References of "Pirotte, Bernard"
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See detailInhibition of LTβR-signalling activates Wnt-induced regeneration in lung
Conlon, Thomas; John-Schuster, Gerrit; Heide, Danijela et al

in Nature (in press)

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See detailGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

in Nature Communications (2020), 11(1), 4752

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over ... [more ▼]

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function. [less ▲]

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See detailSynthesis, crystal structure, Hirshfeld surface and interaction energies analysis of 5-methyl-1,3-bis(3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione
Etse, Koffi Senam ULiege; Comeron Lamela, Laura ULiege; Zaragoza, Guillermo et al

in European Journal of Chemistry (2020), 11/2

The title compound 5-methyl-1,3-bis(3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione was obtained by reaction of thymine with 3-nitrobenzylbromide in the presence of cesium carbonate. Characterization of the ... [more ▼]

The title compound 5-methyl-1,3-bis(3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione was obtained by reaction of thymine with 3-nitrobenzylbromide in the presence of cesium carbonate. Characterization of the product was achieved by NMR spectroscopy and its stability was probed in basic condition using UV-Visible analysis. Furthermore, the molecular structure was confirmed by X-ray diffraction analysis. The compound crystallizes in orthorhombic Pna21 space group with unit cell parameters a = 14.9594 (15) Å, b = 25.711 (3) Å, c = 4.5004 (4) Å, V = 1731.0 (3) Å3 and Z = 4. The crystal packing of the title compound is stabilized by intermolecular hydrogen bond, π···π and C−H···π stacking interactions. The intermolecular interactions were furthermore analyzed through the mapping of different Hirshfeld surfaces. The two-dimensional fingerprint revealed that the most important contributions to these surfaces come from O···H (37.1%), H···H (24%) and H···C/C···H (22.6%) interactions. The interaction energies stabilizing the crystal packing were calculated and were presented graphically as framework energy diagrams. Finally, the energy-framework analysis reveals that π···π and C−H···π interactions energies are mainly dispersive and are the most important forces in the crystal. [less ▲]

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See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase (PDK) Inhibitors
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Noël, Agnès ULiege et al

Poster (2019, December 11)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of wet AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment for AMD disease. [less ▲]

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See detailDimerisation of gallic acid for malaria treatment.
Degotte, Gilles ULiege; Lempereur, Delphine ULiege; Adubofour, Yaa ULiege et al

Poster (2019, December 11)

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See detailTotal synthesis approach: development of new antimalarial compounds.
Degotte, Gilles ULiege; Pirotte, Bernard ULiege; Frederich, Michel ULiege et al

Poster (2019, November 22)

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See detailCrystal structure and Hirshfeld surface analysis of N-(2-(N-methylsulfamoyl)phenyl)formamide: Degradation product of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
Etse, Koffi Senam ULiege; Zaragoza, Guillermo; Pirotte, Bernard ULiege

in European Journal of Chemistry (2019), 10(3), 189-194

The hydrolysis of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (2) during crystallization under humidity (85 %) conditions, lead to N-(2-(N-methylsulfamoyl)phenyl)formamide as second step hydrolysis ... [more ▼]

The hydrolysis of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide (2) during crystallization under humidity (85 %) conditions, lead to N-(2-(N-methylsulfamoyl)phenyl)formamide as second step hydrolysis product, identified in the proposed degradation mechanism. Crystal of N-(2-(N-methylsulfamoyl)phenyl)formamide C8H10N2O3S (4), was obtained and characterized. The molecular structure determination was carried out with MoKα X-ray and data measured at 100 K. The compound 4 crystallizes in triclinic P􀔋1 space group with unit cell parameters a = 4.8465(4) Å, b = 8.1942(9) Å, c = 11.8686(13) Å, α = 77.080(4)°, β = 82.069(4)°, γ = 80.648(4)°, V = 450.76 (8) Å3 and Z = 2. The crystal structure is stabilized by intramolecular N-H···O and intermolecular C-H···O and N-H···O hydrogen bonds that extended as infinite 1D chain along [100]. Stabilization is also ensured by oxygen-π stacking interaction between the aromatic ring and oxygen of the sulfonamide group. The analysis of intermolecular interactions through the mapping of dnorm and shape-index revel that the most significant contributions to the Hirshfeld surface 40.6 and 33.9% are from H···H and O···H contacts, respectively. [less ▲]

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See detailPharmacomodulation of ellagic acid: a total synthesis approach.
Degotte, Gilles ULiege; Pirotte, Bernard ULiege; Frederich, Michel ULiege et al

Poster (2019, September 05)

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See detailNew insight in Metabolomics based study of Age Related Macular Degeneration (AMD): Lipoprotein profile and patients follow-up
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Poster (2019, June 23)

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal neovascularization (CNV) and results in complete loss of central vision acuity leading to severe visual impairment and legal blindness. Currently, AMD diagnosis relies on ophthalmologic exams and treatments of the exudative form using anti-angiogenic drugs targeting vascular endothelial growth factors (VEGF). Despite these advances, the identification of therapeutic treatments and related biomarkers are essentials. In this study, we applied a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine CNV experimental model that mimics the pathology angiogenesis’s development phase. Sera from controls and AMD patients (in active and non-active pathology’s phases) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. This approach allows differentiation between active and non-active AMD patients and between laser-induced and the control mice groups. Moreover, the discriminating spectral zones are the same in both human and mice’s models, leading to the emergence of putative biomarkers of the exudative AMD. Among those, lipoprotein profile is interesting while some studies highlighted HDL cholesterol and oxidized LDL with early and para-inflammatory AMD stages. Our primary studies show similar evolution in lipoprotein profile through the different human and mice’ groups. These data suggest that investigate lipoprotein profile could be the turning point in the pathologic process’s comprehension occurring during the apparition and/or the development of pathologic CNV process. [less ▲]

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See detailDesign of new antimalarials inspired by ellagic acid through a total synthesis approach.
Degotte, Gilles ULiege; Halleux, Annabelle; Pirotte, Bernard ULiege et al

Poster (2019, May)

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See detailFully Automated Synthesis and Evaluation of [ 18 F]BPAM121: Potential of an AMPA Receptor Positive Allosteric Modulator as PET Radiotracer
Manos-Turvey, A.; Becker, Guillaume ULiege; Francotte, Pierre ULiege et al

in ChemMedChem (2019), 14(7), 788-795

Alzheimer's disease (AD) remains a significant burden on society. In the search for new AD drugs, modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are of particular ... [more ▼]

Alzheimer's disease (AD) remains a significant burden on society. In the search for new AD drugs, modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are of particular interest, as loss of synaptic AMPARs has been linked to AD learning and memory deficits. Previously reported fluorine-containing BPAM121, an AMPA positive allosteric modulator (pam) with high activity, low toxicity, and slow metabolism, was considered to be a perfect 18 F-labeled candidate for positron emission tomography (PET) AD diagnostic investigations. For the preclinical use of this compound, an automated synthesis avoiding human radiation exposure was developed. The detailed production of [ 18 F]BPAM121 in relatively high quantity using a commercial FASTlab synthesizer from GE Healthcare coupled with a full set of quality controls is presented, along with procedures for the synthesis of the tosylated precursor and the fluorinated reference. To evaluate the clinical usefulness of [ 18 F]BPAM121 as a potential AD diagnostic, some in vivo studies in mice were then realized, alongside blocking and competition studies. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim [less ▲]

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See detailCrystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor
Laulumaa, Saara; Hansen, Kathrine Voigt; Masternak, Magdalena et al

in ACS Medicinal Chemistry Letters (2019), 10(3), 243-247

The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a ... [more ▼]

The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TDPAM02, with nanomolar potency at GluA2. Using X-ray crystallography, TDPAM01 and TDPAM02 were crystallized in the ligand-binding domain of the GluA2 flop isoform as well as in the flip-like mutant N775S and the preformed dimer L504Y-N775S. In all structures, one modulator molecule binds at the dimer interface with two characteristic hydrogen bonds being formed from the modulator to Pro515. Whereas the GluA2 dimers and modulator binding mode are similar when crystallized in the presence of l-glutamate, the shape of the binding site differs when no l-glutamate is present. TDPAM02 has no effect on domain closure in both apo and l-glutamate bound GluA2 dimers compared to structures without modulator. © 2018 American Chemical Society. [less ▲]

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See detailPreparation of ellagic acid derivatives through a total synthesis approach to improve bioavailability.
Degotte, Gilles ULiege; Halleux, Annabelle; Hans, Aurore et al

Poster (2018, December)

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See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase Inhibitors (PDK)
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Elmoualij, Benaïssa ULiege et al

Poster (2018, November 23)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of wet AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. PDK and its four isoforms (PDK1-4) regulate the activity of the pyruvate dehydrogenase complex (PDH), a mitochondrial enzyme that plays a major role in the metabolic pathway of glucose, by reversible phosphorylation. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment for AMD disease. Different analogues of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (fig.1) have been already synthetized and pharmacologically evaluated. Various pharmacomodulations were then considered. After a structural activity relationship study, the selectivity of the drugs towards the different isoforms will be determined. [less ▲]

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See detailGPR101 orphan receptor: a novel cause of growth hormone deregulation
Abboud, Dayana ULiege; Daly, Adrian ULiege; Laschet, Céline ULiege et al

Conference (2018, July 05)

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See detailNMR-Based metabolomics study of Age-related Macular Degeneration (AMD): from pre-clinic model to new target discovery
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Poster (2018, June 24)

Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is ... [more ▼]

Age-related Macular Degeneration (AMD) is the leading causes of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV). Treatments are mainly based on regular intravitreal injection of anti-VEGF to stabilize CNV. Nevertheless, despite such important advances, some clinical issues remain to be addressed. Among those, the personalization of the therapeutic strategies and the discovery of new therapeutic approach are essential. In order to study CNV occurrence and evolution, we decided to apply a NMR-based metabolomics approach on a murine laser-induced CNV model and on patient’s cohorts. Metabolomics led us to identify some metabolites linked to CNV developments in both human and murine samples. These metabolites could be considered not only as markers of the pathology, but also as putative target for a new treatment of AMD. Among those, lactate emerges as a key metabolite in both settings. Mechanistically, we demonstrated that lactate, initially produced in the eyes increases at the systemic level and plays a critical role in the onset of the inflammatory and angiogenic phases. The control of its systemic concentration by PDHK inhibition or by LDH modulation decreases significantly CNV development. Based on a metabolomics approach, our data support the innovative concept of lactate as a parainflammation- and angio-metabolite associated to AMD and CNV progression. It appears as a putative target for a new therapeutic approach as well as a useful marker for patient’s follow-up during treatment. [less ▲]

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