Dijon, France


Dijon, France
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Deckert V.,French Institute of Health and Medical Research | Deckert V.,University of Burgundy | Deckert V.,LipSTIC LabEx | Lemaire S.,French Institute of Health and Medical Research | And 44 more authors.
Scientific Reports | Year: 2017

Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis. © The Author(s) 2017.

Belkahla H.,University of Burgundy | Belkahla H.,University Paris Diderot | Herlem G.,University of Burgundy | Picaud F.,University of Burgundy | And 5 more authors.
Nanoscale | Year: 2017

Cancer is a worldwide health problem. It is now considered as a leading cause of morbidity and mortality in developed countries. In the last few decades, considerable progress has been made in anti-cancer therapies, allowing the cure of patients suffering from this disease, or at least helping to prolong their lives. Several cancers, such as those of the lung and pancreas, are still devastating in the absence of therapeutic options. In the early 90s, TRAIL (Tumor Necrosis Factor-related apoptosis-inducing ligand), a cytokine belonging to the TNF superfamily, attracted major interest in oncology owing to its selective anti-tumor properties. Clinical trials using soluble TRAIL or antibodies targeting the two main agonist receptors (TRAIL-R1 and TRAIL-R2) have, however, failed to demonstrate their efficacy in the clinic. TRAIL is expressed on the surface of natural killer or CD8+ T activated cells and contributes to tumor surveillance. Nanoparticles functionalized with TRAIL mimic membrane-TRAIL and exhibit stronger antitumoral properties than soluble TRAIL or TRAIL receptor agonist antibodies. This review provides an update on the association and the use of nanoparticles associated with TRAIL for cancer therapy. © The Royal Society of Chemistry 2017.

Gautier T.,French Institute of Health and Medical Research | Gautier T.,University of Burgundy | Gautier T.,LipSTIC LabEx | Masson D.,French Institute of Health and Medical Research | And 7 more authors.
Expert Opinion on Therapeutic Targets | Year: 2016

Introduction: Over recent decades, attempts to ascertain the pro-atherogenic nature of plasma cholesteryl ester transfer protein (CETP) and to establish the relevance of its pharmacological blockade as a promising high density lipoproteins-raising and anti-atherogenic therapy have been disappointing.Areas covered: The current review focuses on CETP as a multifaceted protein, on genetic variations at the CETP gene and on their possible consequences for cardiovascular risk in human populations. Specific attention is given to physiological modulation of endogenous CETP activity by the apoC1 inhibitor. Finally, the rationale behind the need for selection of patients to treat is discussed in the light of recent studies.Expert opinion: At this stage one can only speculate on the clinical outcome of pharmacological CETP inhibitors in high-risk populations, but recent advances give cause to adjust the expectations from now on. The CETP effect is probably largely influenced by the overall metabolic state, and whether CETP blockade may be relevant or not in promoting cholesterol disposal is still questioned. The possible need for a careful stratification of patients to treat with CETP inhibitors is outlined. Finally, manipulation of CETP activity should be considered with caution in the context of sepsis and infectious diseases. © 2015 Taylor & Francis.

De Barros J.-P.P.,French Institute of Health and Medical Research | De Barros J.-P.P.,University of Burgundy | De Barros J.-P.P.,LipSTIC LabEx | Gautier T.,French Institute of Health and Medical Research | And 24 more authors.
Journal of Lipid Research | Year: 2015

Quantitation of plasma lipopolysaccharides (LPSs) might be used to document Gram-negative bacterial infection. In the present work, LPS-derived 3-hydroxymyristate was extracted from plasma samples with an organic solvent, separated by reversed phase HPLC, and quantitated by MS/MS. This mass assay was combined with the limulus amebocyte lysate (LAL) bioassay to monitor neutralization of LPS activity in biological samples. The described HPLC/MS/MS method is a reliable, practical, accurate, and sensitive tool to quantitate LPS. The combination of the LAL and HPLC/MS/MS analyses provided new evidence for the intrinsic capacity of plasma lipoproteins and phospholipid transfer protein to neutralize the activity of LPS. In a subset of patients with systemic inflammatory response syndrome, with documented infection but with a negative plasma LAL test, significant amounts of LPS were measured by the HPLC/MS/MS method. Patients with the highest plasma LPS concentration were more severely ill. HPLC/MS/MS is a relevant method to quantitate endotoxin in a sample, to assess the efficacy of LPS neutralization, and to evaluate the proinflammatory potential of LPS in vivo. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

PubMed | University of British Columbia, LipSTIC Labex, French Institute of Health and Medical Research, University of Burgundy and French National Institute for Agricultural Research
Type: Journal Article | Journal: Oncotarget | Year: 2016

CD45 is a pan-leukocyte protein with tyrosine phosphatase activity involved in the regulation of signal transduction in hematopoiesis. Exploiting CD45 KO mice and lentiviral shRNA, we prove the crucial role that CD45 plays in acute myeloid leukemia (AML) development and maintenance. We discovered that CD45 does not colocalize with lipid rafts on murine and human non-transformed hematopoietic cells. Using a mouse model, we proved that CD45 positioning within lipid rafts is modified during their oncogenic transformation to AML. CD45 colocalized with lipid rafts on AML cells, which contributes to elevated GM-CSF signal intensity involved in proliferation of leukemic cells. We furthermore proved that the GM-CSF/Lyn/Stat3 pathway that contributes to growth of leukemic cells could be profoundly affected, by using a new plasma membrane disrupting agent, which rapidly delocalized CD45 away from lipid rafts. We provide evidence that this mechanism is also effective on human primary AML samples and xenograft transplantation. In conclusion, this study highlights the emerging evidence of the involvement of lipid rafts in oncogenic development of AML and the targeting of CD45 positioning among lipid rafts as a new strategy in the treatment of AML.

Grimm P.,University of Burgundy | Pais de Barros J.P.,University of Burgundy | Pais de Barros J.P.,LipSTIC LabEx | Julliand V.,University of Burgundy
Livestock Science | Year: 2017

Feeding horses with high-starch diet can lead to alteration of their hindgut and fecal bacteria composition, with a potential shift in gram negative and positive bacteria. Gram-negative bacteria contain LPS in their outer membrane, which can translocate into bloodstream following hindgut microbial disturbances. The aim of our study was to evaluate if diet composition (high-fiber or high-starch diets) can modulate the LPS concentration in equine feces and plasma using an innovative measurement method. Six horses were used in a longitudinal study composed of three consecutive periods. During the first period (H1; 3 weeks), they were fed 100% hay. After a gradual transition, they received during the second period (HB; 4 weeks) a diet composed of 57% hay and 43% barley. During the third period (H2; 6 weeks), they returned to the 100% hay diet without transition. Colonic, fecal and blood samples were collected on days 10 and 20 in H1 and HB periods and on days 10, 20 and 40 in H2 period. Total anaerobic, amylolytic and lactate-utilizing bacteria were enumerated in colon and feces using culture technics. Fecal and plasma LPS concentration was determined by direct quantitation of 3HM by high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), using a method described recently in human for plasma samples (Pais de Barros et al., 2015), and by adapting this method for fecal samples. The fecal LPS concentrations increased significantly when horses changed from hay diet to hay/barley diet and significantly decreased when horses returned to the hay diet (values comparable to those found during the first hay diet). Similar variations were observed on the bacteria concentrations in colon and feces of horses. The LPS concentration did not vary in plasma samples when the hay/barley diet was fed. It was assumed that dietary stress was not important enough to disrupted the hindgut mucosa and allow LPS translocation into plasma. These data showed that fecal LPS concentrations are very sensitive to diet changes, and could reflect alteration in the hindgut bacteria composition occurring under the dietary change. The measure of LPS through the 3HM raised the question of the accurate representation of LPS. In conclusion, quantification of 3HM could be a simple method to follow the evolution of bacterial composition in the feces, and rapidly state on the balance or imbalance of the bacteria. Further researches have to be conducted to use this parameter as an indicator of bacterial disturbances. © 2017 Elsevier B.V.

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