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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 ▲]

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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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