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Biomedical subjects

Christophe Morin

Publications and source records attributed to Christophe Morin.

8 recordsLinked to original sources
PubMed2003

Anoxia-reoxygenation-induced cytochrome c and cardiolipin release from rat brain mitochondria.

Rat brain mitochondria were successively submitted to anoxia and reoxygenation. The main mitochondrial functions were assessed at different reoxygenation times. Although the respiratory control ratio decreased, the activity for each one of the enzymes participating in the respiratory chain was not affected. However, during reoxygenation, mitochondrial membrane lipoperoxidation quickly increased and was proportional to the decrease seen in membrane fluidity. Under the same conditions, cytochrome c and cardiolipin were released from mitochondria and their rate of release increased with reoxygenation time. The release of cytochrome c and cardiolipin was followed by the collapse of the membrane potential and it was not inhibited by cyclosporin A. Addition of the antioxidant alpha-tocopherol abolished all these reoxygenation-induced changes. These data indicate that, in this model, reoxygenation promotes the uncoupling of respiratory chain, and cytochrome c and cardiolipin releases. These events are not related to the membrane potential collapse but to an oxidative stress.

Animals↗
PubMed2003

Validation of the hexose transporter of Plasmodium falciparum as a novel drug target.

Chemotherapy of malaria parasites is limited by established drug resistance and lack of novel targets. Intraerythrocytic stages of Plasmodium falciparum are wholly dependent on host glucose for energy. Glucose uptake is mediated by a parasite-encoded facilitative hexose transporter (PfHT). We report that O-3 hexose derivatives inhibit uptake of glucose and fructose by PfHT when expressed in Xenopus oocytes. Selectivity of these derivatives for PfHT is confirmed by lack of inhibition of hexose transport by the major mammalian glucose and fructose transporters (Gluts) 1 and 5. A long chain O-3 hexose derivative is the most effective inhibitor of PfHT and also kills P. falciparum when it is cultured in medium containing either glucose or fructose as a carbon source. To extend our observations to the second most important human malarial pathogen, we have cloned and expressed the Plasmodium vivax orthologue of PfHT, and demonstrate inhibition of glucose uptake by the long chain O-3 hexose derivative. Furthermore, multiplication of Plasmodium berghei in a mouse model is significantly reduced by the O-3 derivative. Our robust expression system conclusively validates PfHT as a novel drug target and is an important step in the development of novel antimalarials directed against membrane transport proteins.

Animals↗
PubMed2003

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

Animals↗
PubMed2002

Transport processes in Plasmodium falciparum-infected erythrocytes: potential as new drug targets.

Plasmodium falciparum infection induces alterations in the transport properties of infected erythrocytes that have recently been defined using electrophysiological techniques. Mechanisms responsible for transport of substrates into intraerythrocytic parasites have also been clarified by studies of three substrate-specific (hexose, nucleoside and aquaglyceroporin) parasite plasma membrane transporters. These have been characterised functionally using the Xenopus laevis oocyte heterologous expression system. The same expression system is currently being used to define the function of parasite 'P' type ATPases responsible for intraparasitic [Ca(2+)] homeostasis. We review studies on these transport processes and examine their potential as novel drug targets.

Adenosine Triphosphatases↗
PubMed2002

Resveratrol-induced limitation of dysfunction of mitochondria isolated from rat brain in an anoxia-reoxygenation model.

Resveratrol protection on the main functions of purified rat brain mitochondria submitted to anoxia-reoxygenation was investigated. Resveratrol (<0.1 microM) reversed partly (23.3%) the respiratory control ratio (RCR) decrease by protecting both states 3 and 4. This effect was both observed when resveratrol was added before anoxia or reoxygenation. Resveratrol fully inhibited the release of cytochrome c in a concentration-dependent manner and significantly decreased the superoxide anion (O2(0-)) production at a concentration of 1 nM. The mitochondrial membranes damaged after the anoxia-reoxygenation were partly protected (about 70%) by resveratrol at 0.1 microM. The oxygen consumption of mitochondria in presence of NADH and cytochrome c was significantly inhibited by resveratrol with a low EC50 of 18.34 pM. Resveratrol inhibited the CCCP-induced uncoupling from about 20%. The effects of resveratrol on oxidative phosphorylation parameters were also investigated in rats after pretreatment (0.4, 2 and 10 mg/kg/day) for one week. After the isolation of brain mitochondria, the RCR was significantly less decreased in the resveratrol group compared to the control group. These results showed that resveratrol could preserve the mitochondrial functions with at least three mechanisms: antioxidant properties, action on complex III and a membrane stabilizing effect.

Animals↗
PubMed1997

Synthesis and Characterization of Nitrido Tc(V) and Re(V) Complexes with Ferrocenedithiocarboxylate {FcCS(2) = [Fe(C(5)H(4)CS(2))(C(5)H(5))](-)}

The first mixed technetium-iron complexes [(99g)Tc(N)(FcCS(2))(2)] {FcCS(2) = [Fe(II)(C(5)H(5))(C(5)H(4)CS(2))](-)} (1) and [(99g)Tc(N)(FcCS(2))(FcCS(2)( bigstar))](+) {FcCS(2) = [Fe(II)(C(5)H(5))(C(5)H(4)CS(2))](-); FcCS(2)( bigstar) = Fe(III)(C(5)H(5))(C(5)H(4)CS(2))} (2) have been prepared and characterized. Complex 1 was obtained by reaction of the precursor complex [(99g)Tc(N)Cl(2)(PPh(3))(2)] with the piperidinium salt of the ligand FcCS(2). The resulting biferrocene complex is formed by two FcCS(2) ligands bound to the Tc atom through the four sulfur atoms of the two CS(2)(-) groups and bridged by a Tc&tbd1;N multiple bond. The mixed-valence Fe(2+)-Fe(3+), monocationic complex 2 was isolated as secondary product of the reaction of the precursor complex [(99g)Tc(N)Cl(4)](-) with the ligand FcCS(2). It has the same composition as 1 except for the fact that the Fe(II) center of one FcCS(2) ligand has been oxidized to Fe(III). The electrochemical properties of 1 and 2 are consistent with their formulations. Cyclic voltammetric studies and controlled potential electrolyses showed that complex 1 undergoes a quasi-reversible, two-electron exchange at 0.320 V (vs ferrocene/ferrocenium couple) attributed to the oxidation of the two Fe(II) ions, while complex 2 undergoes a quasi-reversible, one-electron exchange at nearly the same potential (0.344 V) assigned to the oxidation of the residual Fe(II) ion. These results indicate that in complex 1 the two Fe(II) atoms behave as independent redox centers. The synthesis, characterization, and electrochemical behavior of the analogous, six-coordinated rhenium(V) complex [Re(N)(FcCS(2))(2)(PPh(3))] are also reported.

Journal Article↗