''Deferoxamine blocks death induced by glutathione depletion in PC 12 cells''

Chouraqui, E. | Leon, A. | Repesse, Y. | Prigent-Tessier, A. | Bouhallab, S. | Bougle, D. | Marie, C. | Duval, D.International audience''The purpose of the present work was to investigate the mechanisms by which glutathione depletion induced by treatment with buthionine sulfoximine (BSO) led within 24-30 h to PC 12 cells apoptosis. Our results showed that treatment by relatively low concentrations (10-30 mu M) of deferoxamine (DFx), a natural iron-specific chelator, almost completely shielded the cells from BSO-induced toxicity and that DFx still remained protective when added up to 9-12 h after BSO treatment. On the other hand, phosphopeptides derived from milk casein and known to carry iron across cell membranes, markedly potentiated the toxic action of BSO when loaded with iron but were ineffective in sodium form. Kept for 24 h in serum-free medium, the cells underwent a decrease in glutathione content after BSO treatment, but remained viable. However, these BSO-pre-treated cells showed a rapid (90-120 min) decrease in cell viability when incubated with low doses of iron, whereas a great proportion of them remained viable in the presence of higher concentrations of copper and zinc. We also observed in PC 12 cells an early (4-8 h) and transient increase in the expression of ferritin subunits following BSO addition. Taken together these results suggest that BSO-induced glutathione depletion leads to an alteration of cellular iron homeostasis, which may contribute to its toxicity. (C) 2013 Elsevier Inc. All rights reserved.'

IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans

International audienceSummary The mechanisms of action of intravenous immunoglobulins (IVIg) in autoimmune diseases are not fully understood. The fixed duration of efficacy and noncumulative effects of IVIg in immune thrombocytopenia (ITP) and acquired von Willebrand disease (AVWD) suggest other mechanisms besides immunological ones. Additionally to the peripheral destruction of platelets in ITP, their medullary hypoproduction emerged as a new paradigm with rescue of thrombopoietin receptor agonists (TPO-RA). In an ITP mouse model, interleukin (IL)-11 blood levels increase following IVIg. IL-11 stimulates the production of platelets and other haemostasis factors; recombinant IL-11 (rIL-11) is thus used as a growth factor in post-chemotherapy thrombocytopenia. We therefore hypothesized that IVIg induces IL-11 over-production, which increases platelets, VWF and factor VIII (FVIII) levels in humans and mice. First, in an ITP mouse model, we show that IVIg or rIL-11 induces a rapid increase (72 h) in platelets, FVIII and VWF levels, whereas anti-IL-11 antibody greatly decreased this effect. Secondly, we quantify for the first time in patients with ITP, AVWD, inflammatory myopathies or Guillain–Barré syndrome the dramatic IL-11 increase following IVIg, regardless of the disease. As observed in mice, platelets, VWF and FVIII levels increased following IVIg. The late evolution (4 weeks) of post-IVIg IL-11 levels overlapped with those of VWF and platelets. These data may explain thrombotic events following IVIg and open perspectives to monitor post-IVIg IL-11/thrombopoietin ratios, and to assess rIL-11 use with or without TPO-RA as megakaryopoiesis co-stimulating factors to overcome the relative hypoproduction of platelets or VWF in corresponding autoimmune diseases, besides immunosuppressant

GpIb -VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

International audienceInteractions between platelet glycoprotein (Gp) IIb/IIIa and plasma proteins mediate platelet cross-linking in arterial thrombi. However, GpIIb/IIIa inhibitors fail to disperse platelet aggregates after myocardial infarction or ischemic stroke. These results suggest that stability of occlusive thrombi involves additional and as-yet-unidentified mechanisms. In the present study, we investigated the mechanisms driving platelet cross-linking during occlusive thrombus formation. Using computational fluid dynamic simulations and in vivo thrombosis models, we demonstrated that the inner structure of occlusive thrombi is heterogeneous and primarily determined by the rheological conditions that prevailed during thrombus growth. Unlike the first steps of thrombus formation, which are GpIIb/IIIa-dependent, our findings reveal that closure of the arterial lumen is mediated by GpIbα-von Willebrand Factor (VWF) interactions. Accordingly, disruption of platelet cross-linking using GpIbα-VWF inhibitors restored vessel patency and improved outcome in a mouse model of ischemic stroke, although the thrombi were resistant to fibrinolysis or traditional antithrombotic agents. Overall, our study demonstrates that disruption of GpIbα-VWF interactions restores vessel patency after occlusive thrombosis by specifically disaggregating the external layer of occlusive thrombi, which is constituted of platelet aggregates formed under very high shear rates

FRENCH REAL-WORD DATA ON RIX-FP PROPHYLAXIS USE IN PATIENTS WITH HAEMOPHILIA B

International audienc

FRENCH REAL-WORD DATA ON RIX-FP PROPHYLAXIS USE IN PATIENTS WITH HAEMOPHILIA B

International audienc

FRENCH REAL-WORD DATA ON RIX-FP PROPHYLAXIS USE IN PATIENTS WITH HAEMOPHILIA B

International audienc