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See detailInhibition of the Nf-Kappa B Transcription Factor Increases Bax Expression in Cancer Cell Lines
Bentires-Alj, M.; Dejardin, Emmanuel ULg; Viatour, Patrick ULg et al

in Oncogene (2001), 20(22), 2805-13

The NF-kappa B transcription factor has been shown to inhibit apoptosis in several experimental systems. We therefore investigated whether the expression of the Bax proapoptotic protein could be ... [more ▼]

The NF-kappa B transcription factor has been shown to inhibit apoptosis in several experimental systems. We therefore investigated whether the expression of the Bax proapoptotic protein could be influenced by NF-kappa B activity. Increased Bax protein expression was detected in HCT116, OVCAR-3 and MCF7 cells stably expressing a mutated unresponsive I kappa B-alpha inhibitory protein that blocks NF-kappa B activity. Northern blots showed that bax mRNA expression was increased as a consequence of mutated I kappa B-alpha expression in HCT116 cells. A careful examination of the human bax gene promoter sequence showed three putative binding sites for NF-kappa B, and the kappa B2 site at position -687 could indeed bind NF-kappa B complexes in vitro. Transient transfection of a bax promoter luciferase construct in HCT116 cells showed that NF-kappa B proteins could partially inhibit the transactivation of the bax promoter by p53. Mutations or deletions of the kappa B sites, including kappa B2, indicated that this NF-kappa B-dependent inhibitory effect did not require NF-kappa B DNA-binding, and was thus an indirect effect. However, cotransfection of expression vectors for several known cofactors failed to identify a competition between p53 and NF-kappa B for a transcription coactivator. Our findings thus demonstrate for the first time that NF-kappa B regulates, through an indirect pathway, the bax gene expression. [less ▲]

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See detailInhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks
Coppola, G.; Di Clemente, L.; Fumal, Arnaud ULg et al

in Cephalalgia : An International Journal of Headache (2007), 27(7), 803-808

Coppola G, Di Clemente L, Fumal A, Magis D, De Pasqua V, Pierelli F & Schoenen J. Inhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without ... [more ▼]

Coppola G, Di Clemente L, Fumal A, Magis D, De Pasqua V, Pierelli F & Schoenen J. Inhibition of the nociceptive R2 blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks. Cephalalgia 2007; 27:803-808. London. ISSN 0333-1024 In order to explore possible interictal brainstem dysfunctions in migraine, we have studied the R2 component of the nociceptive specific blink reflex (nBR) after conditioning by supraorbital or index finger stimuli in 14 untreated migraine without aura patients (MO) between attacks and in 15 healthy volunteers. We determined the R2 recovery curve at increasing inter-stimulus intervals between 50 and 600 ms. The nBR was conditioned by a paired supraorbital stimulus and, in another session, by an ipsilateral electrical shock delivered to the index finger. The R2 nBR recovery curves were normal in MO patients for both the supraorbital and peripheral conditioning. These results do not favour persistent interictal sensitization in the spinal trigeminal sensory system. They also suggest that the control exerted by descending brainstem pathways on medullary R2 interneurones is normal in migraine between attacks. [less ▲]

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See detailINHIBITION OF THE PHOTOSYSTEM-II PHOTOACTIVATION PROCESS IN FLASHED LEAVES BY SULFATE
BEAUREGARD, M.; Franck, Fabrice ULg; DUJARDIN, E. et al

in Journal of Plant Physiology (1989), 134(3), 370-374

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See detailInhibition of thrombin by oxobenzopyran derivatives: structure-activity relationships
Kibirev, V. K.; Lacan, F.; Bourdel, F. et al

Poster (2001, July)

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See detailInhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties.
Bono, Francoise; De Smet, Frederik; Herbert, Corentin et al

in Cancer Cell (2013), 23(4), 477-88

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the ... [more ▼]

Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment. [less ▲]

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See detailInhibition of tumor growth and metastasis establishment by adenovirus-mediated gene transfer delivery of the antiangiogenic factor 16K hPRL
Nguyen, Ngoc-Quynh-Nhu ULg; Cornet, Anne ULg; Blacher, Silvia ULg et al

in Molecular Therapy : The Journal of the American Society of Gene Therapy (2007), 15(12), 2094-2100

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic ... [more ▼]

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic therapy, therefore, holds potential as an attractive strategy for inhibiting metastasis development. Human 16K PRL (16K hPRL), a potent inhibitor of angiogenesis, has been demonstrated to prevent tumor growth in two xenograft mouse models, but whether it also affects tumor metastasis is unknown. In this study we will investigate the ability of 16K hPRL to prevent the establishment of metastasis. We demonstrate that 16K hPRL administered via adenovirus-mediated gene transfer, inhibits tumor growth by 86% in a subcutaneous (SC) B16-F10 mouse melanoma model. Computer-assisted image analysis shows that 16K hPRL treatment results in a reduction of tumor-vessel length and width, leading to a 57% reduction of average vessel size. In a pre-established tumor model, moreover, 16K hPRL can significantly delay tumor development. Finally, for the first time, we provide evidence that 16K hPRL considerably reduces the establishment of B16-F10 metastasis in an experimental lung metastasis model. Both the number and size of metastases are reduced by 50% in 16K hPRL-treated mice. These results highlight a potential role for 16K hPRL in anticancer therapy for both primary tumors and metastases. [less ▲]

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See detailInhibition of urokinase activity by the antiangiogenic factor 16K prolactin: activation of plasminogen activator inhibitor 1 expression
Lee, H.; Struman, Ingrid ULg; Clapp, C. et al

in Endocrinology (1998), 139(9), 3696-703

The N-terminal fragment of PRL (16K PRL) is an antiangiogenic factor that, in vitro, inhibits several components of angiogenesis including basic fibroblast growth factor (bFGF)-induced cell division ... [more ▼]

The N-terminal fragment of PRL (16K PRL) is an antiangiogenic factor that, in vitro, inhibits several components of angiogenesis including basic fibroblast growth factor (bFGF)-induced cell division, migration, and organization of capillary endothelial cells. An essential step in the regulation of angiogenesis is the activation of urokinase (urokinase type plasminogen activator, uPA), which in turn activates a cascade of proteases that play essential roles in endothelial cell migration and tissue remodeling. Treatment of bovine capillary endothelial cells (BBEC) with 16K PRL inhibited bFGF-stimulated urokinase activity in BBEC as detected by plasminogen substrate gel assay. 16K PRL did not appear to be acting via an effect on uPA expression because no change in messenger RNA levels were observed. However, protein levels of plasminogen activator inhibitor-1 (PAI-1), a specific inhibitor of urokinase, were increased by 16K PRL independent of the action of bFGF. The 16K PRL-induced increase in PAI-1 protein levels appear to be the result of increased expression of the PAI-1 gene. Increased production of PAI-1 induced by 16K PRL results in the formation of inactive PAI-1/uPA complexes, consistent with the observed decrease in uPA activity. [less ▲]

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See detailThe inhibitor thiomandelic acid binds to both metal ions in metallo-beta-lactamase and induces positive cooperativity in metal binding.
Damblon, Christian ULg; Jensen, Mikael; Ababou, Abdessamad et al

in Journal of Biological Chemistry (2003), 278(31), 29240-51

Thiomandelic acid is a simple, broad spectrum, and reasonably potent inhibitor of metallo-beta-lactamases, enzymes that mediate resistance to beta-lactam antibiotics. We report studies by NMR and ... [more ▼]

Thiomandelic acid is a simple, broad spectrum, and reasonably potent inhibitor of metallo-beta-lactamases, enzymes that mediate resistance to beta-lactam antibiotics. We report studies by NMR and perturbed angular correlation (PAC) spectroscopy of the mode of binding of the R and S enantiomers of thiomandelic acid, focusing on their interaction with the two metal ions in cadmium-substituted Bacillus cereus metallo-beta-lactamase. The 113Cd resonances are specifically assigned to the metals in the two individual sites on the protein by using 113Cd-edited 1H NMR spectra. Each enantiomer of thiomandelate produces large downfield shifts of both 113Cd resonances and changes in the PAC spectra, which indicate that they bind such that the thiol of the inhibitor bridges between the two metals. For R-thiomandelate, this is unambiguously confirmed by the observation of scalar coupling between Halpha of the inhibitor and both cadmium ions. The NMR and PAC spectra reveal that the two chiral forms of the inhibitor differ in the details of their coordination geometry. The complex with R-thiomandelate, but not that with the S-enantiomer, shows evidence in the PAC spectra of a dynamic process in the nanosecond time regime, the possible nature of which is discussed. The thiomandelate complex of the mononuclear enzyme can be detected only at low metal to enzyme stoichiometry; the relative populations of mononuclear and binuclear enzyme as a function of cadmium concentration provide clear evidence for positive cooperativity in metal ion binding in the presence of the inhibitor, in contrast to the negative cooperativity observed in the free enzyme. [less ▲]

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See detailInhibitors of cannabinoid receptors and glucose metabolism.
Scheen, André ULg; Paquot, Nicolas ULg

in Current Opinion in Clinical Nutrition & Metabolic Care (2008), 11(4), 505-11

PURPOSE OF REVIEW: Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in ... [more ▼]

PURPOSE OF REVIEW: Abdominal obesity is closely related to type 2 diabetes and overactivity of the endocannabinoid system. The present review aims at evaluating the role of endocannabinoid system in glucose dysregulation and the effects of cannabinoid 1 receptor blockade on glucose metabolism in both animal models and overweight/obese humans, especially with type 2 diabetes. RECENT FINDINGS: Cannabinoid 1 receptors have been identified not only in the brain, but also in the adipose tissue, the gut, the liver, the skeletal muscle and even the pancreas, all organs playing a key role in glucose metabolism and type 2 diabetes. Rimonabant, the first selective cannabinoid 1 receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, glycated haemoglobin, triglycerides, insulin resistance index, and to increase HDL cholesterol and adiponectin concentrations in patients with type 2 diabetes, confirming data on nondiabetic overweight/obese patients. Almost half of the metabolic changes, including glycated haemoglobin reduction, could not be explained by weight loss, in agreement with direct peripheral effects. SUMMARY: Cannabinoid 1 blockade reduces food intake and body weight and improves metabolic regulation beyond just weight loss. Because of its positive effect on glucose metabolism, rimonabant deserves consideration in the treatment of overweight/obese patients with type 2 diabetes. [less ▲]

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See detailInhibitors of glycosylhydrolases as potential insecticides : focus on aphid model
Bosquée, Emilie ULg; Vandermoten, Sophie; Richel, Aurore ULg et al

Poster (2014, June)

Beside conventional neurotoxic compounds, new kinds of insecticides are investigated and new specific targets are in current research. According to the energy metabolic pathway, several enzymes are ... [more ▼]

Beside conventional neurotoxic compounds, new kinds of insecticides are investigated and new specific targets are in current research. According to the energy metabolic pathway, several enzymes are interesting to bring potential specific control of arthropods. Indeed, glycosylhydrolase group is very diversified from glucanases to trehalases, until chitinases. Different kinds of inhibitors were here tested to determine their potential role as new targetted aphicides. After different assays using the selected inhibitors in artificial diets, the most efficient molecules at 50-100 μg ml-1were kept for further proteomic tasks. The proteome patterns of aphids related to different inhibitor treatments were determined by two dimension electrophoresis, 2D-Differencial In Gel Expression (2D-Dige) coupled with mass spectrometry (ESI-MS-MS and Maldi-Tof-MS-MS) and data bank investigations. Particular proteins of interest were selected and accurately characterised with both fundamental but also applied views. Not only the carbohydrate metabolic pathway was disturbed with the use of glycosylhydolases inhibitors, other primary functions were also modified (amino acid synthesis, stress response, etc). This proteomic approach was discussed as an interesting and reliable tool to study the biologically involved proteins from aphids in response to specific tested enzymatic inhibitors with further ideas to be promoted as new insecticides to control insect pests. [less ▲]

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See detailInhibitors of metallo-beta-lactamase generated from beta-lactam antibiotics.
Badarau, Adriana; Llinas, Antonio; Laws, Andrew P et al

in Biochemistry (2005), 44(24), 8578-89

The resistance of bacteria to the normally lethal action of beta-lactam antibiotics is largely due to the production of beta-lactamases that catalyze the hydrolysis of the beta-lactam. One class of these ... [more ▼]

The resistance of bacteria to the normally lethal action of beta-lactam antibiotics is largely due to the production of beta-lactamases that catalyze the hydrolysis of the beta-lactam. One class of these enzymes is a zinc-dependent metallo-beta-lactamase for which there are no clinically available inhibitors. The hydrolysis of cephalosporin beta-lactam antibiotics generates dihydrothiazines which subsequently undergo isomerization at C6 by C-S bond cleavage and through the intermediacy of a thiol. These thiols can be trapped by the beta-lactamase from Bacillus cereus, causing inhibition of the enzyme. The rate of production of the thiol corresponds to the rate of inhibition, and the inhibition constants are in the micromolar range but vary with the nature of the cephalosporin derivative. NMR studies have identified the structure of the thiols causing inhibition and also show that the thiol binds to the zinc ion, which in turn perturbs the metal-bound histidines. Inhibition is slowly removed as the thiol becomes oxidized or undergoes further degradation. The thiol intermediate generated from cephalothin is a slow binding inhibitor. There is no observed inhibition from the analogous degradation products from penicillins. [less ▲]

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See detailInhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
Minond, D.; Saldanha, S. A.; Spaargaren, M. et al

in Bioorganic & Medicinal Chemistry (2009), 17

VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area ... [more ▼]

VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine K(i) and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K(i)=K(i)(')=1.5+/-0.2microM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzenesulfonamide (1, K(i)=0.41+/-0.03microM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K(i)=1.4+/-0.10microM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays. [less ▲]

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See detailInhibitory Action Of A New Lectin From Xerocomus Chrysenteron On Cell-Substrate Adhesion
Marty-Detraves, C.; Francis, Frédéric ULg; Baricault, L. et al

in Molecular and Cellular Biochemistry (2004), 258(1-2), 49-55

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See detailInhibitory activity of lactobacillus curvatus CWBI-B28 against Listeria monocytogenes and ST2-verotoxin producing Escherichia coli O157
Ghalfi, H.; Thonart, Philippe ULg; Benkerroum, N.

in African Journal of Biotechnology (2006), 5(22), 2303-2306

A bacteriocin- producing strain of Lactobacillus curvatus CWBI- B28 isolated from raw meat was shown to inhibit Listeria monocytogenes and pathogenic strains of Escherichia coli by the well diffusion ... [more ▼]

A bacteriocin- producing strain of Lactobacillus curvatus CWBI- B28 isolated from raw meat was shown to inhibit Listeria monocytogenes and pathogenic strains of Escherichia coli by the well diffusion assay. To confirm whether the bacteriocin was involved in E. coli O157 inhibition, growth of the pathogen was monitored in the neutralized cell- free supernatant ( NCFS) pre- treated with pronase E or catalase. Alternatively, E. coli O157 ( VH21) was co- cultured with Lb. curvatus CWBI- B28 in MRS broth. The results of the well- diffusion assay suggested that the inhibition of E. coli O157 ( VH21) was partially due to the bacteriocin; however, growth monitoring indicated that such inhibition is exclusively due to hydrogen peroxide. In pronase- added NCFS ( i. e., absence of bacteriocin) the colony forming units ( cfus) of E. coli O157 ( VHA21) declined to below the detectable limit after 24 h of incubation at 37 C. However, in presence of catalase no inhibition of the pathogen was observed and the cfus increased steadily to reach 8 log units in 24 h. Moreover, in co- culture, a significantly accelerated inhibition of E. coli O157 ( VH21) was observed in MRS broth as compared to the NCFS without added catalase and the cfus decreased to below the detectable limit in 8 h instead of 24 h, respectively. [less ▲]

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See detailInhibitory control of memory in normal ageing: Dissociation between impaired intentional and preserved unintentional processes.
Collette, Fabienne ULg; Germain, Sophie ULg; Hogge, Michaël et al

in Memory (2009), 17(1), 104-122

The aim of this study was to compare the performance of elderly and young participants on a series of memory tasks involving either intentional or unintentional inhibitory control of memory content ... [more ▼]

The aim of this study was to compare the performance of elderly and young participants on a series of memory tasks involving either intentional or unintentional inhibitory control of memory content. Intentional inhibition processes in working and episodic memory were explored with directed forgetting tasks and in semantic memory with the Hayling task. Unintentional inhibitory processes in working memory, long-term memory, and semantic memory were explored with an interference resolution task, the retrieval practice paradigm, and the flanker task, respectively. The results indicate that elderly participants' performance on the two directed forgetting tasks and the Hayling task is lower than that of young ones, and that this impairment is not related to their initial memory capacity. This suggests that there is a specific dysfunction affecting intentional inhibitory control of memory contents in normal ageing. [less ▲]

Detailed reference viewed: 96 (15 ULg)