John Lee - Academia.edu (original) (raw)

Papers by John Lee

The Journal of neuroscience : the official journal of the Society for Neuroscience, 1998

Tumor necrosis factor-alpha (TNFalpha) and nitric oxide (NO), the product of inducible NO synthas... more Tumor necrosis factor-alpha (TNFalpha) and nitric oxide (NO), the product of inducible NO synthase (iNOS), mediate inflammatory and immune responses in the CNS under a variety of neuropathological situations. They are produced mainly by "activated" astrocytes and microglia, the two immune regulatory cells of the CNS. In this study we have examined the regulation of TNFalpha and iNOS gene expression in endotoxin-stimulated primary glial cultures, focusing on the role of mitogen-activated protein (MAP) kinase cascades. The bacterial lipopolysaccharide (LPS) was able to activate extracellular signal-regulated kinase (ERK) and p38 kinase subgroups of MAP kinases in microglia and astrocytes. ERK activation was sensitive to PD98059, the kinase inhibitor that is specific for ERK kinase. The activity of p38 kinase was inhibited by SB203580, a member of the novel class of cytokine suppressive anti-inflammatory drugs (CSAIDs), as revealed by blocked activation of the downstream kina...

International journal of immunopharmacology, 1994

Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the... more Bacterial endotoxins (lipopolysaccharide or LPS) provoke shock and tissue injury by eliciting the release of toxic factors from reticuloendothelial cells. One of the principal endogenous factors involved in this process is tumor necrosis factor alpha (TNF alpha). In this study, inhibitors selective for different classes of phosphodiesterases (PDE), were examined for their effects on LPS-induced TNF alpha production by human monocytes. The selective cAMP-PDE IV inhibitors, rolipram and RO-20-1724 were capable of inhibiting LPS-induced TNF alpha production by human monocytes in a concentration-dependent manner. Rolipram was used to examine further the cellular pharmacology of PDE IV inhibitors on cytokine production. The IC50 for inhibition of LPS-induced TNF alpha production by rolipram was 0.1 microM, whereas production of IL-1 beta or IL-6 was unaffected. Furthermore, rolipram was equally effective in inhibiting TNF alpha production by a number of other stimuli. Inhibition of TNF a...

European Journal of Biochemistry, 1992

6,7-Dimethyllumazine derivatives, substituted at the 8-position with aldityls or monohydroxyalkyl... more 6,7-Dimethyllumazine derivatives, substituted at the 8-position with aldityls or monohydroxyalkyl groups, have been examined for their binding ability to lumazine apo-protein from two strains of Photobacterium phosphoreum using fluorescence dynamics techniques. On the protein the lumazine has a nearly monoexponential decay of fluorescence with lifetime 13.8 ns (20°C). In free solution the lifetime is 9.6 ns. The concentration of free and bound lumazine in an equilibrium mixture can be recovered readily by analysis of the fluorescence decay. Only the aldityl derivatives D-xylityl and 3'deoxy-D-ribityl, having stereoconfigurations at the 2' and 4' positions identical to the natural ligand, 8-(1'-~-ribityl), show comparable dissociation constants (0.3 FM, 20 "C, pH 7.0). D-Erythrityl and Larabityl have dissociation constants of 1-2 pM. All other ligands show no interaction at all or have dissociation constants in the range 6 -80 pM, which can still be determined semi-quantitatively using the fluorescence decay technique. In the case of these very weakly bound ligands, unambiguous detection of bound ligand can be shown by a long correlation time (23 ns, 2 "C) for the fluorescence anisotropy decay. Examination of the bound D-xylityl compound's fluorescence anisotropy decay at high time resolution (< 100 ps) shows rigid association, i.e. no mobility independent of the macromolecule. All bound ligands appear to be similarly positioned in the binding site. The influence of the stereoconfiguration at the 8-position found for lumazine protein parallels that previously observed for the enzyme riboflavin synthase, where the lumazines are substrates or inhibitors. This is consistent with the finding of significant sequence similarity between these proteins. The binding rigidity may have implications for the mechanism of the enzyme.

Pharmacology & Therapeutics, 1999

The pyridinylimidazole compounds, exemplified by SB 203580, originally were prepared as inflammat... more The pyridinylimidazole compounds, exemplified by SB 203580, originally were prepared as inflammatory cytokine synthesis inhibitors. Subsequently, the compounds were found to be selective inhibitors for p38 mitogen-activated protein kinase (MAPK), a member of the MAPK family. SB 203580 inhibits the catalytic activity of p38 MAPK by competitive binding in the ATP pocket. Four homologues of p38 MAPK have been identified to date, and interestingly, their biochemical properties and their respective sensitivities to the inhibitors are distinct. X-ray crystallographic analysis of p38-inhibitor complexes reinforces the observations made from site-directed mutagenesis studies, thereby providing a molecular basis for understanding the kinase selectivity of these inhibitors. The p38 MAPK inhibitors are efficacious in several disease models, including inflammation, arthritis and other joint diseases, septic shock, and myocardial injury.

Nature Reviews Drug Discovery, 2003

Part of the sequence in a messenger RNA molecule at the 3′ end of the coding sequence that is not... more Part of the sequence in a messenger RNA molecule at the 3′ end of the coding sequence that is not translated. This structural feature is involved in mRNA stability or turnover.

Journal of Chromatography A, 1988

The molecular size of Haemophilus influenzae (Hib) type b polysaccharide-protein conjugate vaccin... more The molecular size of Haemophilus influenzae (Hib) type b polysaccharide-protein conjugate vaccines is an important physico-chemical parameter which correlates with immunogenicity. This paper describes the experimental conditions for high-performance size-exclusion chromatography on a PL Aquagel-OH 60 column to determine the size distribution of Hib high-molecular-weight conjugate vaccines.

Free Radical Biology and Medicine, 1996

Exposure of cells to either proliferative or stressful stimuli elicits a complex response involvi... more Exposure of cells to either proliferative or stressful stimuli elicits a complex response involving one or more distinct phosphorylation cascades culminating in the activation of multiple members of the mitogen-activated protein kinase (MAPK) family, including ...

FEBS Letters, 1995

A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase... more A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739-746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (ICs0 = 0.6 pM), suppresses the activation of MAPKAP kinase-2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin-1, cellular stresses and bacterial endotoxin in vivo.

Cytokine, 2002

We have recently reported the identification of four novel members of the interleukin-1 (IL-1) fa... more We have recently reported the identification of four novel members of the interleukin-1 (IL-1) family which we designated as IL-1 homologue 1-4 (IL-1H1-4). These proteins exhibit significant sequence homology to other members of the IL-1 family. Of these homologues, only IL-1H4 (renamed IL-1F7b) was predicted to contain a propeptide domain and a caspase cleavage site. We now report that caspase-1 cleaves IL-1F7b at the predicted site to generate mature IL-1F7b. Caspase-4 was also able to process IL-1F7b, albeit inefficiently. Other caspases and Granzyme-B did not cleave IL-1F7b. Furthermore, adenovirus-mediated expression of IL-1F7b in HEK 293 cells led to in situ processing and secretion of mature IL-1F7b. In a screen to identify a potential receptor, both pro and mature IL-1F7b bound to the soluble

Bioorganic & Medicinal Chemistry Letters, 1998

Pyrimidine analogs of the pyridinylimidazole class of CSBP/p38 kinase inhibitors were prepared in... more Pyrimidine analogs of the pyridinylimidazole class of CSBP/p38 kinase inhibitors were prepared in an effort to reduce the potent inhibition of hepatic cytochrome P450 observed for the pyridinyl compounds. The substitution of pyrimidin-4-yl, 2-methoxypyrimidin-4-yl, or 2-methylaminopyrimidin-4-yl for pyridin-4-yl effectively dissociates CSBP/p38 kinase from P450 inhibition for this series and furthermore achieves an increase in oral activity.

Bioorganic & Medicinal Chemistry Letters, 1995

As part of an effort to define the pharmacophore and discover the mechanism by which the antiinfl... more As part of an effort to define the pharmacophore and discover the mechanism by which the antiinflammatory dual cyclooxygenase / 5-11poxygenase inhibitors SK&F 86002 and SK&F 105809 inhibit IL-1 biosynthesis, a series of substituted 2,4,5-triarylimidazole derivatives were prepared and evaluated as inhibitors of ILl and 5-1ipoxygenase biosyntl~sis.

Bioorganic & Medicinal Chemistry Letters, 2003

The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38a kinas... more The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38a kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38a kinase, which was predicted to have several key interactions in common with SB-203580, was confirmed by X-ray crystallography of 19 (p38 IC 50 =82 nM). #

Bioorganic & Medicinal Chemistry, 1997

Biochemistry, 1980

The resonance coherent anti-Stokes Raman technique was used to obtain vibrational spectra of flav... more The resonance coherent anti-Stokes Raman technique was used to obtain vibrational spectra of flavin in flavodoxins from Desulfovibrio gigas and Desulfovibrio vulgaris and of the simpler 6,7-dimethyl-8-ribityllumazine chromophore in the blue fluorescence lumazine protein from the bioluminescent bacterium Photobacterium phosphoreum. In the region examined, 1100-1700 cm-', the Raman spectrum of the lumazine is less crowded than that of the flavin and this facilitates assignment of observed frequencies to particular vibrational modes. Certain modes are not affected by chromophore binding to the protein, but others are changed in frequency or intensity in a way that can be rationalized by expected interactions of the chromophore with the amino acid residues of the binding site. For example, a tentative assignment of change in hydrogen bonding at N(5) is suggested w h e n a small molecule binds to a motein the smific eroum

Biochemical and Biophysical Research Communications, 1997

Accounts of Chemical Research, 2004

The bioluminescent jellyfish has contributed two famous proteins to modern science: green fluores... more The bioluminescent jellyfish has contributed two famous proteins to modern science: green fluorescent protein or GFP, which finds wide use as a probe in cell biology studies, and aequorin, which has been used for intracellular calcium measurement for more than 30 years. More recently, obelin, a protein from the bioluminescent hydroid and also in the family of what are called "Ca 2+ -regulated photoproteins", has been shown to have very attractive properties both in general applications and for basic structural biology investigations. This review will survey the new information into their molecular mechanism of bioluminescence action. † Russian Academy of Sciences, Siberian Branch.

Radiation is a widely used treatment for head and neck cancers, and one of its most severe side e... more Radiation is a widely used treatment for head and neck cancers, and one of its most severe side effects is ototoxicity. Radiation-induced ototoxicity has been demonstrated to be linked to the increased production of ROS and MAPK. We intended to investigate the effect of p38 inhibition on radiation-induced ototoxicity in cochlea-derived HEI-OC1 cells and in a zebrafish model. The otoprotective effect of p38 inhibition against radiation was tested in vitro in the organ of Corti-derived cell line, HEI-OC1, and in vivo in a zebrafish model. Radiation-induced apoptosis, mitochondrial dysfunction, and an increase of intracellular NO generation were demonstrated in HEI-OC1 cells. The p38-specific inhibitor, SB203580, ameliorated radiation-induced apoptosis and mitochondrial injury in HEI-OC1 cells. p38 inhibition reduced radiation-induced activation of JNK, p38, cytochrome c, and cleavage of caspase-3 and PARP in HEI-OC1 cells. Scanning electron micrography showed that SB203580 prevented radiation-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. The results of this study suggest that p38 plays an important role in mediating radiation-induced ototoxicity and inhibition of p38 could be a plausible option for preventing radiation ototoxicity.

Information Science and Statistics, 2007

... de Louvain Université catholique de Louvain Place du Levant 3 Avenue Hippocrate 54/69 B-1348 ... more ... de Louvain Université catholique de Louvain Place du Levant 3 Avenue Hippocrate 54/69 B-1348 Louvain-la-Neuve B-1200 Bruxelles Belgium Belgium john.lee@uclouvain.be michel.verleysen@uclouvain.be Series Editors: Michael Jordan Jon Kleinberg Bernhard Schölkopf ...