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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 32 (1991), S. 289-294 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract TNF is a potent cytokine which can induce many of the pathological changes associated with inflammatory disease.In vitro studies have demonstrated that 5-lipoxygenase products promote the production of TNF by activated macrophages, suggesting that 5-lipoxygenase inhibitors may have therapeutic utility for the treatment of inflammatory conditions. A rat airpouch model of inflammation has been used to investigate the relationship between eicosanoid generation and TNF productionin vivo. Injection of zymosan into the airpouch caused a time-dependent stimulation of TNF production which preceded leukotriene generation by at least 30 minutes. Injection of LPS into the airpouch also stimulated TNF production but not leukotriene generation. The selective 5-lipoxygenase inhibitors, ICI207968, A64077 and BWA4C, and the 5-lipoxygenase translocation inhibitor MK886, decreased leukotriene generation but enhanced TNF production. Taken together, these results do not support a role for 5-lipoxygenase products in the regulation of TNF productionin vivo.
    Type of Medium: Electronic Resource
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  • 12
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 16 (1985), S. 58-59 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 14
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumour necrosis factorα (TNFα) has been reported to play a key role in the pathogenesis of sepsis and chronic inflammatory diseases, including rheumatoid arthritis and atherosclerosis, suggesting that agents which inhibit TNFα production may have therapeutic utility for the treatment of such conditions. Production of TNFα by LPS (lipopolysaccharide)-stimulated murine, rat and human heparinized blood was investigated. LPS (1–100 μg/ml) caused a similar concentration- and time-dependent stimulation of TNFα production by rat and human blood, achieving levels of 750–5000 U/ml (L929 bioassay) at 6h. In contrast, TNFα production by LPS-stimulated murine blood was poor and variable (0–150 U/ml). Dexamethasone and pentoxifylline caused a concentration-dependent inhibition of TNFα production by LPS-stimulated human and rat blood with IC50s of 0.26±0.05 and 73.0±26.4 μM for human and 5.7±1.8 nM and 20.6±8.0 μM for rat blood, respectively. Therefore, LPS-stimulated rat and human, but not murine, blood are suitable systems for the detection and evaluation of inhibitors of TNFα production.
    Type of Medium: Electronic Resource
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 39 (1993), S. C61 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rat blood was investigated as a suitable test system for the discovery of inhibitors of tumour necrosis factor α (TNFα) biosynthesis. Lipopolysaccharide (LPS) caused a concentration- and time-dependent stimulation of TNFα production by heparinised rat blood with peak levels (1000–5000 U/ml; L929 bioassay) at 6h. Bioactive material was neutralised with a polyclonal rabbit anti-murine TNFα antibody which cross-reacts with rat TNFα. Dexamethasone, pentoxifylline and denbufylline inhibited TNFα production with IC50s of 6.0±2.0 nM, 20.6±8.00 μM and 138.0 nM, respectively. When rats were dosed p.o. with dexamethasone or pentoxifylline or i.p. with denbufylline and 1.5h later TNFα production was assessedex vivo by LPS-stimulated blood, a dose-related inhibition of TNFα production occurred with ID50s of approximately 0.08, 250.0 and 5.0 mg/kg, respectively. These results demonstrate that rat blood provides a useful test system for the detection andex vivo evaluation of inhibitors of TNFα biosynthesis.
    Type of Medium: Electronic Resource
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Inflammation research 17 (1986), S. 358-359 
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 17
    ISSN: 1420-908X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Methoxyalkyl thiazoles are novel 5-lipoxygenase inhibitors which are neither redox agents nor iron chelators and are exemplified by ICI211965 [1-(3-naphth-2-ylmethoxy)phenyl)-1-(thiazol-2-yl)propyl methyl ether]. ICI211965 potently inhibits LTC4 synthesis in murine macrophages (IC50=0.0085 μM) and its selectivity with respect to cyclo-oxygenase (〉5800) is greater than any previously reported lipoxygenase inhibitor. ICI211965 also selectively inhibits LTB4 synthesis by human bloodin vitro (IC50=0.45 μM) and rat bloodex vivo (ED50=10 mg/Kg, p.o.). Methoxyalkyl thiazoles exhibit a tight structure activity relationship and resolution of a chiral member of the series demonstrates that 5-lipoxygenase inhibition resides largely in one enantiomer. Methoxyalkyl thiazoles represent the first class of agents for which 5-lipoxygenase inhibition is mediated by specific, enantioselective interaction with the enzyme.
    Type of Medium: Electronic Resource
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Graefe's archive for clinical and experimental ophthalmology 218 (1982), S. 153-155 
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cultures of rabbit retinal pigment epithelium (RPE) were exposed to normal vitreous and to vitreous injured by intravitreal injection of foreign particles. Counts of labeled RPE nuclei after incubation with3H-thymidine in vitro indicated an increase in DNA synthesis with exposure to normal vitreous and an even greater increase with exposure to injured vitreous. Fractionation of injured vitreous demonstrated that the apparent proliferation stimulus resided in the cell-free supernate. The data suggest that normal vitreous contains a humoral factor that stimulates RPE proliferation and that levels of an active agent increase after vitreal injury. RPE injected into the vitreous also responds by increased DNA synthesis to subsequent vitreal injury. This observation implies that foreign substances in the vitreous, as after vitreal hemorrhage, promote development of extraretinopathies involving RPE by stimulating intravitreal proliferation of invasive RPE cells.
    Type of Medium: Electronic Resource
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  • 19
    ISSN: 1617-4623
    Keywords: Key wordsStaphylococcus aureus ; Regulation ; Toxin ; Virulence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The accessory gene regulator (agr) and staphylococcal accessory regulator (sar) loci are important regulators of toxin production in Staphylococcus aureus. In this study we examined how environmental conditions – degree of aeration and salt concentration – affect the transcription and translation of mRNAs for α- haemolysin (Hla) and serine protease (Ssp) via these pathways and influence the stability of these proteins. Using Northern analysis, we have confirmed earlier observations that sarA is involved in the upregulation of RNAIII, the effector molecule encoded by the agr locus. However, this effect was abolished in highly aerated cultures. While sarA does appear to have an up-regulatory effect on hla transcription that is independent of agr, we propose that the PC1839 (sarA) mutant produces less α-haemolysin activity mainly as a result of post-translational inactivation by proteases. The most obvious phenotypic feature of PC1839 (sarA) is the upregulation of proteases. In this study we show that ssp is repressed by SarA at the transcriptional level. Western analysis using an anti-α-haemolysin antibody identified a major breakdown product that is only present in the supernatant of strains that are overexpressing serine protease. We have also confirmed that agr exerts a significant regulatory influence on hla at the level of translation, as well as transcription. Finally, the addition of salt upregulates ssp transcription and dramatically downregulates transcription of hla, and is an example of an environmental parameter that affects toxin production independently of agr and sarA. How environmental signals are transduced to control α-haemolysin and serine protease production, activity and stability at multiple levels are discussed.
    Type of Medium: Electronic Resource
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