onset of symptoms. We studied prospectively 167 patients that received 1000 IU/h intravenous UFH (n=70) or 300 mg oral aspirin (n=97) at a mean treatment delay of 6.7 h. Repeated plasma levels of interleukin (IL)-6, IL-10, IL-4, tumor necrosis factor (TNF)-alpha, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were compared in both groups using multivariate analyses. Whereas TNF-alpha and sICAM-1 decreased at 48 h, IL-6, IL-4, and sVCAM-1 increased compared with baseline values (P<0.01). The rise of sVCAM-1 levels at 48 h was significantly lower in patients treated with UFH (P=0.017) and a two-fold increase of baseline sVCAM-1 was an independent predictor of poor outcome (odds ratio, 2.19, 1.1-4.39). These results suggest that adjusted high-dose UFH has anti-inflammatory effects which might improve recovery if administered early after stroke onset.
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PMID:Unfractionated heparin is associated with a lower rise of serum vascular cell adhesion molecule-1 in acute ischemic stroke patients. 1214 13

The gene expression profile in the cortex was analyzed in a rat model of focal cerebral ischemia by use of cDNA array. It was attempted to monitor changes of gene expression and to profile them into functional classification between ipsilateral and contralateral cortex at 6h after middle cerebral artery (MCA) occlusion. Seventy-one genes out of 1174 genes were significantly modulated by ischemia. Metabolism-, cell communication- and signal transduction-related genes were down-regulated, whereas genes involved in stress response were markedly increased. Besides numerous established ischemia-induced gene products such as macrophage inflammatory protein-1 alpha (MIP-1 alpha), orphan nuclear receptor Nurr 77, secretogranin II (SCG-II), and tumor necrosis factor-alpha (TNF-alpha), several genes were identified which have not previously been shown to be modulated following focal ischemia; these genes include interferon-induced protein (IFN-IP), neurodegeneration-associated protein-1 (NDGAP-1), and neuronal pentraxin receptor (NPR). The RT-PCR analyses of these genes at various time points revealed that mRNA level of IFN-IP was up-regulated, while NDGAP-1 and NPR were transcriptionally down-regulated. The results suggest of the involvement of these genes in neuronal cell damage caused by ischemia and the potential use as targets for the development of preventives/therapeutics of brain stroke.
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PMID:DNA array reveals altered gene expression in response to focal cerebral ischemia. 1224 2

Side-stream cigarette smoke (SSCS), a major component of secondhand smoke, induces reactive oxygen species, which promote oxidative damage in tissues and organs. Inflammatory cytokines play an important role in the pathogenesis of atherosclerosis and heart failure. The present 4-month study examined the effect of various chronic SSCS exposure levels on splenic inflammatory cytokine secretion, heart contractile function, and pathology at 60- and 120-min per day, 5 days per week, for a total of 16 weeks. Tissue vitamin E level and lipid peroxide production also were tested to estimate the oxidative stress. The study found that the pro-inflammatory cytokines, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1beta, significantly increased in 120-min SSCS-exposed mice. Decreased stroke volume and increased peripheral arterial resistance were observed in mice exposed to 120-min SSCS per day. Heart pathology was only found in 120-min SSCS-exposed mice. Cardiac and hepatic antioxidant vitamin E levels were decreased as a result of oxidative stress. Hepatic lipid peroxides were increased upon 60-min SSCS exposure. The data also demonstrated that the cardiac alpha-tocopherol level has a strong correlation with stroke volume; splenic IL-1beta has a strong negative correlation with stroke volume; splenic TNF-alpha has a very strong negative correlation with stroke volume. In conclusion, SSCS exposure induced systemic inflammatory responses. SSCS exposure also accentuated systemic lipid peroxidation with depletion of cardiac and hepatic antioxidant vitamin E level. Finally, SSCS exposure at 120 min per day decreased stroke volume and increased vascular resistance. Systemic IL-1beta and TNF-alpha production are responsible for heart contractile dysfunction. Free radicals may be responsible for the progression to heart contractile dysfunction induced, in part, by SSCS. Oxidized lipoprotein could contribute to the vascular functional changes. Exploring the mechanism of vascular dysfunction in mice is warranted. A more precise quantification of the smoking exposure dose in mice needs to be determined as well.
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PMID:Side-stream cigarette smoke induces dose-response in systemic inflammatory cytokine production and oxidative stress. 1232 64

Research during the last two decades established atheromatous lesions as active sites of inflammation and immune responses, contrasting to the traditional view of atherosclerosis as an acellular lesion composed of lipid deposits. In particular, cytokines appear to orchestrate the chronic development of atherosclerosis, eventually leading to the formation of complex atherosclerotic plaques, which can trigger acute thromboembolic complications, such as myocardial infarction or stroke. Indeed the rupture-prone plaque, characterized by a thin fibrous cap overlaying a voluminous lipid core, exhibits accumulation of various pro-inflammatory cytokines. These cytokines may control the clinical consequences of plaques by mediating infiltration and accumulation of immunocompetent cells, directing the turnover of fibrillar collagens (governing the fragility of the fibrous cap), or enhancing foam cell formation and thrombogenicity of the lipid core, among other processes outlined in this review. Thus, understanding the role of cytokines in the pathophysiology of the atherosclerotic plaque might provide a promising therapeutic avenue for this prevalent human disease. This review will focus on members of the interleukin, tumor necrosis factor, and interferon families of cytokines in modulating key processes of atherogenesis.
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PMID:Cytokines in the pathogenesis of atherosclerosis. 1236 24

Following stroke, an intracerebral inflammatory response develops that may contribute to postischemic central nervous system injury. This study's objective was to determine whether the anti-inflammatory neuropeptide alpha-melanocyte stimulating hormone (MSH) can suppress postischemic activation of intracerebral tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) gene expression. Ipsilateral TNF-alpha levels were increased in cerebrocortical territory of the middle cerebral artery (MCA) following transient unilateral MCA occlusion (MCAO) and reperfusion in mice, and systemic alpha-MSH treatment (0.5 mg/kg i.p.) suppressed this increase. Systemic alpha-MSH treatment also inhibited the marked increases in cortical TNF-alpha and IL-1beta mRNA levels following MCAO, and reduced the intracerebral TNF-alpha protein levels seen after transient global ischemia. We conclude that alpha-MSH treatment suppresses intracerebral proinflammatory cytokine gene expression following transient cerebral ischemia, suggesting that systemically administered melanocortins may exert neuroprotective effects in cerebral ischemia.
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PMID:Alpha-melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-alpha and interleukin-1beta gene expression following transient cerebral ischemia in mice. 1245 26

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.
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PMID:Differences in immune cell invasion into the cerebrospinal fluid and brain parenchyma during cerebral infusion of interleukin-1beta. 1252 76

Prostate apoptosis response-4 (par-4) is a pro-apoptotic gene identified in prostate cancer cells undergoing apoptosis. Par-4 protein, which contains a leucine zipper domain at the carboxy-terminus, functions as a transcriptional repressor in the nucleus. Par-4 selectively induces apoptosis in androgen-independent prostate cancer cells and Ras-transformed cells but not in androgen-dependent prostate cancer cells or normal cells. Cells that are resistant to apoptosis by Par-4 alone, however, are greatly sensitized by Par-4 to the action of other pro-apoptotic insults such as growth factor withdrawal, tumor necrosis factor, ionizing radiation, intracellular calcium elevation, or those involved in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and stroke. Apoptosis induction by Par-4 involves a complex mechanism that requires activation of the Fas death receptor signaling pathway and coparallel inhibition of cell survival NF-kappaB transcription activity. The unique ability of Par-4 to induce apoptosis in cancer cells but not normal cells and the ability of Par-4 antisense or dominant-negative mutant to abrogate apoptosis in neurodegenerative disease paradigms makes it an appealing candidate for molecular therapy of cancer and neuronal diseases.
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PMID:Apoptosis by Par-4 in cancer and neurodegenerative diseases. 1256 19

Lesions in the nervous system induce rapid activation of glial cells and under certain conditions additional recruitment of granulocytes, T-cells and monocytes/macrophages from the blood stream triggered by upregulation of cell adhesion molecules, chemokines and cytokines. Hematogenous cell infiltration is not restricted to infectious or autoimmune disorders of the nervous system, but also occurs in response to cerebral ischemia and traumatic lesions. Neuroinflammation can cause neuronal damage, but also confers neuroprotection. Granulocytes occlude vessels during reperfusion after transient focal ischemia, while the functional role of T-cells and macrophages in stroke development awaits further clarification. After focal cerebral ischemia neurotoxic mediators released by microglia such as the inducible nitric oxide synthase (leading to NO synthesis) and the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are upregulated prior to cellular inflammation in the evolving lesion and functionally contribute to secondary infarct growth as revealed by numerous pharmacological experiments and by use of transgenic animals. On the other hand, cytokine induction remote from ischemic lesions involves NMDA-mediated signalling pathways and confers neuroprotection. After nerve injury T cells can rescue CNS neurons. In the peripheral nervous system neuroinflammation is a prerequisite for successful regeneration that is impeded in the CNS. In conclusion, there is increasing evidence that neuroinflammation represents a double edged sword. The opposing neurotoxic and neuroprotective properties of neuroinflammation during CNS injury provide arich and currently unexplored set of research problems.
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PMID:Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. 1257 18

An alteration of the blood-brain barrier (BBB) permeability contributes to the development of brain edema after stroke. In this study, we evaluated the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, on brain edema formation and BBB integrity in rats subjected to transient focal ischemia. DY-9760e (1 mg/kg/h) was intravenously infused for 6 h, starting immediately after reperfusion of a 1-h middle cerebral artery occlusion. Treatment with DY-9760e significantly suppressed the increase in water content and the extravasation of Evans blue dye after transient focal ischemia. Analysis of a magnetic resonance imaging method revealed that DY-9760e significantly prevented the development of brain edema in the cortical region of the ipsilateral hemisphere. Trifluoperazine, a calmodulin antagonist that is structurally different from DY-9760e, also attenuated brain edema elicited by transient focal ischemia. Furthermore, DY-9760e and trifluoperazine reduced tumor necrosis factor-alpha-induced hyperpermeability of inulin through a cultured brain microvascular endothelial cell monolayer, suggesting an involvement of calmodulin in the regulation of brain microvascular barrier function. The present results demonstrate that DY-9760e ameliorates brain edema formation and suggest that this effect may be mediated in part by the inhibition of enhanced BBB permeability after ischemic insults. Thus, DY-9760e is expected to be a therapeutic drug for treatment of acute stroke patients.
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PMID:3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, reduces brain edema through the inhibition of enhanced blood-brain barrier permeability after transient focal ischemia. 1260 80


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