Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unconjugated bilirubin (UCB) encephalopathy is a predominantly early life condition resulting from the impairment of several cellular functions in the brain of severely jaundiced infants. However, only few data exist on the age-dependent effects of UCB and their association with increased vulnerability of premature newborns, particularly in a sepsis condition. We investigated cell death, glutamate efflux, and inflammatory cytokine dynamics after exposure of astrocytes at different stages of differentiation to clinically relevant concentrations of UCB and/or lipopolysaccharide (LPS). Younger astrocytes were more prone to UCB-induced cell death, glutamate efflux, and inflammatory response than older ones. Furthermore, in immature cells, LPS exacerbated UCB effects, such as cell death by necrosis. These findings provide a basis for the increased susceptibility of premature newborns to UCB deleterious effects, namely when associated with sepsis, and underline how crucial the course of cell maturation can be to UCB encephalopathy during moderate to severe neonatal jaundice.
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PMID:Bilirubin-induced inflammatory response, glutamate release, and cell death in rat cortical astrocytes are enhanced in younger cells. 1624 28

Several mechanisms have been proposed for neuroimmune communication supporting the sickness syndrome (fever, anorexia, inactivity, and cachexia) following infection. We examined the role of glutamate as a neurochemical intermediary of sickness behavior induced by intraperitoneal lipopolysaccharide (LPS). Mice implanted with biotelemetry devices capable of detecting body temperature (Tb) were administered LPS (50 or 500 microg/kg i.p., serotype 0111:B4) with or without i.p. pretreatment with vehicle or broad-spectrum antagonists selective for N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic (AMPA)/kainite, or metabotropic glutamate (mGlu) receptors. While NMDA and AMPA/kainate receptor antagonism failed to attenuate LPS-induced sickness behavior, antagonism of metabotropic receptors with l(+)-AP3 reduced the febrile (0-11h: control: 37.32+/-0.16 degrees C, l(+)-AP3: 36.66+/-0.27), anorexic (control: -87+/-5%, l(+)-AP3: 48+/-12% scotophase food intake), and cachexic (control: -8.9+/-0.4%, l(+)-AP3: -6.1+/-1.3% body weight) effects of 500 microg/kg LPS, and produced a biphasic Tb effect in response to 50 microg/kg LPS (1h: -0.90+/-0.26; 6h: 1.78+/-0.35 degrees C relative to baseline). At this dose the Tb of l(+)-AP3-treated mice was 1.18 degrees C lower than controls 2h post-injection, and 0.68 degrees C greater that controls 8h post-injection. These results suggest a role for mGlu receptors in mediating fever, anorexia, and cachexia possibly via activation of extra-vagal pathways, since the attenuating effect of l(+)-AP3 increased with increasing dosages of LPS. Given the critical role ascribed to mGlu receptors in neurotransmitter release and astrocytic processes, it is possible that these observations reflect an l(+)-AP3-induced attenuation of these systems.
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PMID:Metabotropic glutamate receptors mediate lipopolysaccharide-induced fever and sickness behavior. 1646 Sep 9

Xanthorrhizol, a natural sesquiterpenoid isolated from the rhizome of Curcuma xanthorrhiza Roxb (Zingiberaceae), has antibacterial activities and protective effects against cisplatin-induced hepatotoxicity. In this study, we investigated the activities of xanthorrhizol as an antioxidant or antiinflammatory agent using neuronal and microglial cells. Xanthorrhizol had potent neuroprotective effects on glutamate-induced neurotoxicity and reactive oxygen species (ROS) generation in the murine hippocampal HT22 cell line. Also, xanthorrhizol inhibited H(2)O(2)-induced lipid peroxidation in rat brain homogenates. The properties of xanthorrhizol as an antiinflammatory agent were investigated in microglial activation by lipopolysaccharide. It reduced the expression of cyclooxygenase-2 and the inducible nitric oxide synthase, which consequently resulted in the reduction of nitric oxide. The production of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha in activated microglial cells, was reduced by xanthorrhizol. These results suggest that xanthorrhizol could be an effective candidate for the treatment of Alzheimer's disease- and other neurological disease-related ROS and inflammation.
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PMID:Antioxidant and antiinflammatory activities of xanthorrhizol in hippocampal neurons and primary cultured microglia. 1627 45

Basal phagocytosis of neutrophils, a crucial component of non-specific immunity, is an eminently circadian parameter. In mice and rats, rates of phagocytosis peak in the second half of the dark span. A lipopolysaccharide-induced phagocytic response challenged in this period appears the most significant in amplitude and duration. Neonatal administration in rats of the neurotoxic agent monosodium glutamate, which induces massive destruction of the arcuate nucleus, suppresses the phagocytic response and moderately inhibits basal phagocytosis. Physiological phagocytosis in vivo appears to depend on the presence of the nocturnal melatonin surge. Functional pinealectomy, achieved in rats by a 2-week exposure to constant light, lowered the average circadian level of phagocytosis, damped the characteristic rhythm of neutrophil adherence, and decreased the neutrophil count and the amplitude of its circadian oscillation. In an in vivo study, adult rats were given alcohol intraperitoneally (0.1 mL ethanol/kg body weight, 1:10 in saline solution), alone or co-administered with melatonin (1 mg/kg body weight), for 16 days, once a day at 20:00 h. Alcohol-treated animals displayed a drastically depressed and flattened phagocytic curve, a marked decline of the adherence ability, and a reduction of the mean circadian neutrophil and lymphocyte count. Addition of melatonin significantly increased circadian values of phagocytosis, restored adherence, and prevented the numeric depletion of lymphocytes induced by alcohol. In correlation with other experimental evidence, our data speak for a physiological role of melatonin in upkeep of neutrophil phagocytosis and hint towards the existence of several pineal-hypothalamic pathways regulating different components of phagocytosis in vivo.
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PMID:Modulatory factors of circadian phagocytic activity. 1639 10

The aim of this study was to investigate the effects of antioxidants (e.g. alpha-lipoic acid and N-acetyl-L-cysteine) as well as N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. MK-801 and LY235959) on the changes of both core temperature and hypothalamic levels of 2,3-dihydroxybenzoic acid (2,3-DHBA) induced by systemic administration of lipopolysaccharide (LPS) in rabbits. The measurements of 2,3-DHBA were used as an index of the intrahypothalamic levels of hydroxyl radicals. Intravenous administration of LPS (2-10 microg/kg) elicited a biphasic febrile response, with the core temperature maxima at 80 and 200 min post-injection. Each core temperature rise was accompanied by a distinct wave of cellular concentrations of 2,3-DHBA in the hypothalamus. The rise in both the core temperature and hypothalamic 2,3-DHBA could be induced by direct injection of glutamate (100-400 microg in 10 microl/rabbit) into the cerebroventricular fluid system. Either the early or the late phase of fever rise and increased hypothalamic levels of 2,3-DHBA following systemic injection of LPS were significantly antagonized by pretreatment with injection of alpha-lipoic acid (5-60 mg/kg, i.v.), N-acetyl-L-cysteine (2-20 mg/kg, i.v.), MK-801 (0.1-1 mg/kg, i.m.), or LY235959 (0.1-1 mg/kg, i.v.) 1 h before LPS injection. The increased levels of prostaglandin E(2) in the hypothalamus induced by LPS could be suppressed by alpha-lipoic acid or N-acetyl-L-cysteine pretreatment. These findings suggest that an NMDA receptor-dependent hydroxyl radical pathway in the hypothalamus of rabbit brain may mediate both the early and late phases of the fever induced by LPS.
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PMID:An NMDA receptor-dependent hydroxyl radical pathway in the rabbit hypothalamus may mediate lipopolysaccharide fever. 1640 85

Animal models have assisted in understanding the mechanisms of brain injury underlying cerebral palsy. Nevertheless, no such models replicate every aspect of the human disease. This review summarizes the classic and more recent studies of the neuropathology of human perinatal brain injury most commonly associated with cerebral palsy, for use by researchers and clinicians alike who need to analyze published animal models with respect to their fidelity to the human disorder. The neuropathology underlying cerebral palsy includes white-matter injury, known as periventricular leukomalacia, as well as germinal matrix hemorrhage with intraventricular extension, and injury to the cortex, basal ganglia, and thalamus. Each has distinctive features while sharing some risk factors, such as prematurity and/or hypoxia-ischemia in the perinatal period. Periventricular leukomalacia consists of diffuse injury of deep cerebral white matter, with or without focal necrosis. Recent work directly in human postmortem tissue has focused on the role of free radical injury, cytokine toxicity (especially in light of the epidemiologic association of periventricular leukomalacia with maternofetal infection), and excitotoxicity in the development of periventricular leukomalacia. Premyelinating oligodendrocytes, which predominate in periventricular regions during the window of vulnerability to periventricular leukomalacia (24-34 postconceptional weeks), are the targets of free radical injury, as determined by immunocytochemical markers of lipid peroxidation and protein nitration. This maturational susceptibility can be attributed in part to a relative deficiency of superoxide dismutases in developing white matter. Microglia, which respond to cytokines and to bacterial products such as lipopolysaccharide via Toll-like receptors, are increased in periventricular leukomalacia white matter and can contribute to cellular damage. Indeed, several cytokines, including tumor necrosis factor-a and interleukins 2 and 6, as well as interferon-g, have been demonstrated in periventricular leukomalacia. Preliminary work suggests a role for glutamate receptors and glutamate transporters in periventricular leukomalacia based on expression in human developing oligodendrocytes. Germinal matrix hemorrhage, with or without intraventricular hemorrhage, occurs in premature infants and can coexist with periventricular leukomalacia. Studies in human germinal matrix tissue have focused on maturation-based vascular factors, such as morphometry and expression of molecules related to the structure of the blood-brain barrier. Gray-matter injury, seen more commonly in term infants, includes cortical infarcts and status marmoratus. Subtle cortical injury overlying periventricular leukomalacia is the subject of current interest as a possible substrate for the cognitive difficulties seen in patients with cerebral palsy. In summary, it is hoped that work in human tissue, in conjunction with experimental animal models, will lead to eventual therapeutic or preventive strategies for the perinatal brain injury underlying cerebral palsy.
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PMID:Neuropathologic substrate of cerebral palsy. 1641 40

The present study investigates the effect of the glucocorticoid corticosterone on microglial glutamate transporters in vitro. Microglial cultures obtained from rat cerebral cortex were found to express the excitatory amino acid transporter GLT-1, but not GLAST, and this expression was increased by 1 ng/ml lipopolysaccharide after 12 h of stimulation. This increase has previously been shown to be mediated by tumor necrosis factor-alpha, a cytokine released by microglia during pathological conditions. Furthermore, lipopolysaccharide increased the microglial release of tumor necrosis factor-alpha and 1 microM corticosterone inhibited this effect. Corticosterone also inhibited the lipopolysaccharide-induced increase of the GLT-1 expression as well as the expression in non-activated cells. The effect of corticosterone on the GLT-1 expression was dose dependent and accompanied by similar effects on the microglial glutamate uptake capacity. Additionally, exogenous tumor necrosis factor-alpha was found to counteract the effect of corticosterone on microglial GLT-1 expression. The effect of corticosterone appeared to be glucocorticoid receptor specific since 10 microM of the glucocorticoid receptor antagonist mifepristone inhibited the effect. Thus, corticosterone decreased the microglial uptake of glutamate by decreasing the expression of glutamate transporters, probably due to the inhibited microglial tumor necrosis factor-alpha release. These results provide insights into the mechanisms behind microglial glutamate transporter expression during pathological conditions, and contribute to the debate about the beneficial or harmful effects of glucocorticoids.
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PMID:Corticosterone inhibits expression of the microglial glutamate transporter GLT-1 in vitro. 1647 74

Excitatory amino acid transporters (EAATs) are responsible for homeostasis of extracellular L-glutamate, and the glial transporters are functionally dominant. EAAT expression or function is altered in acute and chronic neurological conditions, but little is known about the regulation of EAATs in reactive astroglia found in such neuropathologies. These studies examined the effects of the bacterial endotoxin lipopolysaccharide (LPS) on glial EAATs in vitro. The effects of LPS (1 microg/ml, 24-72 h) on EAAT activity and expression were examined in primary cultures of mouse astrocytes. [(3)H]D-aspartate uptake increased to 129% of control by 72 h treatment with LPS. Saturation analysis revealed that apparent K(m) was unchanged whilst V(max) was significantly increased to 172% of control by 72 h LPS treatment. Biotinylation and Western blotting indicated that cell-surface expression of GLT-1 was significantly elevated (146% control) by LPS treatment whereas GLAST expression was unchanged. Confocal analyses revealed that LPS treatment resulted in cytoskeletal changes and stellation of astrocytes, with rearrangement of F-actin (as shown by phalloidin labelling). Immunocytochemistry revealed clustering of GLAST, and increased expression and redistribution of GLT-1 to the cell-surface following treatment with LPS. Similar experiments were conducted in microglia, where LPS (50 ng/ml) was found to up-regulate expression of GLT-1 at 24 and 72 h in concert with cytoskeletal changes accompanying activation. These findings suggest an association of cytoskeletal changes in glia with EAAT activity, with the predominant adaptation involving up-regulation and redistribution of GLT-1.
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PMID:Effects of lipopolysaccharide on glial phenotype and activity of glutamate transporters: Evidence for delayed up-regulation and redistribution of GLT-1. 1653 Feb 95

Bromelain has been reported to have anti-inflammatory and immunomodulatory effects. It has been cross-linked with organic acids and polysaccharides by gamma irradiation. The cross-linked (CL)-bromelain preparation resisted an acidic environment of pH 3 for 2 h and preserved 80% of its enzyme activity. Pretreatment of rats with CL-bromelain intragastrically for 7 days significantly reduced serum cytokine production induced by injected i.p. with 2.5 mg/kg of lipopolysaccharide (LPS). Bromelain significantly reduced serum glutamate-oxalacetate transaminase induced by LPS. The anti-inflammatory effect of CL-bromelain was correlated with reduced LPS-induced NF-kappaB activity and cyclooxygenase 2 (COX-2) mRNA expression in rat livers. In addition, CL-bromelain dose-dependently inhibited LPS-induced COX-2 mRNA and prostaglandin E2 (PGE2) in BV-2 microglial cells. CL-Bromelain also suppressed the LPS-activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). In conclusion, the anti-inflammatory effects of the CL-bromelain preparation in vivo and in vitro suggest its therapeutic potentials.
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PMID:Cross-linked bromelain inhibits lipopolysaccharide-induced cytokine production involving cellular signaling suppression in rats. 1653 95

The prevailing view is that the glutamine (Gln) transporter (GlnT/ATA1/SAT1/SNAT1) is a member of the system A transporter superfamily with the ability to fuel the glutamate/Gln cycle at nerve terminals in glutamatergic neurons. Semiquantitative reverse transcription-polymerase chain reaction revealed similarly high expression of mRNA for GlnT by rat brain neocortical astrocytes as well as neurons, with progressively lower expression by cerebellar astrocytes, hippocampal astrocytes, and whole-brain microglia in culture. [(3)H]Gln was accumulated in a temperature-dependent manner with a saturable profile in both cultured neocortical neurons and astrocytes, whereas biochemical and pharmacological analyses on [(3)H]Gln accumulation revealed the expression of both system A and system L transporters by cultured neocortical neurons and astrocytes. Exposure to lipopolysaccharide (LPS) for 24 hr resulted in a significant decrease in both GlnT mRNA expression and [(3)H]Gln accumulation, with a concomitant drastic increase in nitrite formation in cultured neocortical astrocytes. Moreover, LPS significantly inhibited the promoter activity of GlnT in the astrocytic cell line C6 glioma cells as well as primary rat neocortical astrocytes in culture. These results suggest that activation by LPS would lead to down-regulation of the expression of GlnT responsible for the incorporation of extracellular Gln into intracellular spaces across plasma membranes through the inhibition of its promoter activity in cultured rat neocortical astrocytes.
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PMID:Functional expression of A glutamine transporter responsive to down-regulation by lipopolysaccharide through reduced promoter activity in cultured rat neocortical astrocytes. 1658 2


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