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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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See detailInhibition of Stromal Matrix Metalloproteases: Effects on Breast-Tumor Promotion by Fibroblasts
Noël, Agnès ULg; Hajitou, Amin; L'Hoir, Cécile et al

in International Journal of Cancer = Journal International du Cancer (1998), 76(2), 267-73

Co-injection of fibroblasts with human epithelial breast-tumor MCF7 cells in the presence of Matrigel enhances tumor growth in nude mice. While most of the matrix metalloproteinases (MMPs) have been shown ... [more ▼]

Co-injection of fibroblasts with human epithelial breast-tumor MCF7 cells in the presence of Matrigel enhances tumor growth in nude mice. While most of the matrix metalloproteinases (MMPs) have been shown to be produced by stromal cells, tumor cells such as MCF7 cells are unable to produce MMPs. We therefore, hypothesized that the tumor-promoting effect of fibroblasts could be related to their production of MMPs. In order to inhibit stromal proteases, over-production of TIMP-2 was induced in MCF7 cells by in vitro retroviral-mediated gene transfer. TIMP-2-producing MCF7 cells were then co-injected with fibroblasts into nude mice. Alternatively, we evaluated the effect of Batimastat, a synthetic inhibitor of MMPs, on the tumorigenicity of MCF7 cells co-inoculated with fibroblasts into nude mice. Both physiological (TIMP-2) and synthetic (Batimastat) inhibitors of MMPs were able to abolish the tumor-promoting effect of fibroblasts. On the contrary, they failed to modulate the tumorigenicity of MCF7 cells injected alone. Interestingly, Matrigel from which low-molecular-weight proteins or growth factors had been removed failed to favor the tumorigenicity of MCF7 cells inoculated with fibroblasts. These findings emphasize the importance of fibroblasts in cancer progression, and suggest that their role could be related at least in part to production of proteases which can induce the release of factors from the extracellular matrix. [less ▲]

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See detailInhibition of Tax transformation activity using a small molecule targetting Tax/PDZ domain interactions.
Blibek, Karim ULg; Fujii, Naoaki; Legros, Sebastien et al

Poster (2013, June 29)

Primate T-lymphotropic virus species comprise four members (HTLV-1 to -4) that have been discovered in human. Only the HTLV-1 infection leads to adult T-cell leukemia/lymphoma (ATLL) and tropical spastic ... [more ▼]

Primate T-lymphotropic virus species comprise four members (HTLV-1 to -4) that have been discovered in human. Only the HTLV-1 infection leads to adult T-cell leukemia/lymphoma (ATLL) and tropical spastic paraparesis (TSP), an immune degenerative neurologic syndrome. All the four viruses share a similar genomic organization and encode transforming Tax oncoproteins. In contrast to HTLV-2 and 4, HTLV-1 and 3 Tax proteins contain a PSD-95/Drosophila Discs Large/Zona Occludens-I (PDZ) binding motif at their C-terminal that has been shown to play crucial roles in the distinct transforming properties of the Tax proteins. To systematically investigate PDZ-containing proteins roles in HTLV-1 biology, we initiated a global interactome network analysis of Tax and associated human PDZ-containing proteins. This was accomplished through the use of our framework of binary interactome mapping that includes stringent yeast two hybrid and pulldown screening, systematic retesting by protein complementation assay and evaluation of PDZ gene expression in T lymphocytes. [less ▲]

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See detailInhibition of Tax transformation activity using a small molecule targetting Tax/PDZ domain interactions.
Blibek, Karim ULg; Fujii, Naoki; Legros, Sebastien et al

Poster (2013, June 29)

Primate T-lymphotropic virus species comprise four members (HTLV-1 to -4) that have been discovered in human. Only the HTLV-1 infection leads to adult T-cell leukemia/lymphoma (ATLL). All the four viruses ... [more ▼]

Primate T-lymphotropic virus species comprise four members (HTLV-1 to -4) that have been discovered in human. Only the HTLV-1 infection leads to adult T-cell leukemia/lymphoma (ATLL). All the four viruses share a similar genomic organization and encode transforming Tax oncoproteins. In contrast to HTLV-2 and 4, HTLV-1 and 3 Tax proteins contain a PSD-95/Drosophila Discs Large/Zona Occludens-I (PDZ) binding motif at their C-terminal that has been shown to play crucial roles in the distinct transforming properties of the Tax proteins. Here, we used a collection of human full-length protein-coding open reading frames (ORFeome v3.1) to identify novel PDZ domain containing proteins that specifically interact with HTLV-1 Tax. Novel Tax interactors include syntenin-1 and -2, LNX2, DVL3, GIPC2, INTU, PDLIM4 and -7, RADIL and RGS3. These proteins are involved in diverse biological processes including cell division, cell fate determination and cell suvival. We further characterized interaction between Tax and syntenins and showed that, FJ9 a small molecule able to disrupt Tax/PDZ interactions, could antagonize Tax-transformation activity in rat-1 model. Our study identify novel PDZ-containg proteins interacting with HTLV-1 Tax and provides the first example where Tax protein-protein interactions whith PDZ-containing proteins and Tax-transformation capacity could be inhibited by a small molecule. [less ▲]

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See detailInhibition of temporal second exteroceptive suppression produced by single or long-lasting electrical stimuli and noxious thermal stimuli in peripheral limbs: effects of Naloxone
Schoenen, Jean ULg; Lenaerts, M.; Gérard, P.

in Olesen, J.; Schoenen, Jean (Eds.) Tension-Type Headache: classification, mechanisms, treatment (Frontiers in Headache Research) (1993)

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See detailInhibition of testosterone metabolism in the brain and cloacal gland of the quail by specific inhibitors and antihormones.
Alexandre, Corine; Balthazart, Jacques ULg

in Journal of Endocrinology (1987), 112(2), 189-95

The effects of antioestrogens, antiandrogens and of various inhibitors of testosterone metabolism on testosterone metabolism in the quail hypothalamus and cloacal gland were studied by an in-vitro ... [more ▼]

The effects of antioestrogens, antiandrogens and of various inhibitors of testosterone metabolism on testosterone metabolism in the quail hypothalamus and cloacal gland were studied by an in-vitro radioenzymatic assay. It was found that antioestrogens and antiandrogens generally had little or no effect on aromatase and 5 alpha- and 5 beta-reductases of testosterone, except when used at very high doses. The 5 alpha-reductase inhibitor, 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one, inhibited both 5 alpha- and 5 beta-dihydrotestosterone production without markedly affecting aromatase activity. Surprisingly, the aromatase inhibitor, 1,4,6-androstatriene-3,17-dione, inhibited not only the production of oestradiol but also that of 5 beta-dihydrotestosterone and, to a lesser extent, 5 alpha-dihydrotestosterone. These unexpected properties should be taken into account when interpreting the results of in-vivo experiments using these compounds. [less ▲]

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See detailInhibition of the Blink Reflex R2 Component after Supraorbital and Index Finger Stimulations Is Reduced in Cluster Headache: An Indication for Both Segmental and Suprasegmental Dysfunction?
Lozza, A.; Schoenen, Jean ULg; Delwaide, P. J.

in Pain (1997), 71(1), 81-8

Peripheral as well as central mechanisms are thought to play a role in cluster headache pathogenesis. We have studied recovery curves of the R2 component of the blink reflex after conditioning by ... [more ▼]

Peripheral as well as central mechanisms are thought to play a role in cluster headache pathogenesis. We have studied recovery curves of the R2 component of the blink reflex after conditioning by supraorbital or index finger stimuli in 10 episodic cluster headache (CH) patients during a cluster period and in 10 healthy controls. There was no significant change of R2 threshold, latency or area in CH patients. After paired supraorbital stimuli, R2 recovered more rapidly in patients on the symptomatic side. After index stimulations, R2 recovery was more rapid on both symptomatic and non-symptomatic sides in patients compared to controls. Naloxone (0.4 mg) i.v. in two subjects partially reversed the R2 suppression induced by index finger stimuli. The unilateral decrease of R2 inhibition after a segmental supraorbital stimulus most likely reflects sensitisation in the spinal trigeminal nucleus. Whether the latter is due to irritation of the ophthalmic nerve within the cavernous sinus region, which is thought to be pivotal in CH pathogenesis, remains to be proven. In addition, we propose that the bilateral deficit of R2 inhibition after an extrasegmental exteroceptive stimulus might reflect hypoactivity of reticular nuclei, possibly because of reduced central opioid activity. [less ▲]

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See detailThe inhibition of the expression of the small Rho GTPase Rac1 induces differentiation with no effect on cell proliferation in growing human adult keratinocytes.
Nikolova, Ekaterina; Mitev, Vanio; Minner, Frederic et al

in Journal of Cellular Biochemistry (2008), 103(3), 857-64

Rac1 is a Rho subfamily small GTPase which is highly expressed in epidermal keratinocytes. In mice the significance of Rac1 for the maintenance of the epidermis has been controversial. In keratinocytes ... [more ▼]

Rac1 is a Rho subfamily small GTPase which is highly expressed in epidermal keratinocytes. In mice the significance of Rac1 for the maintenance of the epidermis has been controversial. In keratinocytes from human origin, the role of Rac1 in the control of growth/differentiation is still obscure. In this study we used RNA interference to induce specific inhibition of Rac1 expression in cultured human keratinocytes and analyzed the consequences on proliferation and differentiation. We found that the autocrine proliferation of keratinocytes is unaltered by Rac1 silencing. However, the suppression of Rac1 induced premature differentiation as revealed by the expression of markers (keratin 10, involucrin), but the involved mechanism is independent of the activity of p38 mitogen-activated protein kinase. Rather, we found that the effects of Rac1 silencing on keratinocytes differentiation are concomitant with negative regulation of the Ser62/Thr58 phosphorylation on the transcription factor c-myc, a mechanism known to control post-translational stability of the c-myc protein. Thus, in growing human keratinocytes, Rac1 could impede the expression of premature differentiation markers, probably by exerting positive control on c-myc activity and its binding to specific promoters. [less ▲]

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See detailInhibition of the Jagged-1/Notch pathway increases the hematopoiesis-supportive activity of mesenchymal stem cells
Briquet, Alexandra ULg; Dolhet, Marie; Beguin, Yves ULg et al

in Experimental Hematology (2009), 37(9), 77

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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 ▲]

Detailed reference viewed: 17 (2 ULg)