Benoît Laleu
Goethe University Frankfurt
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Featured researches published by Benoît Laleu.
Hepatology | 2012
Tomonori Aoyama; Sumio Watanabe; Benoît Laleu; Francesca Gaggini; Laetitia Fioraso-Cartier; Sophie Molango; Freddy Heitz; Cedric Merlot; Cedric Szyndralewiez; Patrick Page; David A. Brenner
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) generates reactive oxygen species (ROS) in hepatic stellate cells (HSCs) during liver fibrosis. In response to fibrogenic agonists, such as angiotensin II (Ang II), the NOX1 components form an active complex, including Ras‐related botulinum toxin substrate 1 (Rac1). Superoxide dismutase 1 (SOD1) interacts with the NOX‐Rac1 complex to stimulate NOX activity. NOX4 is also induced in activated HSCs/myofibroblast by increased gene expression. Here, we investigate the role of an enhanced activity SOD1 G37R mutation (SODmu) and the effects of GKT137831, a dual NOX1/4 inhibitor, on HSCs and liver fibrosis. To induce liver fibrosis, wild‐type (WT) and SOD1mu mice were treated with CCl4 or bile duct ligation (BDL). Then, to address the role of NOX‐SOD1‐mediated ROS production in HSC activation and liver fibrosis, mice were treated with a NOX1/4 inhibitor. Fibrosis and ROS generation was assessed by histology and measurement of thiobarbituric acid reactive substances and NOX‐related genes. Primary cultured HSCs isolated from WT, SODmu, and NOX1 knockout (KO) mice were assessed for ROS production, Rac1 activity, and NOX gene expression. Liver fibrosis was increased in SOD1mu mice, and ROS production and Rac1 activity were increased in SOD1mu HSCs. The NOX1/4 inhibitor, GKT137831, attenuated liver fibrosis and ROS production in both SOD1mu and WT mice as well as messenger RNA expression of fibrotic and NOX genes. Treatment with GKT137831 suppressed ROS production and NOX and fibrotic gene expression, but not Rac1 activity, in SOD1mut and WT HSCs. Both Ang II and tumor growth factor beta up‐regulated NOX4, but Ang II required NOX1. Conclusions: SOD1mu induces excessive NOX1 activation through Rac1 in HSCs, causing enhanced NOX4 up‐regulation, ROS generation, and liver fibrosis. Treatment targeting NOX1/4 may be a new therapy for liver fibrosis. (HEPATOLOGY 2012)
Bioorganic & Medicinal Chemistry | 2011
Francesca Gaggini; Benoît Laleu; Mike Orchard; Laetitia Fioraso-Cartier; Laurène Cagnon; Sophie Houngninou-Molango; Angelo Gradia; Guillaume Duboux; Cedric Merlot; Freddy Heitz; Cedric Szyndralewiez; Patrick Page
Pyrazolo-pyrido-diazepine, -pyrazine and -oxazine dione derivatives are new chemical entities with good and attractive druglikeness properties. A series of pyrazolo-pyrido-diazepine dione analogs demonstrated to be particularly amenable to lead optimization through a couple of cycles in order to improve specificity for isoforms Nox4 and Nox1 and had excellent pharmacokinetic parameters by oral route. Several molecules such as compound 7c proved to be highly potent in in vitro assays on human lung fibroblasts differentiation as well as in curative murine models of bleomycin-induced pulmonary fibrosis with superior efficiency over Pirfenidone. Pyrazolo-pyrido-diazepine dione derivatives targeting Nox4 and Nox1 isoforms appear highly promising therapeutics for the treatment of idiopathic pulmonary fibrosis.
Archive | 2009
Patrick Page; Mike Orchard; Benoît Laleu; Francesca Gaggini
Archive | 2010
Patrick Page; Francesca Gaggini; Benoît Laleu
Archive | 2012
Ralf P. Brandes; Katrin Schröder; Patrick Page; Benoît Laleu; Francesca Gaggini
Archive | 2017
Benoît Laleu; Francesca Gaggini; Katrin Schröder; Patrick Page; Ralf Brandes
Archive | 2015
Patrick Page; Mike Orchard; Benoît Laleu; Francesca Gaggini
Archive | 2009
Patrick Page; Mike Orchard; Benoît Laleu; Francesca Gaggini
Archive | 2009
Patrick Page; Mike Orchard; Benoît Laleu; Francesca Gaggini
Archive | 2008
Patrick Page; Mike Orchard; Benoît Laleu; Francesca Gaggini