Vendredi 28 mars 2014 à 11h
Salle de conférence du CBM
Séminaire externe
" Targeting the Nrf2/heme oxygenase-1 axis with naturally-based compouds."
Heme oxygenase-1 (HO-1), an inducible stress protein that is under control of the transcription factor Nrf2, degrades heme to carbon monoxide (CO) and the bile pigments biliverdin
and bilirubin. In the last two decades substantial scientific evidence has been collected on
the function of HO-1 demonstrating that CO and the bile pigments dynamically participate in cellular adaptation to stress and are inherently involved in the mechanisms of defence against oxidative damage and inflammation (1). Thus, the Nrf2/HO-1 axis is a valuable target for the identification of chemicals capable of triggering the intracellular defensive system.
Based on our original findings that curcumin, the active principle of curry, contains an α-β unsaturated
carbonyl group that is essential for the activation of Nrf2/HO-1 (2), we have now discovered a series of
natural compounds with similar chemical features which can be used as scaffolds for the design of
small active molecules possessing more potent cytoprotective and anti-inflammatory activities (3).
1. Motterlini R, and Foresti R. Heme oxygenase-1 as a target for drug discovery. Antioxid Redox Signal In press, 2014.
2. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, and Motterlini R. Curcumin activates the heme oxygenase-1 gene via regulation of Nrf2 and the antioxidant responsive element. Biochem J 371: 887-895, 2003.
3. Foresti R, Bains SK, Pitchumony TS, Castro Bras LE, Drago F, Dubois-Rande JL, Bucolo C, and Motterlini R. Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.
Pharmacol Res 76: 132-148, 2013.
" Carbon monoxide: biological function and therapeutic potential."
Carbon monoxide (CO) is produced endogenously in mammals during the degradation of
heme by constitutive (HO-2) and inducible (HO-1) heme oxygenase enzymes. We have
gradually learnt that heme oxygenase-derived CO serves as a signaling mediator in a wide
array of physiological functions. The cytoprotective and anti-inflammatory effects observed when small amounts of CO are administered in vivo suggests that this gas may be
exploited for therapeutic purposes (1). In this context, we have developed CO-releasing
molecules (CO-RMs) as an effective pharmacological stratagem to deliver CO in a controlled fashion
for the treatment of vascular and inflammatory disorders (1,2). Recent evidence indicate that CO-RMs
can positively compete with O2 for mitochondrial respiration and the production of reactive oxygen
species (ROS) pointing to these organelles as plausible targets of the signals transduced by CO (3).
1.
2.
3.
Motterlini R, and Otterbein LE. The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 9: 728-743, 2010.
Clark JE, Naughton P, Shurey S, Green CJ, Johnson TR, Mann BE, Foresti R, and Motterlini R. Cardioprotective actions by
a water-soluble carbon monoxide-releasing molecule. Circ Res 93: e2-e8, 2003.
Lo Iacono L, Boczkowski J, Zini R, Salouage I, Berdeaux A, Motterlini R, and Morin D. A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species. Free Rad
Biol Med 50: 1556-1564, 2011.
Dr Roberta FORESTI & Dr Roberto MOTTERLINI
INSERM U955 - IMRB
Physiopathologie et pharmacologie des insuffisances coronaire et cardiaque
Faculté de Médecine - Université Paris-Est, Créteil
Invités par Claudine Kieda
Rue Charles Sadron - 45071 Orléans Cedex 2 - http://cbm.cnrs-orleans.fr - cbmdir@cnrs-orleans.fr