References of "Hanson, Julien"
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See detailBM-573 INHIBITS THE EARLY ATHEROSCLEROTIC LESIONS IN APO-E DEFICIENT MICE BY BLOCKING TP RECEPTORS AND THROMBOXANE SYNTHASE
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

in Congress of the International Society of Thrombosis and Hemostasis- 57th Annual SSC Meeting (2011, July)

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently ... [more ▼]

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2(). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation. [less ▲]

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See detailMechanism of Nicotinic acid-induced Flushing
Hanson, Julien ULg

Conference (2011, June 10)

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See detailBM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase.
Cherdon, Céline ULg; Rolin, Stephanie; Hanson, Julien ULg et al

in Prostaglandins & Other Lipid Mediators (2011)

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently ... [more ▼]

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2(). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation. [less ▲]

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See detailNicotinic acid (niacin): new lipid-independent mechanisms of action and therapeutic potentials
lukasova, Martina; Hanson, Julien ULg; Tunaru, Sorin et al

in Trends in Pharmacological Sciences (2011)

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See detailRole of Keratinocytes GPR109A and COX-2 in Nicotinic Acid and Mono-methyl Fumarate Induced Flushing
Hanson, Julien ULg; Gille, Andreas; Zwykiel, Sabrina et al

Poster (2010, July 17)

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See detailNicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice.
Hanson, Julien ULg; Gille, Andreas; Zwykiel, Sabrina et al

in Journal of Clinical Investigation (2010), 120(8), 2910-9

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome ... [more ▼]

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type-specific GPR109A expression in Gpr109a-/- mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid-induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin. [less ▲]

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See detailAn autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81.
Ahmed, Kashan; Tunaru, Sorin; Tang, Cong et al

in Cell Metabolism (2010), 11(4), 311-9

Lactate is an important metabolic intermediate released by skeletal muscle and other organs including the adipose tissue, which converts glucose into lactate under the influence of insulin. Here we show ... [more ▼]

Lactate is an important metabolic intermediate released by skeletal muscle and other organs including the adipose tissue, which converts glucose into lactate under the influence of insulin. Here we show that lactate activates the G protein-coupled receptor GPR81, which is expressed in adipocytes and mediates antilipolytic effects through G(i)-dependent inhibition of adenylyl cyclase. Using GPR81-deficient mice, we demonstrate that the receptor is not involved in the regulation of lipolysis during intensive exercise. However, insulin-induced inhibition of lipolysis and insulin-induced decrease in adipocyte cAMP levels were strongly reduced in mice lacking GPR81, although insulin-dependent release of lactate by adipocytes was comparable between wild-type and GPR81-deficient mice. Thus, lactate and its receptor GPR81 unexpectedly function in an autocrine and paracrine loop to mediate insulin-induced antilipolytic effects. These data show that lactate can directly modulate metabolic processes in a hormone-like manner, and they reveal a new mechanism underlying the antilipolytic effects of insulin. [less ▲]

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See detailDeorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis
Ahmed, Kashan; Tunaru, Sorin; Langhans, C. D. et al

in Journal of Biological Chemistry (2009), 284(33), 21928-33

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See detailBm-573, an original thromboxane receptor antagonist, reduces development of atherosclerosis in apoe–deficient (apo e-/-) mice
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

Poster (2007, October 11)

To test the efficacy of BM-573 in atherogenesis, the effect of 10 weeks of treatment with BM573 (10 mg/l) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice were fed ... [more ▼]

To test the efficacy of BM-573 in atherogenesis, the effect of 10 weeks of treatment with BM573 (10 mg/l) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice were fed with chow diet, with spontaneous increase of total plasma cholesterol and triglycerides. In this experiment, while BM-573 did not affect body weight, it significantly decreases early atherogenesis lesions confirmed by macroscopic, microscopic and biochemical analysis. These results confirm that selective antagonism of TP receptor is effective in reducing atherosclerotic lesion in apo E deficient mice. Consequently, BM-573 could be a potential drug for prevention of atherosclerosis [less ▲]

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See detailBm-573, a thromboxane receptor antagonist, reduces development of atherosclerosis in apoe–deficient mice
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

Poster (2007, June 22)

Atherosclerotic cardiovascular disease, according to World Health Organization, is the primary cause of heart disease and stroke. Atherosclerosis is a chronic vascular disease whose development is ... [more ▼]

Atherosclerotic cardiovascular disease, according to World Health Organization, is the primary cause of heart disease and stroke. Atherosclerosis is a chronic vascular disease whose development is influenced by several mediators. Among them, the action of eicosanoïds such as thromboxane A2 and 8-iso-PGF2a have recently received a lot of attention. The aim of our study was the evaluation of benefits of original molecules, synthesised in our lab, targeting the thromboxane receptor (TP) in an apo E deficient mouse. We previously demonstrated in several in vitro and in vivo pharmacological experiments that our original sulfonylurea derivate, BM-573 was a potent combined inhibitor of the thromboxane synthase and antagonist of TP. Since TP is implied in atherosclerosis development, such antagonist could have a great therapeutic impact in atherogenesis.To test the efficacy of BM-573 in atherogenesis, the effect of 10 weeks of treatment with BM573 (10 mg/kg) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice were fed with chow diet, with spontaneous increase of total plasma cholesterol and triglycerides. In this experiment, while BM-573 did not affect body weight, it significantly decreased early atherogenesis lesions confirmed by macroscopic, microscopic and biochemical analysis. These results confirm that selective antagonism of TP receptor is effective in reducing atherosclerotic lesion in apo E deficient mice. Consequently, BM-573 could be a potential drug for prevention of atherosclerosis. [less ▲]

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See detailLe bm-573, un antagoniste original de récepteur au thromboxane a2, réduit le développement des lesions atheromateuses chez des souris deficientes en apolipoproteine e (apo e-/-)
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

Poster (2007, May 10)

Afin d’examiner l'efficacité du BM-573 dans l'athérogenèse, des souris apo E-/- ont été traitées durant 10 semaines avec le BM573 (10mg/kg). Au cours de cette expérience, le traitement des animaux par le ... [more ▼]

Afin d’examiner l'efficacité du BM-573 dans l'athérogenèse, des souris apo E-/- ont été traitées durant 10 semaines avec le BM573 (10mg/kg). Au cours de cette expérience, le traitement des animaux par le BM-573, a eu pour effet de diminuer les lésions athéromateuses précoces de manière significative. Ces données ont été confirmées par des analyses histopathologiques et biochimiques. Ces résultats confirment que l'antagonisme sélectif des récepteurs TP associé à une inhibition de la thromboxane synthase réduit significativement les lésions athéromateuses chez les souris apoE-/-.. Le BM-573 est, par conséquent, un agent thérapeutique potentiel pour la prévention de l'athérosclérose [less ▲]

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See detailConception et synthèse d’outils pharmacologiques originaux pour l’étude des récepteurs au thromboxane
Moray, A. L.; Dogne, J. M.; Neven, P. et al

Poster (2007, May)

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See detailCardiovascular haemodynamics and ventriculo-arterial coupling in an acute pig model of coronary ischaemia-reperfusion
Lanoye, Lieve; Segers, Patrick; Tchana-Sato, Vincent ULg et al

in Experimental Physiology (2007), 92(1), 127-137

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated ... [more ▼]

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated effects of reperfusion on left ventricular (LV) haemodynamics and ventriculo-arterial (VA) coupling in pigs following acute myocardial ischaemia induced by coronary artery occlusion. Experiments were performed in six animals, with measurements of cardiac and arterial function at baseline, after 60 min of ischaemia (T60) and after 2 (T180) and 4 h of reperfusion (T300). Ventriculo-arterial coupling was assessed using the ventriculo-arterial elastance ratio of paper, as well as using a 'stiffness coupling' and 'temporal coupling' index. Reperfusion following ischaemia (T180 versus T60) induced a progressive decline in cardiovascular function, evidenced by a decrease in mean arterial blood pressure, cardiac output and ejection fraction which was not restored at T300. Although reperfusion also induced an increase in slope of the end-systolic pressure-volume relationship (ESPVR), the ESPVR curve shifted to the right, associated with a depression of contractile function. Histology demonstrated irreversible myocardial damage at T300. The ventriculo-arterial elastance ratio and the 'stiffness coupling' index were unaffected throughout the protocol, but the 'temporal coupling' parameter indicated a relative shift between heart period and the time constant of the arterial system. It is unlikely that these alterations are attributable to ischaemic injury alone. The combination of both the stiffness and temporal coupling index may provide more information when studying ventriculo-arterial coupling than the more commonly used ventricular end-systolic stiffness/effection arterial elastance (E-es/E-a) ratio. [less ▲]

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See detailDesign, synthesis and pharmacological evaluation of sulfonylureas and sulfonycyanoguanidines as thromboxane A2 receptor antagonists. Insights into selectivity between thromboxane A2 receptor isoforms (TPα et TPβ)
Hanson, Julien ULg

Doctoral thesis (2007)

Thromboxane A2 (TXA2) is an important mediator metabolized from arachidonic acid through the cyclooxygenase pathway, mainly in platelets and macrophages. It is a potent inducer of platelet aggregation and ... [more ▼]

Thromboxane A2 (TXA2) is an important mediator metabolized from arachidonic acid through the cyclooxygenase pathway, mainly in platelets and macrophages. It is a potent inducer of platelet aggregation and smooth muscle contraction. Its overproduction has been detected in pathologies such as stroke, asthma, myocardial infarction or atherosclerosis. The action of TXA2 is mediated by a specific G-protein coupled receptor (TP) of which two alternative spliced isoforms, TPalpha and TPbeta, have been described. The exact role of these two isoforms is not clearly understood. However, recent studies have described their implications in vascular physiology and pathology. The inhibition of the action of TXA2 on platelets and blood vessels would be interesting as original therapies against cardiovascular diseases. Consequently, the design of TP receptor antagonists remains of great interest in cardiovascular medicine. In the laboratory of medicinal chemistry (University of Liège, Belgium), several nitrobenzenesulfonylureas, derived from torasemide (a loop diuretic), have been previously described as TP receptor antagonists. Two compounds, BM573 and BM613 were among the most interesting molecules identified in that previous work. The present project is divided in two parts. First, we have determined the pharmacological properties of BM573 and BM613 as thromboxane synthase inhibitors and TP receptor antagonists, in vitro and in vivo. In our assays, these two compounds were proved to have high affinity for both TPalpha and TPbeta, to be potent antiplatelet agents, to inhibit thromboxane synthase and TP-mediated smooth muscle contraction. Additionally, they significantly reduced the size of the thrombus in a rat model of ferric chloride-induced arterial thrombosis. Consequently, we demonstrated that the TP receptor antagonists BM573 and BM613, belonging to the chemical family of nitrobenzenesulfonylureas, could be regarded as antiplatelet and antithrombotic agents potentially useful in thromboxane-related diseases such as stroke or myocardial infarction. Secondly, given the interesting pharmacological profile of BM573 and BM613, we have designed and synthesized several series of compounds derived from these two agents. We have evaluated the binding properties (affinity) of the first generation (+/- 35 original derivatives) of compounds on either TPalpha or TPbeta, transiently expressed in COS-7 cell lines. Additionally, we have measured the ability of our drugs to inhibit the intracellular calcium mobilization upon TPalpha or TPbeta stimulation. To confirm our results, we also assessed the antiplatelet properties of our drugs by means of determination of inhibition of human platelet aggregation. On the basis of the results obtained with these in vitro assays, we have synthesized and evaluated a second generation of derivatives (+/- 35 original compounds) and improved the selectivity of several original compounds for TP receptor isoforms. The originality of this work was to evaluate a large library of synthetic compounds on both TP receptor isoforms, using specific pharmacological tests. By means of structure-activity relationship studies, we were able to identify chemical groups implicated in selectivity and to propose lead compounds for development of highly specific TPalpha or TPbeta antagonists. Besides, we have identified an in vivo drug candidates for prevention of thrombosis and pathological platelet aggregation. [less ▲]

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See detailBM-573, a thromboxane receptor antagonist, reduces development of atherosclerosis in apoE–deficient mice
Cherdon, Céline ULg; Rolin, Stéphanie; Hanson, Julien ULg et al

in Journal of Molecular and Cellular Cardiology (2007), 42(suppl 1.), 33-34

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