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

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

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

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

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See detailInhibition Studies of Mycobacterium tuberculosis Salicylate Synthase (MbtI)
Manos-Turvey, Alexandra ULg; Bulloch, Esther M. M.; Rutledge, Peter J. et al

in ChemMedChem (2010), 5(7), 1067-1079

Mycobacterium tuberculosis salicylate synthase (MbtI), a member of the chorismate-utilizing enzyme family, catalyses the first committed step in the biosynthesis of the siderophore mycobactin T. This ... [more ▼]

Mycobacterium tuberculosis salicylate synthase (MbtI), a member of the chorismate-utilizing enzyme family, catalyses the first committed step in the biosynthesis of the siderophore mycobactin T. This complex secondary metabolite is essential for both virulence and survival of M. tuberculosis, the etiological agent of tuberculosis (TB). It is therefore anticipated that inhibitors of this enzyme may serve as TB therapies with a novel mode of action. Herein we describe the first inhibition study of M. tuberculosis MbtI using a library of functionalized benzoate-based inhibitors designed to mimic the substrate (chorismate) and intermediate (isochorismate) of the MbtI-catalyzed reaction. The most potent inhibitors prepared were those designed to mimic the enzyme intermediate, isochorismate. These compounds, based on a 2,3-dihydroxybenzoate scaffold, proved to be low-micromolar inhibitors of MbtI. The most potent inhibitors in this series possessed hydrophobic enol ether side chains at C3 in place of the enol-pyruvyl side chain found in chorismate and isochorismate. [less ▲]

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

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

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

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

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

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

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

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

Detailed reference viewed: 34 (3 ULg)