Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heatstroke is a life-threatening illness characterized by an elevated core body temperature (>40 degrees C) and dysfunction of central nervous system, which results in delirium, convulsions, or coma. Despite adequate hypothermia or other care-therapy, heatstroke is often fatal. On the basis of our knowledge of the pathophysiology on heatstroke, we hypothesized that heatstroke is a form of hyperthermia associated with the acute physiological alterations, the cytotoxicity of heat, systemic inflammatory response, oxidative damage and attenuated heat-shock response leading to a syndrome of multi-organ dysfunction. In view of above-mentioned situation, the physiological factors underlying heatstroke and the corresponding possible therapeutic strategies to avert the complications of this disorder would be summarized in this review so as to provide some therapeutic guidelines for heatstroke. Heatstroke is a very complicated process. Acute physiological alterations, such as low arterial hypotension, intracranial hypertension, cerebral hypoperfusion, cerebral ischemia, and increased intracellular metabolism rate, occurred while exposed to a high ambient temperature. Hyperpyrexia caused cytotoxicity, resulting the degradation and aggregation of extensive intracellular proteins, influencing the change of membrane stability and fluidity, damaging the transmembrane transport of protein and the function of surface receptor, and inducing different cytoskeletal changes. Heatstroke resembles sepsis in many aspects, and endotoxemia and cytokines may be implicated in its pathogenesis. The concentration of interleukin-6 was positively correlated with the severity of heatstroke. The excessive accumulation of cytotoxic free radicals and oxidative damage may occur in the brain tissues during the genesis and development of heatstroke. The circulatory shock and cerebral ischemia resultant from heatstroke correlated closely with the free radicals (especially free radicals of peroxide and superoxide), the peroxidation of lipids, and low activity of antioxidase in the brain. Heat-shock proteins (Hsps) played a critical role during the process obtaining thermotolerance, therefore, protected from stress-induce cellular damage. Host factors or physiologically limiting factors, for instance, aging, existing illness, dehydration, deep insomnia, lack of acclimation to heat, inadequate physical fitness, and certain genetic polymorphisms were associated with a low level of Hsps expression and might favor the progression from heat stress to heatstroke. Some measures, such as molecular chaperonines, anti-inflammatory agents, antioxidant agents, and modulators of Hsps would be good for the patients with heatstroke.
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PMID:Pathophysiological factors underlying heatstroke. 1663 16

CCAAT/enhancer binding protein beta (C/EBPbeta) is a leucine-zipper transcription factor that regulates cell growth and differentiation in mammals. Expression of many pro-inflammatory genes including the cytokine interleukin-6 is known to be controlled by C/EBPbeta. We report that focal cerebral ischemia induced by transient middle cerebral artery occlusion (MCAO) significantly increases C/EBPbeta gene expression in mouse brain at between 6 and 72 h of reperfusion. To understand the functional significance of C/EBPbeta in postischemic inflammation and brain damage, we induced transient MCAO in cohorts of adult C/EBPbeta null mice and their wild-type littermates. At 3 days of reperfusion following transient MCAO, C/EBPbeta null mice showed significantly smaller infarcts, reduced neurological deficits, decreased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells, decreased intercellular adhesion molecule 1 (ICAM1) immunopositive vessels, decreased extravasated neutrophils and fewer activated microglia/macrophages, compared with their wild-type littermates. Furthermore, GeneChip analysis showed that postischemic induction of many transcripts known to promote inflammation and neuronal damage was less pronounced in the brains of C/EBPbeta-/- mice compared with C/EBPbeta+/+ mice. These results suggest a significant role for C/EBPbeta in postischemic inflammation and brain damage.
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PMID:Decreased brain damage and curtailed inflammation in transcription factor CCAAT/enhancer binding protein beta knockout mice following transient focal cerebral ischemia. 1689 75

Possible strategies for treating ischaemic stroke include: (i) neuroprotection (preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischaemia), and (ii) neurosupplementation (the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischaemia). In this paper, we review our recent progress in development of these distinct new strategies for treatment of damaged brain following a stroke. Firstly, we investigated the role of endogenous IL-6 (interleukin-6), which is one of the cytokines drastically induced by ischaemic stimuli, by administering IL-6RA (anti-IL-6 receptor monoclonal antibody) to mice. We found that endogenous IL-6 plays a critical role in neuroprotection and that its role may be mediated by STAT3 (signal transducer and activator of transcription-3) activation. Secondly, we studied the endogenous sources of the newly born neurons in the ischaemic striatum by region- and cell-type-specific cell labelling techniques. The results revealed that the SVZ (subventricular zone) is the principal source of the neuronal progenitors that migrate laterally towards the infarcted regions, and differentiate into newly born neurons. Finally, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is an appropriate poly-porous structure releasing bioactive substances such as neurotrophic factor. This bio-affinitive scaffold is able to give an appropriate environment for newly born neurons. In future, we will combine these strategies to develop more effective therapies for treatment of strokes.
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PMID:Neuroprotection and neurosupplementation in ischaemic brain. 1707 9

Brazilein isolated from Caesalpinia sappan was evaluated for neuroprotection against transient focal cerebral ischemia/reperfusion in rats. The results showed that administration of brazilein after the onset of cerebral ischemia reperfusion can reduce the brain infarction area and improve the neurological score. The mechanisms underlying the action were investigated and attributed to the anti-inflammatory effect of brazilein, because a decrease of the mRNA level of pro-inflammatory cytokines (tumor necrosis factor-alpha(TNF-alpha) and interleukin-6 (IL-6)) was found in the ischemic animals with brazilein treatment. To further substantiate the anti-inflammatory effect of brazilein, we examined the mRNA expression of the cytokines in the lipopolysaccharide (LPS) induced microglial cell line BV2 cells; TNF-alpha and IL-6 mRNA expressions were significantly suppressed by brazilein treatment but the decrease of interleukin-1beta (IL-1beta) expression was not detected. Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS), another indicator of the inflammatory response of the immune cells was measured in RAW 264.7 macrophages and BV2 cells; brazilein inhibited its production induced by LPS in both types of cells in a dose-dependent manner. Consistently, the mRNA level of iNOS was also decreased by brazilein. Together, these results illustrate that brazilein can protect the brain against ischemia/reperfusion injury and the anti-inflammatory effect was believed to be one of the contributive mechanisms.
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PMID:Brazilein protects the brain against focal cerebral ischemia reperfusion injury correlating to inflammatory response suppression. 1723 68

Pro-inflammatory cytokines and neurotrophins in the central nervous system (CNS) have been recognized as mediators of both neurodegenerative and neuroprotective mechanisms in a number of CNS pathologies. A rapid, sustained elevation of these molecules was recently reported after traumatic and ischemic brain injury. Inflammatory mechanisms and immune activation have been hypothesized to play a role in the pathogenesis of cerebral ischemia. Stroke is the third largest cause of death next to heart disease and cancer in the world, and it is an important cause of death and disability in developed countries. Role of excitatory amino acids receptors activation, calcium overload, nitric oxide and oxidative stress in the pathogenesis of ischemic brain damage is well established. Stroke may modulate peripheral neurotrophic factors levels. In experimental animal models, neurotrophin-3 (NT-3) has been shown to be produced by glial cells as an adaptability response to hypoxia. In spite of substantial research and significant number of neuroprotective drugs that have been developed to limit ischemic brain damage and to improve the outcome for stroke patients, no specific therapy for stroke is available. The neurotrophins have been proposed as therapeutic agents for the treatment of neurodegenerative disorders and ischemic injury. In the present work, we investigated the possible correlation of NT-3 with tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in the serum and cerebrospinal fluid (CSF) from patients with ischemic stroke (IS).
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PMID:Neurotrophin-3, TNF-alpha and IL-6 relations in serum and cerebrospinal fluid of ischemic stroke patients. 1740 11

In order to evaluate the neuroprotective effect of Rosiglitazone Maleate (RSG) against brain ischemic injury, the effects of Rosiglitazone Maleate on the inflammation following cerebral ischemia/reperfusion were investigated. Focal cerebral ischemia was induced by the intraluminal thread for cerebral middle artery (MCA) occlusion. Rosiglitazone Maleate at concentrations of 0.5, 2 and 5 mg/kg was infused by intragastric gavage twice immediately and 2 h after MCA occlusion, respectively. The effects of Rosiglitazone Maleate on brain swelling, myeloperoxidase and interleukin-6 mRNA level in brain tissue after MCA occlusion and reperfusion were evaluated. The results showed that as compared with the model control group, RSG (0.5 mg/kg) had no significant influence on brain swelling (P>0.05), but 2 mg/kg and 5 mg/kg RSG could significantly alleviate brain swelling (P<0.05). All different doses of RSG could obviously reduce MPO activity in brain tissue after MCA occlusion and reperfusion in a dose-dependent manner. RSG (0.5 and 2 mg/kg) could decrease the expression levels of IL-6 mRNA in brain tissue after MCA occlusion and reperfusion to varying degrees (P<0.05) with the difference being significant between them. It was concluded that RSG could effectively ameliorate brain ischemic injury after 24 h MCA occlusion and inhibit the inflammatory response after ischemia-reperfusion in this model.
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PMID:Effect of Rosiglitazone Maleate on inflammation following cerebral ischemia/reperfusion in rats. 1764 46

Rapid diagnosis and management of stroke patients is becoming increasingly important with the emergence of new interventional strategies for acute cerebral ischemia. A biochemical surrogate of cerebral ischemia, rapidly detectable in the serum before radiological diagnosis, might have clinical utility in the setting of acute stroke, high-risk cardiovascular procedures, and subarachnoid hemorrhage. Such a marker might also aid in the neurological prognosis of anoxic brain injury. Several serum markers have been evaluated in acute cerebral ischemia. These include neuronal enzymes such as neuron-specific enolase; markers of glial injury and activation, such as protein S100beta; and mediators of inflammation, such as interleukin-6. The clinical and preclinical data supporting the use of these biochemical surrogates of cerebral ischemia are reviewed.
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PMID:Serum markers of cerebral ischemia. 1789 90

This study investigates the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), on neurodegeneration, gliosis and changes in the neurotrophic protein brain-derived neurotrophic factor (BDNF) and in pro-inflammatory cytokines, following kainic acid (KA)-induced excitotoxic damage in the rat. Male Sprague-Dawley rats were treated with alpha-MSH (intraperitoneally, i.p.) at 20 min, and 24 and 48 h following administration of 10 mg/kg KA (i.p.). The animals were sacrificed at 30 min, 4 h, 24 h and 72 h after KA-administration and the levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were analysed in samples of hippocampus and hypothalamus. Levels of BDNF were analysed in the hippocampus. Stereological quantification showed a markedly reduced number of viable neurons in the CA1 pyramidal cell layer upon KA-administration as compared to animals injected with vehicle (p < 0.05, 79,587 +/- 25,554 vs. 145,254 +/- 27,871). The number of viable neurons upon administration of alpha-MSH was significantly higher than upon KA alone (p < 0.05, 119,776 +/- 33,158, KA+alpha-MSH vs. 79,587 +/- 27,554, KA + Saline). Astrocyte activation due to the KA-induced excitotoxicity was reduced, and the KA-induced increase in IL-1beta levels was delayed by the treatment with alpha-MSH. In conclusion, the degree of reduction in cell viability in the hippocampus CA1 pyramidal cell layer upon KA-induced excitotoxicity was similar to that seen previously upon global cerebral ischaemia. Furthermore, the administration of alpha-MSH resulted in a similar increase in cell viability, supporting the hypothesis that administration of alpha-MSH has rescuing effects on neurons subjected to excitotoxic insults.
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PMID:Alpha-MSH rescues neurons from excitotoxic cell death. 1795 33

Acute cerebral ischemia triggers interleukin-6 (IL-6) release into cerebrospinal fluid and blood. IL-6 induces synthesis of the acute phase proteins (APPs) in the liver. Higher blood IL-6 level in stroke patients is associated with larger infarct size, greater neurological deficit on admission, early neurological worsening, and increased risk of death or poor functional outcome. The level of C-reactive protein (CRP), the major APP in man, rises in blood during acute stroke reaching maximal values between 5 and 7 day after stroke onset. Elevated CRP level in acute ischemic stroke predicts unfavorable outcome and is associated with increased risk of recurrent stroke or other cardiovascular events. Increased level of fibrinogen, another APP, is associated with worse outcome in patients with ischemic stroke. The acute phase reaction accompanies also intracerebral hemorrhage. Serum IL-6 and CRP level increases in the first days after intracerebral hemorrhage. Plasma IL-6 is independently associated with hematoma enlargement and fibrinogen level predicts early neurological deterioration and outcome in patients with intracerebral hemorrhage.
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PMID:Clinical significance of acute phase reaction in stroke patients. 1798 65

To assess the effects of acetylsalicylic acid (ASA) on glutamate and interleukin-6 (IL-6) release in the striatum of rats suffering from cerebral ischemia, we used the microdialysis technique with probes implanted 2 h prior to stroke onset. A total of 36 rats were randomly assigned to either temporary (90 min, n=18) or permanent (n=18) middle cerebral artery occlusion (MCAO). Animals received either a bolus of 40 mg/kg ASA or saline as control 30 min after stroke onset. Permanent MCAO led to large infarct volumes with no differences between treatment with ASA (239.8+/-4.1 mm3) and saline (230.1+/-3.9 mm3, p=0.15). In contrast, ASA therapy in temporary ischemia (87.2+/-6.2 mm3) reduced infarct size significantly compared to placebo (155.6+/-4.8 mm3, p<0.0001). Only in temporary ischemia, ASA application reduced glutamate significantly at the time points 90, 120, and 150 min after MCAO. Pooled post-ischemic microdialysate concentrations of IL-6 in temporary MCAO were significantly higher after ASA treatment (215+/-81 pg/mL, p=0.0297) than in saline-treated rats (80+/-13 pg/mL). In the permanent MCAO group, no difference in IL-6 between the ASA (125+/-21 pg/mL) and saline group (68+/-34 pg/mL) was noted. No differences were seen for c-fos positive neurons in the penumbra and hippocampus between all groups. These results suggest that the neuroprotective effect of ASA is reflected by glutamate attenuation and IL-6 induction even if given after stroke onset, but only if reperfusion is achieved.
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PMID:Neuroprotection and glutamate attenuation by acetylsalicylic acid in temporary but not in permanent cerebral ischemia. 1818 32


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