Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are a recently described group of metalloproteinases. The substrates degraded by ADAMTS-1, -4 and -5 suggest that they play a role in turnover of extracellular matrix in the central nervous system (CNS). ADAMTS-1 is also known to exhibit anti-angiogenic activity. Their main endogenous inhibitor is tissue inhibitor of metalloproteinases (TIMP)-3. The present study was designed to investigate ADAMTS-1, -4 and -5 and TIMP-3 expression after experimental cerebral ischaemia and to examine whether cytokines known to be up-regulated in stroke could alter their expression by astrocytes in vitro. Focal cerebral ischaemia was induced by transient middle cerebral artery occlusion in the rat using the filament method. Our results demonstrate a significant increase in expression of ADAMTS-1 and -4 in the occluded hemisphere but no significant change in TIMP-3. This was accompanied by an increase in mRNA levels for interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra) and tumour necrosis factor (TNF). ADAMTS-4 mRNA and protein were up-regulated by TNF in primary human astrocyte cultures. The increased ADAMTS-1 and -4 in experimental stroke, together with no change in TIMP-3, may promote ECM breakdown after stroke, enabling infiltration of inflammatory cells and contributing to brain injury. In vitro studies suggest that the in vivo modulation of ADAMTS-1 and -4 may be controlled in part by TNF.
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PMID:ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes. 1663 May 94

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.
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PMID:[Atherosclerosis and rheumatoid arthritis]. 1678 83

Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.
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PMID:Twenty years of research on cytokine-induced sickness behavior. 1708 43

Cerebral ischemia initiates an inflammatory response in the brain that is associated with the induction of a variety of cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1alpha/beta (IL-1alpha/beta) that contributes to stroke injury. Transient middle cerebral artery occlusion (tMCAO) in spontaneously hypertensive rat (SHR) resulted in significant increases in TNF-alpha and IL-1beta levels. We have previously demonstrated up-regulation of secretory phospholipase A2 IIA (sPLA2 IIA) mRNA and protein expression, increased PLA2 activity, and loss of phosphatidylcholine after 1-h tMCAO and 24-h reperfusion in SHR. Treatment with TNF-alpha antibody or IL-1 receptor antagonist significantly attenuated infarction volume, sPLA2 IIA protein expression, PLA2 activity and significantly restored phosphatidylcholine levels after tMCAO. This suggests that cytokine induction up-regulates sPLA2 IIA protein expression, resulting in altered lipid metabolism that contributes to stroke injury.
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PMID:Secretory phospholipase A2 IIA is up-regulated by TNF-alpha and IL-1alpha/beta after transient focal cerebral ischemia in rat. 2773 30

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 microM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.
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PMID:A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1. 1733 85

Systemic inflammatory stimuli, such as infection, increase the risk of stroke and are associated with poorer clinical outcome. The mechanisms underlying the impact of systemic inflammatory stimuli on stroke are not well defined. We investigated the impact of systemic inflammation on experimental stroke and potential mechanisms involved. Focal cerebral ischemia was induced by intraluminal filament occlusion of the middle cerebral artery (MCAo). Brain damage and neurological deficit 24 h after MCAo were exacerbated by systemic lipopolysaccharide (LPS) administration. This exacerbation was critically dependent on interleukin (IL)-1, because coadministration of IL-1 receptor antagonist abolished the effect of LPS on brain damage. Systemic administration of IL-1 increased ischemic damage to a similar extent as LPS and also exacerbated brain edema. IL-1 markedly potentiated circulating levels of the acute phase proteins, serum amyloid A and IL-6, and the neutrophil-selective CXC chemokines, KC and macrophage inflammatory protein-2. Neutrophil mobilization and cortical neutrophil infiltration were aggravated by IL-1 before changes in ischemic damage. Neutropenia abolished the damaging effects of systemic IL-1. These data show for the first time that an acute systemic inflammatory stimulus is detrimental to outcome after experimental stroke and highlight IL-1 as a critical mediator in this paradigm. Our data suggest IL-1-induced potentiation of neutrophil mobilization via CXC chemokine induction is a putative mechanism underlying this effect. Our results may help to explain the poorer outcome in stroke patients presenting with infection and may have implications for neurodegenerative diseases involving neurovascular alterations, such as Alzheimer's disease, in which systemic inflammation can modulate disease progression.
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PMID:Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. 1744 25

The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12+/-2 microg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22+/-4 microg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.
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PMID:Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations. 1768 19

Inflammation is associated with both acute and chronic neurological disorders, including stroke and Alzheimer's disease (AD). Cytokines such as interleukin (IL)-1 have several activities in the brain both under physiological and pathophysiological conditions. The objective of this study was to evaluate consequences of the central blockade of IL-1 transmission in a previously developed transgenic mouse strain with brain-directed overexpression of human soluble IL-1 receptor antagonist (Tg hsIL-1ra). Effects on brain morphology and brain levels of the AD-related proteins beta-amyloid precursor protein (APP) and presenilin 1(PS1), as well as the levels of IL-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were analysed in homozygotic and heterozygotic mice and wild type (WT) controls, of both genders and of young (30-40 days) and adult (13-14 months) age. A marked reduction in brain volume was observed in transgenic mice as determined by volumetry. Western blot analysis showed higher levels of APP, but lower levels of PS1, in adult animals than in young ones. In the cerebellum, heterozygotic (Tg hsIL-1ra(+/-)) mice had lower levels of APP and PS1 than WT mice. With one exception, there were no genotypic differences in the levels of IL-1beta, IL-6 and TNF-alpha. The cytokine levels were generally higher in adult than in young mice. In conclusion, the chronic blockade of IL-1 signalling in the brain was associated with an atrophic phenotype of the brain, and with modified levels of APP and PS1. Brain-directed overexpression of hsIL-1ra was not followed by major compensatory changes in the levels of pro-inflammatory cytokines.
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PMID:Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist. 1776 Aug 42

In January 2004, the normally picturesque Cache Valley in northern Utah made national headlines with the highest PM2.5 levels in the nation. Epidemiological studies linked exposure to particulate air pollution in other locations with stroke and Alzheimer's disease and to early mortality from all causes, cancer, and cardiopulmonary diseases. To determine potential effects of these particles on human health, human bronchial epithelial cells (BEAS-2B) were cultured with PM2.5 collected from various locations in the Cache Valley. These particles were slightly cytotoxic, but more potent than NH4NO3, the major chemical component of Cache Valley PM2.5. Gene expression analysis of PM2.5-exposed cells was performed using microarray and quantitative reverse-transcription polymerase chain reaction (RT-PCR). Among other genes, PM2.5 exposure induced genes and proteins involved in the inflammatory response. Most notably, PM2.5-exposed cells showed significant gene level upregulation of activating receptors to interleukins 1 and 6 (IL-1R1 and IL-6R), as well as concomitant increases in protein. Increases in IL-1 receptor associated kinase-1 (IRAK) protein were observed. PM2.5 exposure resulted in release of IL-6, as well phosphorylated STAT3 protein, providing evidence that PM activates the IL-6/gp130/STAT3 signaling pathway in BEAS-2B cells. IL-20 and major histocompatibility complex peptide class-1 (MICA) were upregulated and cleavage of caspase-12 was detected. In total, our results indicate that Cache Valley PM2.5 produces the upregulation of important cytokine receptors and is able to activate both IL-1R- and IL-6R-mediated signaling pathways in human lung cells. These observations are generally consistent with the adverse effects associated with inhalation of fine particulate matter like PM2.5.
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PMID:Effects of PM2.5 collected from Cache Valley Utah on genes associated with the inflammatory response in human lung cells. 1788 30

Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time, for example in Alzheimer's or Parkinson's diseases and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration under these conditions, and that the cytokine IL-1 (interleukin-1) is a pivotal mediator. IL-1 is expressed rapidly in response to neuronal injury, predominantly by microglia, and elevated levels of endogenous or exogenous IL-1 markedly exacerbate injury. The naturally occurring IL-1RA (IL-1 receptor antagonist) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS (central nervous system) invasion, and cell death via activation of matrix metalloproteinase-9. IL-1 also influences the release of toxins from glial and endothelial cells. Neuronal responses to excitotoxins and physiological factors may have an impact on neuronal survival. IL-1RA, delivered peripherally, can enter the CNS in animals and humans and has no adverse effects in stroke or subarachnoid haemorrhage patients, but shows potential benefit in acute stroke patients.
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PMID:Interleukin-1 and inflammatory neurodegeneration. 1795 93


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