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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 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 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 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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See detailInhibition of protein phosphatase PP1 in GH3B6, but not in GH3 cells, activates the MEK/ERK/c-fos pathway and the human prolactin promoter, involving the coactivator CPB/p300
Manfroid, Isabelle ULg; Martial, Joseph ULg; Muller, Marc ULg

in Molecular Endocrinology (Baltimore, Md.) (2001), 15(4), 625-37

The human (hPRL) PRL gene proximal promoter (-164/+15) is the target for numerous signal transduction pathways involving protein kinases. The inhibitor of Ser/Thr-protein phosphatases okadaic acid (OA ... [more ▼]

The human (hPRL) PRL gene proximal promoter (-164/+15) is the target for numerous signal transduction pathways involving protein kinases. The inhibitor of Ser/Thr-protein phosphatases okadaic acid (OA) was shown to induce this promoter in rat pituitary GH3B6 through a synergism between increased amounts of the ubiquitous factor AP-1 and the pituitary-specific factor Pit-1. Here we show that this activation results mainly from transcriptional stimulation of the c-fos promoter leading to increased AP-1 activity. We report the surprising absence of the hPRL and c-fos promoter stimulation by OA in GH3 cells, closely related to GH3B6 cells, and we use this discrepancy to dissect the precise mechanism of action. c-fos gene activation involves the mitogen-activated kinase (MAPK)-ternary complex factor (TCF) pathway and can be obtained by expressing active V12ras in both cell lines. We show that OA acts by inhibiting protein phosphatase PP1, thereby protecting MAPK kinase (MEK)1/2 and/or a MEK1/2-kinase from dephosphorylation. PP1 inhibition of MEK activation by V12ras does not occur in GH3 cells, indicating that a distinct, PP1-sensitive phosphorylation site is used in GH3B6 cells to activate the TCF pathway in GH3B6 cells. Finally, we show that the synergistic OA activation of the hPRL promoter by Pit-1 and AP-1 is independent of the Pit-1 transactivation domain and is mediated by the general coactivator (CRE-binding protein)-binding protein (CBP)/p300. [less ▲]

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See detailInhibition of radiographic progression with combination etanercept and methotrexate in patients with moderately active rheumatoid arthritis previously treated with monotherapy
van der Heijde, D.; Burmester, G.; Melo-Gomes, J. et al

in Annals of the Rheumatic Diseases (2009), 68(7), 1113-1118

OBJECTIVE: To determine the effect of changing from etanercept or methotrexate monotherapy to etanercept plus methotrexate combination therapy on radiographic progression in rheumatoid arthritis (RA ... [more ▼]

OBJECTIVE: To determine the effect of changing from etanercept or methotrexate monotherapy to etanercept plus methotrexate combination therapy on radiographic progression in rheumatoid arthritis (RA) patients. METHODS: Patients enrolled in this 1-year open-label study previously completed a 3-year blinded study in which they received methotrexate or etanercept monotherapy or the combination of both. All patients received the combination of etanercept 25 mg subcutaneously twice weekly plus oral methotrexate up to 20 mg/week. The primary radiographic endpoint was a change in modified total Sharp score (TSS), as assessed by blinded readers. RESULTS: At baseline, patients previously receiving methotrexate monotherapy (etanercept-added, n = 52) or etanercept monotherapy (methotrexate-added, n = 68) had moderate disease activity levels (mean disease activity score (DAS) of 2.6 and 2.5, respectively), whereas patients previously receiving combination therapy (n = 90) had a low disease activity level (mean DAS of 2.0). The addition of etanercept to methotrexate monotherapy resulted in a significant reduction in radiographic progression (p<0.05). Mean TSS changes in the previous year versus the current year were +1.79 versus +0.25 for the etanercept-added group (p<0.05); +0.51 versus -0.18 for the methotrexate-added group (NS) and +0.42 versus +0.24 for the combination group (NS). CONCLUSION: In these RA patients with on average moderate disease activity despite previous methotrexate monotherapy, combination treatment with etanercept and methotrexate inhibited radiographic progression and improved radiographic outcomes. These data, in conjunction with the previously published clinical data, support the use of combination therapy in RA patients with moderate disease activity. [less ▲]

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See detailInhibition of sclerostin with romosozumab in postmenopausal women with low BMD : phase 2 trial results
McClung, M; Grauer, A; Boonen, S et al

in Osteoporosis International (2013), 24(1), 38-39

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See detailInhibition of serotonin-induced pulmonary alterations in calves by a selective S2 serotonergic antagonist
Linden, Annick ULg; Desmecht, Daniel ULg; Amory, Hélène ULg et al

in Archives Internationales de Physiologie et de Biochimie (1991)

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See detailInhibition of steroid receptor coactivator-1 blocks estrogen and androgen action on male sex behavior and associated brain plasticity.
Charlier, Thierry ULg; Ball, Gregory F; Balthazart, Jacques ULg

in Journal of Neuroscience (2005), 25(4), 906-13

Studies of eukaryotic gene expression demonstrate the importance of nuclear steroid receptor coactivators in mediating efficient gene transcription. However, little is known about the physiological role ... [more ▼]

Studies of eukaryotic gene expression demonstrate the importance of nuclear steroid receptor coactivators in mediating efficient gene transcription. However, little is known about the physiological role of these coactivators in vivo. In Japanese quail, the steroid receptor coactivator-1 (SRC-1) is broadly expressed in steroid-sensitive brain areas that control the expression of male copulatory behavior, and we investigated the role of this coactivator by antisense technology. Daily intracerebroventricular injections of locked nucleic acid (LNA) antisense (AS) oligonucleotides targeting SRC-1 significantly reduced the expression of androgen- and estrogen-dependent male-typical sexual behaviors compared with control animals that received the vehicle alone or scrambled oligonucleotides. Sexual behavior was restored and even enhanced within 48 h after interruption of LNA injections. Western blot analysis confirmed the decrease of SRC-1 expression in AS animals and suggested an overexpression 48 h after the end of injections. The effects of SRC-1 knock-down on behavior correlated with a reduction in volume of the preoptic medial nucleus (POM) when its borders were defined by Nissl staining or by aromatase immunohistochemistry. The amount of aromatase-immunoreactive material in POM was also reduced in the AS compared with the control group. Previous work on SRC-1 knock-out mice raised questions about the importance of this specific coactivator in the regulation of reproductive behavior and development of sexually dimorphic structures in the CNS. Together, the present findings indicate that SRC-1 modulates steroid-dependent gene transcription and behavior and highlight the rapid time course of steroid-induced brain plasticity in adult quail. [less ▲]

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See detailInhibition of Streptococcus pneumoniae pencillin-binding protein 2x and Actinomadura R39 DD-peptidase activities by ceftaroline.
Zervosen, Astrid ULg; Zapun, Andre; Frère, Jean-Marie ULg

in Antimicrobial Agents and Chemotherapy (2013), 57(1), 661-663

Although the rate of acylation of a penicillin-resistant form of Streptococcus pneumoniae PBP2x by ceftaroline is 80-fold lower than that of its penicillin-sensitive counterpart, it remains sufficiently ... [more ▼]

Although the rate of acylation of a penicillin-resistant form of Streptococcus pneumoniae PBP2x by ceftaroline is 80-fold lower than that of its penicillin-sensitive counterpart, it remains sufficiently high (k(2)/K = 12600 M(-1)s(-1)) to explain the sensitivity of the penicillin-resistant strain to this new cephalosporin. Surprisingly, the Actinomadura R39 DD-peptidase is not very sensitive to ceftaroline. [less ▲]

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