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  • 1
    Electronic Resource
    Electronic Resource
    Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARγ (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 81 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Malignant astrocytomas are among the most common brain tumours and few therapeutic options exist. It has recently been recognized that the ligand-activated nuclear receptor PPARγ can regulate cellular proliferation and induce apoptosis in different malignant cells. We report the effect of three structurally different PPARγ agonists inducing apoptosis in human (U87MG and A172) and rat (C6) glioma cells. The PPARγ agonists ciglitazone, LY171 833 and prostaglandin-J2, but not the PPARα agonist WY14643, inhibited proliferation and induced cell death. PPARγ agonist-induced cell death was characterized by DNA fragmentation and nuclear condensation, as well as inhibited by the synthetic receptor-antagonist bisphenol A diglycidyl ether (BADGE). In contrast, primary murine astrocytes were not affected by PPARγ agonist treatment. The apoptotic death in the glioma cell lines treated with PPARγ agonists was correlated with the transient up-regulation of Bax and Bad protein levels. Furthermore, inhibition of Bax expression by specific antisense oligonucleotides protected glioma cells against PPARγ-mediated apoptosis, indicating an essential role of Bax in PPARγ-induced apoptosis. However, PPARγ agonists not only induced apoptosis but also caused redifferentiation as indicated by outgrowth of long processes and expression of the redifferentiation marker N-cadherin in response to PPARγ agonists. Taken together, treatment of glioma cells with PPARγ agonists may hold therapeutic potential for the treatment of gliomas.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.00899.x
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  • 2
    Electronic Resource
    Electronic Resource
    Noradrenergic depletion increases inflammatory responses in brain: effects on IκB and HSP70 expression (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 85 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The inflammatory responses in many cell types are reduced by noradrenaline (NA) binding to β-adrenergic receptors. We previously demonstrated that cortical inflammatory responses to aggregated amyloid beta (Aβ) are increased if NA levels were first depleted by lesioning locus ceruleus (LC) noradrenergic neurons, which replicates the loss of LC occurring in Alzheimer's disease. To examine the molecular basis for increased responses, we used the selective neurotoxin DSP4 to lesion the LC, and then examined levels of putative anti-inflammatory molecules. Inflammatory responses were achieved by injection of aggregated Aβ1–42 peptide and IL-1β into frontal cortex, which induced neuronal inducible nitric oxide synthase (iNOS) and microglial IL-1β expression. DSP4-treatment reduced basal levels of nuclear factor kappa B (NF-κB) inhibitory IκB proteins, and of heat shock protein (HSP)70. Inflammatory responses were prevented by co-injection (ibuprofen or ciglitzaone) or oral administration (pioglitazone) of peroxisome proliferator-activated receptor gamma (PPARγ) agonists. Treatment with PPARγ agonists restored IκBα, IκBβ, and HSP70 levels to values equal or above those observed in control animals, and reduced activation of cortical NF-κB. These results suggest that noradrenergic depletion reduces levels of anti-inflammatory molecules which normally limit cortical responses to Aβ, and that PPARγ agonists can reverse that effect. These findings suggest one mechanism by which PPARγ agonists could provide benefit in neurological diseases having an inflammatory component.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01694.x
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  • 3
    Electronic Resource
    Electronic Resource
    Norepinephrine Suppresses Inducible Nitric Oxide Synthase Activity in Rat Astroglial Cultures (1993)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 60 (1993), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Exposure of primary rat astrocyte cultures to bacterial endotoxin lipopolysaccharide (LPS) causes expression of a Ca2+-in-dependent form of nitric oxide synthase (NOS). In these cells, the presence of norepinephrine (NE) caused a dose-dependent inhibition of the LPS induction of NOS activity, with an IC50 value of 100 nMand significant suppression at 100 pAf. Short incubations (5-40 min) with NE were as effective as 24-h continuous exposure, and inhibition was observed up to the longest incubation period measured (56 h). In contrast, previously induced NOS activity was not affected by exposure to NE. The effects of NE were mediated primarily by binding to β-adrenergic receptors (β-ARs) because (a) the β-AR antagonist propranolol, but not the n-AR antagonist phentol-amine, could reverse the effects of NE; (b) the β-AR agonist isoproterenol. but not the a-AR agonist phenylephrine, was as effective as NE in blocking the effects of LPS; and (c) incubation with the cyclic AMP analogue dibutyryl cyclic AMP replicated the effects of NE. In contrast to astroglial cultures, LPS induction of NOS activity in RAW 264.7 macrophage cells was not affected by NE or dibutyryl cyclic AMP. These results indicate that in brain, inducible NOS in astrocytes can be regulated by neurotransmitter binding to glial receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1993.tb13425.x
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  • 4
    Electronic Resource
    Electronic Resource
    Induction of Nitric Oxide Synthase in Rat C6 Glioma Cells (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 62 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have examined the induction of nitric oxide syhthase (NOS) activity in the rat astrocyte-derived C6 glioma cell line. In contrast to the previous results with primary astrocyte cultures, incubation of C6 cells with bacterial endotoxin lipopolysaccharide (LPS; 1 μg/ml for 24 h) did not stimulate NO2 production. However, addition of either tumor necrosis factor-a (TNF-α) or interferon-γ (IFN-γ), cytokines that by themselves had no effect on NOS activity, imparted LPS responsiveness onto these cells in a dose-dependent manner (EC50 values of 39 ng/ml of TNF-α and 9.4 U/ml of IFN-γ), and the effect of TNF-α could be further potentiated (twofold) by the presence of interleukin-1β. The simultaneous presence of TNF-α and IFN-γ yielded a greater response than either cytokine alone; however, the respective EC50 values were not affected. A cytoplasmic extract from induced C6 cells catalyzed the Ca2+-independent conversion of l-arginine to l- citrulline, with an apparent Km of 51.2 nM, and this activity could be blocked by l-arginine analogues in the potency order amino 〉 methyl 〉 nitroarginine. Immunoblot analysis revealed an apparent molecular mass of 125 kDa for the NOS protein induced in C6 cells. These results indicate that the combination of LPS plus cytokines can induce NOS activity in C6 glioma cells with properties similar to those of the enzyme expressed in primary astrocyte cultures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.62010315.x
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  • 5
    Electronic Resource
    Electronic Resource
    Nitric Oxide Synthase Expression in Glial Cells: Suppression by Tyrosine Kinase Inhibitors (1994)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 62 (1994), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Rat brain glial cells have the capacity to express a calcium-independent form of nitric oxide synthase (iNOS). To test if iNOS induction required tyrosine kinase activity, we made use of genistein, a selective inhibitor of tyrosine kinases. In both primary astrocyte cultures and C6 glioma cells, the presence of genistein prevented both lipopolysaccharide- and cytokine-induced NOS activity in a dose-dependent manner. The presence of tyrphostin-25 (10 µM), which is highly specific for tyrosine kinases, also blocked iNOS induction. Additional characterization showed that genistein blocked iNOS induction in a dose-dependent manner (IC50 of ∼ 40 µM), that the continuous presence of genistein was not necessary to observe inhibition, and that preincubation with genistein led to higher levels of inhibition than the simultaneous addition of genistein and inducers. The decrease in iNOS activity due to genistein was accompanied by a decrease in iNOS mRNA level as detected by a specific PCR assay. These results indicate that induction of astroglial iNOS expression requires tyrosine kinase activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1994.62020811.x
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  • 6
    Electronic Resource
    Electronic Resource
    A 27-bp region of the inducible nitric oxide synthase promoter regulates expression in glial cells (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 78 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The expression of inducible nitric oxide synthase (NOS2) in glial cells is inhibited by neurotransmitters such as norepinephrine (NE) which elevate cAMP levels. We examined the molecular basis for this effect using a 2.2-kb fragment of the rat NOS2 promoter transfected into rat C6 glioma cells. Promoter activation (up to six-fold) by lipopolysaccharide (LPS) and interferon-γ (IFNγ) was reduced by NE, which alone had no effect. However, a promoter construct extending to bp −130 and containing the proximal nuclear factor-kappa B (NF-κB) binding site was minimally activated by LPS and cytokines, but activated up to three-fold by NE. Deletion analysis identified a 27-bp region (bp −187 to −160) as critical for mediating this suppressive effect. This region also enhanced promoter activation by LPS and cytokines, and prevented activation by NE alone. Gel shift analysis revealed constitutive binding to this region, and induction by NE of additional complexes which could be blocked by an antibody against CREB. NE also increased levels of the IκBα protein which could contribute to its suppressive effects. These results identify a critical role for this 27-bp region in regulation of NOS2 promoter activation and suppression by cAMP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00375.x
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  • 7
    Electronic Resource
    Electronic Resource
    Messenger RNAs Located in Myelin Sheath Assembly Sites (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The targeting of mRNAs to specific subcellular locations is believed to facilitate the rapid and selective incorporation of their protein products into complexes that may include membrane organelles. In oligodendrocytes, mRNAs that encode myelin basic protein (MBP) and select myelin-associated oligodendrocytic basic proteins (MOBPs) locate in myelin sheath assembly sites (MSAS). To identify additional mRNAs located in MSAS, we used a combination of subcellular fractionation and suppression subtractive hybridization. More than 50% of the 1,080 cDNAs that were analyzed were derived from MBP or MOBP mRNAs, confirming that the method selected mRNAs enriched in MSAS. Of 90 other cDNAs identified, most represent one or more mRNAs enriched in rat brain myelin. Five cDNAs, which encode known proteins, were characterized for mRNA size(s), enrichment in myelin, and tissue and developmental expression patterns. Two of these, peptidylarginine deiminase and ferritin heavy chain, have recognized roles in myelination. The corresponding mRNAs were of different sizes than the previously identified mRNA, and they had tissue and development expression patterns that were indistinguishable from those of MBP mRNA. Three other cDNAs recognize mRNAs whose proteins (SH3p13, KIF1A, and dynein light intermediate chain) are involved in membrane biogenesis. Although enriched in myelin, the tissue and developmental distribution patterns of these mRNAs differed from those of MBP mRNA. Six other cDNAs, which did not share significant sequence homology to known mRNAs, were also examined. The corresponding mRNAs were highly enriched in myelin, and four had tissue and developmental distribution patterns indistinguishable from those of MBP mRNA. These studies demonstrate that MSAS contain a diverse population of mRNAs, whose locally synthesized proteins are placed to contribute to myelin sheath assembly and maintenance. Characterization of these mRNAs and proteins will help provide a comprehensive picture of myelin sheath assembly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0751834.x
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  • 8
    Electronic Resource
    Electronic Resource
    The heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 77 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The stress response (SR) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-κB). As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG35−55) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG35−55 peptide injection. The HSR reduced the incidence of EAE by 70%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon γ (IFNγ) in response to MOG35−55, was also decreased by the HSR. The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-κB was also blocked by the HSR. The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00260.x
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  • 9
    Electronic Resource
    Electronic Resource
    Suppression of Astroglial Nitric Oxide Synthase Expression by Norepinephrine Results from Decreased NOS-2 Promoter Activity (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 70 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We previously demonstrated that norepinephrine (NE) inhibits induction of the calcium-independent isoform of nitric oxide synthase (NOS-2) in primary rat astrocyte cultures. However, the molecular mechanisms underlying this effect are unknown. In C6 cells and astrocytes, NE suppressed both cytokine- and lipopolysaccharide (LPS)-dependent nitrite accumulation, an index of NOS-2 activity. NE reduced the steady-state levels of NOS-2 mRNA induced by LPS plus cytokines but did not decrease NOS-2 mRNA stability or inhibit activation or subunit composition of transcription factor nuclear factor κB, which is necessary for NOS-2 induction. In C6 cells stably transfected with a 1,588-bp mouse NOS-2 promoter, NE reduced LPS plus cytokine-induced reporter gene expression, suggesting inhibition of NOS-2 promoter activity. In contrast, suppression was lost when a truncated 85-bp NOS-2 promoter was used, and in these cells NE potentiated reporter gene expression, alone or in the presence of LPS and cytokines. These results suggest that the suppressive effects of NE are due to modification of transcription factor activity in a region located between −1,588 and −85 of the NOS-2 promoter and may help explain observations that in some cells cyclic AMP can potentiate, rather than suppress, NOS-2 expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.70041484.x
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  • 10
    Electronic Resource
    Electronic Resource
    Potentiation of Astroglial Nitric Oxide Synthase Type-2 Expression by Lithium Chloride (1998)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 71 (1998), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The mechanisms underlying the antimanic effects of lithium are largely unknown but may involve long-term changes in brain gene expression. To determine if lithium could modify gene expression in astrocytes, the predominant cell type in brain, we tested the effects of LiCl on expression of nitric oxide synthase type 2 (NOS-2) in cultured glial cells. Incubation of primary rat astrocytes with endotoxin [lipopolysaccharide (LPS)] and proinflammatory cytokines induced NOS-2 gene and protein expression, as assessed by nitrite production and measurement of l-citrulline synthesis in whole cell lysates. Incubation with LiCl, but not KCl, increased NOS-2 activity up to 1.6-fold. LiCl also potentiated (up to 2.7-fold) the induction of NOS-2 expression by LPS plus interferon-γ in C6 glioma cells but had little effect on LPS-induced nitrite accumulation from mouse RAW 264.7 macrophages. LiCl increased NOS-2 mRNA steady-state levels, suggesting an effect on mRNA stability and/or NOS-2 gene transcription. These results demonstrate that LiCl can modify astroglial gene expression and suggest that chronic treatment with lithium could exacerbate inflammatory responses in brain glial cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1998.71020883.x
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