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See detailInhibition of Croton Oil-Induced Oedema in Mice Ear Skin by Capsular Polysaccharides from Cyanobacteria
Garbacki, Nancy ULg; Gloaguen, Vincent; Damas, Jacques ULg et al

in Naunyn-Schmiedeberg's Archives of Pharmacology (2000), 361(4), 460-4

The anti-inflammatory properties of hydrophilic extracts of the capsular polymers of twelve cyanobacterial strains belonging to the genera Phormidium and Nostoc from marine and terrestrial habitats were ... [more ▼]

The anti-inflammatory properties of hydrophilic extracts of the capsular polymers of twelve cyanobacterial strains belonging to the genera Phormidium and Nostoc from marine and terrestrial habitats were tested topically on croton oil-induced oedema in mice ear skin. The screening program identified several strains as producers of anti-inflammatory products (up to 56% inhibition of the oedema). The inhibition response was dose-dependent. The application of trichloroacetic acid-treated extracts reduced the oedema by about 60%. On the other hand, one of the strains enhanced the inflammatory response. Analysis of five of the extracts showed the presence of neutral sugars (from 34.3% to 47.1%, w/w), uronic acids (from 7.1% to 26.7%, w/w) and proteins (from 30.1% to 57.0%, w/w) in the crude polymer. Rhamnose, fucose, arabinose, xylose, mannose, glucose, galactose, galacturonic acid and glucuronic acid were detected as well as sulphate groups (from 9.6% to 21.5%, w/w of sugars). The main components found were glucose and mannose. [less ▲]

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See detailThe Inhibition of Cyclin-Dependent Kinases Induces Differentiation of Supernumerary Hair Cells and Deiters' Cells in the Developing Organ of Corti
Malgrange, Brigitte ULg; Knockaert, Marie; Belachew, Shibeshih ULg et al

in FASEB Journal (2003), 17(14), 2136-8

In the embryonic day 19 organs of Corti, we showed that roscovitine, a chemical inhibitor of cyclin-dependent kinases (CDKs), significantly increased the number of hair cells (HCs) and corresponding ... [more ▼]

In the embryonic day 19 organs of Corti, we showed that roscovitine, a chemical inhibitor of cyclin-dependent kinases (CDKs), significantly increased the number of hair cells (HCs) and corresponding supporting cells (SCs) by triggering differentiation of precursor cells without interacting with cell proliferation. The effect of roscovitine was mimicked by other CDK1, 2, 5, and 7 inhibitors but not by CDK4/6 and mitogen-activated protein kinase pathway antagonists. Immunohistochemical analysis indicated that roscovitine-specific intracellular targets, CDK1, 2, 5, and 7, were expressed in the organ of Corti and especially in Hensen's cells. Affinity chromatography studies showed a tight correlation between the protein levels of CDK1/2 and 5 and the rate of roscovitine-induced supernumerary cells in the organ of Corti. In addition, we demonstrated that basal CDK activity was higher and more roscovitine-sensitive at developmental stages that are selectively permissive for the emergence of supernumerary cells. These results suggest that CDKs are involved in the normal development of the organ of Corti and that, at least in E19 embryos, inhibition of CDKs is sufficient to trigger the differentiation of HCs and corresponding SCs, presumably from the Hensen's cell progenitors and/or from progenitors located in the greater epithelial ridge area. [less ▲]

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See detailInhibition of dd-Peptidases by a Specific Trifluoroketone: Crystal Structure of a Complex with the Actinomadura R39 dd-Peptidase.
Dzhekieva, Liudmila; Adediran, S. A.; Herman, Raphaël ULg et al

in Biochemistry (2013)

Inhibitors of bacterial dd-peptidases represent potential antibiotics. In the search for alternatives to beta-lactams, we have investigated a series of compounds designed to generate transition state ... [more ▼]

Inhibitors of bacterial dd-peptidases represent potential antibiotics. In the search for alternatives to beta-lactams, we have investigated a series of compounds designed to generate transition state analogue structures upon reaction with dd-peptidases. The compounds contain a combination of a peptidoglycan-mimetic specificity handle and a warhead capable of delivering a tetrahedral anion to the enzyme active site. The latter includes a boronic acid, two alcohols, an aldehyde, and a trifluoroketone. The compounds were tested against two low-molecular mass class C dd-peptidases. As expected from previous observations, the boronic acid was a potent inhibitor, but rather unexpectedly from precedent, the trifluoroketone [d-alpha-aminopimelyl(1,1,1-trifluoro-3-amino)butan-2-one] was also very effective. Taking into account competing hydration, we found the trifluoroketone was the strongest inhibitor of the Actinomadura R39 dd-peptidase, with a subnanomolar (free ketone) inhibition constant. A crystal structure of the complex between the trifluoroketone and the R39 enzyme showed that a tetrahedral adduct had indeed formed with the active site serine nucleophile. The trifluoroketone moiety, therefore, should be considered along with boronic acids and phosphonates as a warhead that can be incorporated into new and effective dd-peptidase inhibitors and therefore, perhaps, antibiotics. [less ▲]

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See detailInhibition of Experimental Corneal Neovascularization by Sunitinib Administration
Detry, Benoît ULg; BLACHER, Silvia ULg; Erpicum, Charlotte ULg et al

Poster (2011, October)

Cornea engraftment is the most common organ transplantation practiced around the world. The cornea is totally devoid of blood or lymphatic vessels, except in a peripheral zone called the limbus. This ... [more ▼]

Cornea engraftment is the most common organ transplantation practiced around the world. The cornea is totally devoid of blood or lymphatic vessels, except in a peripheral zone called the limbus. This property, named “corneal angiogenic privilege”, is conserved among all mammals to maintain cornea transparency and optimal visual acuity. In pathological conditions such as trauma, infections or hypoxia, blood and lymphatic vessels can grow into the avascular cornea, reducing visual acuity. In case of keratoplasty, it also considerably increases the risk of cornea graft rejection and is so considered as a high-risk keratoplasty. Treatments improving cornea survival after transplantation need to be developed, notably aiming at blocking corneal neovascularization. Here, we evaluated the efficacy of Sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor, to reduce experimental corneal neovascularization. Cornea vascularization was induced by thermal cauterization applied in the center of C57Bl6 mice cornea, daily feeded with 40mg/kg Sunitinib or vehicule. Corneas were immunolabeled as whole mounts for CD31 and Lyve-1 to evidence blood and lymphatic vessels, 7, 11 and 17 days after cauterization. Whole mount pictures were analyzed by computer-assisted quantification, and relative vascular area, end-point density, node density, length density and maximal length of the vessels were determined to finely characterize blood and lymphatic vascular networks. We observed an inhibition of angiogenesis after 17 days in Sunitinib treated mice, where blood vessel relative surface, end-point density, branching density and length density were 1.8-fold decreased. Maximum length of blood vessels was also significantly reduced in the Sunitinib treated group at days 11 and 17. Lymphangiogenesis was strongly inhibited from day 6 to day 17 after cauterization where all parameters, except maximum length of lymphatic vessels, were significantly decreased. In case of transient Sunitinib administration (feeding during the 7 first days), we did not observe any reduction in the extent of blood or lymphatic networks developing 21 days after lesion induction. In vitro experimentations using the aortic and lymphatic ring assays showed a strong angiogenesis inhibition induced by Sunitinib while lymphangiogenesis was not inhibited. Our results show that the use of Sunitinib can strongly affect corneal neovascularisation and could enter in early treatment of such eye lesions to avoid vision loss and risk of cornea graft rejection. However, a punctual use of such tyrosine kinase inhibitor is not sufficient to stem neovascular reaction. In vitro experimentations show strong angiogenesis inhibition but normal lymphangiogenesis, suggesting indirect inhibitory effect of Sunitinib on corneal lymphangiogenesis. [less ▲]

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See detailInhibition of Fusarium culmorum and Cochliobolus sativus growth
Kaddes, Amine ULg

Poster (2013, March 19)

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See detailInhibition of growth of normal and human papillomavirus-transformed keratinocytes in monolayer and organotypic cultures by interferon-gamma and tumor necrosis factor-alpha.
Delvenne, Philippe ULg; al-Saleh, W.; Gilles, Christine ULg et al

in American Journal of Pathology (1995), 146(3), 589-98

The growth response of normal and human papillomavirus (HPV)-transformed cervical keratinocytes to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha was investigated in monolayer and ... [more ▼]

The growth response of normal and human papillomavirus (HPV)-transformed cervical keratinocytes to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha was investigated in monolayer and organotypic raft cultures. The proliferation rates of monolayer cultures were assessed by [3H]TdR incorporation and fluorimetric DNA titration. The growth of keratinocytes in organotypic cultures was estimated by their ability to stratify on collagen rafts and by immunohistochemistry for Ki67 antigen expression. IFN-gamma reduced the DNA synthesis of normal and HPV-transformed keratinocytes in monolayer cultures and exerted a marked growth inhibitory effect in organotypic raft cultures. In control raft cultures, normal keratinocytes produced an epithelial sheet of approximately 10 cells in thickness that closely resembled normal cervical epithelium and was characterized by sparse Ki67 antigen-positive cells whereas HPV-transformed keratinocytes produced up to 15 poorly differentiated epithelial layers that were reminiscent of high grade cervical lesions seen in vivo and exhibited a full thickness Ki67 antigen expression. When normal and HPV-transformed keratinocytes were maintained in the presence of IFN-gamma, the epithelial sheet was reduced to a few cells in thickness and the density of Ki67 antigen-positive cells was decreased. A more pronounced growth inhibitory effect in monolayer and organotypic cultures was observed when IFN-gamma was associated with tumor necrosis factor-alpha Tumor necrosis factor-alpha alone reduced the DNA synthesis of normal keratinocytes but was significantly less effective than IFN-gamma to inhibit the growth of HPV-transformed keratinocytes. These results suggest that similar responses in vivo to regulatory molecules may play a role in the development of HPV-related lesions. [less ▲]

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See detailInhibition Of Histone Deacetylases Induces Bovine Leukemia Virus Expression In Vitro And In Vivo
Merezak, C.; Reichert, M.; Van Lint, C. et al

in Journal of Virology (2002), 76(10),

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See detailInhibition of insulin secretion by BPDZ 44 involves the activation of ATP-sensitive K+ channels
Kane, C.; Harding, E. A.; Pirotte, Bernard ULg et al

Poster (1994, September)

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See detailInhibition of KCa 2.2 and KCa 2.3 channel currents by protonation of outer pore histidine residues
Goodchild, Samuel; Lamy, Cédric ULg; Seutin, Vincent ULg et al

in Journal of General Physiology (2009), 134(4), 295-308

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See detailInhibition of Matrix Metalloproteinase 2 Maturation and Ht1080 Invasiveness by a Synthetic Furin Inhibitor
Maquoi, Erik ULg; Noël, Agnès ULg; Frankenne, F. et al

in FEBS Letters (1998), 424(3), 262-6

The close correlation observed between matrix metalloproteinase 2 (MMP-2) activation and metastatic progression in various tumors suggests that MMP-2 is a 'master switch' triggering tumor spread. Recently ... [more ▼]

The close correlation observed between matrix metalloproteinase 2 (MMP-2) activation and metastatic progression in various tumors suggests that MMP-2 is a 'master switch' triggering tumor spread. Recently, membrane type 1 MMP (MT1-MMP) was identified as a potential physiological activator of MMP-2. Like all other MMPs, MT1-MMP possesses a pro-domain which must be removed for the enzyme to acquire its catalytic potential. The presence of a typical recognition motif (RXKR) for the furin-like convertases at the end of its pro-domain suggests a potential role for these proteinases in MT1-MMP processing. In order to evaluate the implication of furin in pro-MT1-MMP processing, we treated HT1080 cells with a synthetic furin inhibitor and monitored their ability to activate pro-MMP-2 as well as their invasive potential. Our results demonstrated that the furin inhibitor decreased pro-MT1-MMP processing as well as pro-MMP-2 activation and cell invasiveness. Therefore, our data bring further evidence that furin is a key factor in the maturation of MMPs associated with the invasive and metastatic potential of tumor cells. [less ▲]

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See detailInhibition of membrane-bound acetylcholinesterase by d-tubocurarine and its reversal by bivalent cations
Wins, P.; Schoffeniels, E.; Foidart, Jean-Michel ULg

in Life Sciences (1970), 9(5), 259-267

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See detailThe inhibition of metallo-beta-lactamase by thioxo-cephalosporin derivatives
Tsang, W. Y.; Dhanda, A.; Schofield, C. J. et al

in Bioorganic & Medicinal Chemistry Letters (2004), 14(7), 1737-1739

The 8-thioxocephalosporins are poor substrates for the B. cereus metallo beta-lactamase (k(cat)/K-m = 61.4 M-1 s(-1)) and act as weak competitive inhibitors (K-i similar to 700 muM). The hydrolysis ... [more ▼]

The 8-thioxocephalosporins are poor substrates for the B. cereus metallo beta-lactamase (k(cat)/K-m = 61.4 M-1 s(-1)) and act as weak competitive inhibitors (K-i similar to 700 muM). The hydrolysis product of thioxocephalosporin, a thioacid, also inhibits the enzyme competitively with a K-i = 96 muM, whereas the cyclic thioxo-piperazinedione, formed by intramolecular aminolysis of thioxo-cephalexin has a K-i of 29 muM. (C) 2004 Elsevier Ltd. All rights reserved. [less ▲]

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See detailThe inhibition of metalloproteinases to treat osteoarthritis: reality and new perspectives
Henrotin, Yves ULg; Sanchez, Christelle ULg; Reginster, Jean-Yves ULg

in Expert Opinion on Therapeutic Patents (2002), 12(1), 29-43

The objective of this paper is to analyse the potential therapeutic action of MMP inhibitors in the management of osteoarthritis (OA), based on a critical review of the literature. The role played by ... [more ▼]

The objective of this paper is to analyse the potential therapeutic action of MMP inhibitors in the management of osteoarthritis (OA), based on a critical review of the literature. The role played by metalloproteinases (MPs) in the pathophysiology of osteoarthritis is discussed, as well as their regulation by tissular inhibitors, activators and cytokines. The evidences that commonly used drugs for treating osteoarthritis are also active on MPs synthesis is also reported. Finally, this paper provides an analysis of the recent patents published with promising therapeutic potential and gives new perspectives for anti-MPs therapy. [less ▲]

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See detailInhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolismdependent manner
Bunik, Victoria; Mkrtchyan, Garait; Grabarska, Aneta et al

in Oncotarget (2016), 7(26400), 26421

2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific ... [more ▼]

2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific inhibition of OGDH by succinyl phosphonate (SP). SP action on different cancer cells was investigated using indicators of cellular viability and reactive oxygen species (ROS), metabolic profiling and transcriptomics. Relative sensitivity of various cancer cells to SP changed with increasing SP exposure and could differ in the ATP- and NAD(P)H-based assays. Glioblastoma responses to SP revealed metabolic sub-types increasing or decreasing cellular ATP/NAD(P)H ratio under OGDH inhibition. Cancer cell homeostasis was perturbed also when viability indicators were SPresistant, e.g. in U87 and N2A cells. The transcriptomics database analysis showed that the SP-sensitive cells, such as A549 and T98G, exhibit the lowest expression of OGDH compared to other TCA cycle enzymes, associated with higher expression of affiliated pathways utilizing 2-oxoglutarate. Metabolic profiling confirmed the dependence of cellular SP reactivity on cell-specific expression of the pathways. Thus, oxidative decarboxylation of 2-oxoglutarate is significant for the interdependent homeostasis of NAD(P)H, ATP, ROS and key metabolites in various cancer cells. Assessment of cellspecific responses to OGDH inhibition is of diagnostic value for anticancer strategies. [less ▲]

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See detailINHIBITION OF mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein
RICOUR, Céline ULg; DELHAYE, S; HATO, SV et al

in Journal of General Virology (2009), 90

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See detailInhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study
Duijkers, I. J. M.; Klipping, C.; Zimmerman, Y. et al

in European Journal of Contraception & Reproductive Health Care (2015), 20(6), 476-489

Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E<inf>4</inf>) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in ... [more ▼]

Objectives The aim of the study was to evaluate the efficacy of different dosages of estetrol (E<inf>4</inf>) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women.Methods This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E<inf>4</inf>/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E<inf>4</inf>/150 g levonorgestrel; or 20 g ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication.Results A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E<inf>4</inf> dosage: the highest suppression was observed in the 20 mg E<inf>4</inf> group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe.Conclusions Combined with a progestin, E<inf>4</inf> adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day. © 2015 The European Society of Contraception and Reproductive Health. [less ▲]

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See detailInhibition of Paf-Induced Platelet Aggregation by Web 2086 'in-Vitro', an Antagonist to the Receptor for Platelet-Activating Factor, in Bovine
Bastos da Silva, Miriam; Herion, Francine ULg; Raskinet, Renée ULg et al

in Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine (1996), 43(7), 399-413

The sensitivity of bovine platelet aggregation in response to PAF stimulation and the ability of WEB 2086 (a thieno-triazolodiazepine) to inhibit response to PAF-induced platelet aggregation were ... [more ▼]

The sensitivity of bovine platelet aggregation in response to PAF stimulation and the ability of WEB 2086 (a thieno-triazolodiazepine) to inhibit response to PAF-induced platelet aggregation were investigated in the blood from five healthy male Belgian Blue calves. The recorded response to PAF showed a plateau which was dependent on the PAF concentration. Platelet aggregation induced by PAF consists of two mechanisms: reversible and irreversible aggregations which are accompanied by the release of platelet granule contents. Reversible aggregation occurred above (2 . 10(-9) mol/l) PAF, and irreversible aggregation occurred above (2 . 10(-7) mol/l) PAF. Addition of WEB 2086 to bovine platelets in vitro induced a rightward shift in the dose-response curve to PAF. WEB 2086 inhibited PAF-induced aggregation in a competitive reversible manner (pA2 = 7.61). The results of our study show that PAF induces platelet aggregation in platelet-rich plasma (PRP) and that addition of WEB 2086 to bovine platelets in vitro inhibits PAF-induced Platelet Aggregation. [less ▲]

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See detailInhibition of PDH Kinase as a new therapeutic target for Age-related Macular Degeneration (AMD)
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, June)

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a ... [more ▼]

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a cell, an organism or a biological system. This approach gives rise to a growing number of applications in many areas, such as biomarkers discovery, clinical studies, drug efficacy and toxicity evaluation, diagnostic tools, quality control. One of the most interesting features of metabolomics is its capability to extract biochemical information reflecting biological events and then to be a powerful tool in the knowledge of the aetiology of some pathologies. Indeed, it is clear that every disease could alter more or less drastically the metabolic profile of the patients. Then a metabolomics approach could highlight the biochemical pathways affected and could allow the identification of new putative therapeutic strategies or targets that could be useful in a new drug discovery strategy. As proteomics, metabolomics approach represents a new and powerful tool for Medicinal Chemistry. Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate DesHydrogenase Kinase inhibitors (PDHK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease. [less ▲]

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