Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity

Chronic low-grade inflammation is known to be linked to obesity, and to occur in the early stages of the disease. This mechanism is complex and involves numerous organs, cells, and cytokines. In this context, inflammation of white adipose tissue seems to play a key role in the development of obesity. Because of its properties, prostaglandin E2 (PGE2), an emblematic inflammatory mediator, has been proposed as an actor linking inflammation and obesity. Indeed, PGE2 is involved in mechanisms that are dysregulated in obesity such as lipolysis and adipogenesis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which specifically catalyzes the final step of PGE2 biosynthesis. Interestingly, mPGES-1 invalidation dramatically alters the production of PGE2 during inflammation. In the present work, we sought to determine whether mPGES-1 could contribute to inflammation associated with obesity. To this end, we analyzed the energy metabolism of mPGES-1 deficient mice (mPGES-1-/-) and littermate controls, fed with a high-fat diet. Our data showed that mPGES-1-/- mice exhibited resistance to diet-induced obesity when compared to wild-type littermates. mPGES-1-/- mice fed with a high-fat diet, showed a lower body weight gain and a reduced adiposity, which were accompanied by a decrease in adipose tissues inflammation. We also observed an increase in energy expenditures in mPGES-1-/- mice fed with a high-fat diet without any changes in activity and browning process. Altogether, these data suggest that mPGES-1 inhibition may prevent diet-induced obesity

Relationships between the anti-HIV V 3 -derived peptide SPC 3 and lymphocyte membrane properties involved in virus entry: SPC 3 interferes with CXCR 4

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An Anti-HIV Peptide Construct Derived from the Cleavage Region of the Env Precursor Acts on Env Fusogenicity through the Presence of a Functional Cleavage Sequence

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Cerastatin, a new potent inhibitor of platelet aggregation from the venom of the Tunisian viper, Cerastes cerastes.

International audienceCerastatin, a potent platelet aggregation inhibitor, was purified by gel nitration on Sephadex G-75, followed by two ion exchange chromatographies on Mono-S columns. Cerastatin is a neutral glycoprotein (pI = 6.2) of 32 kDa, made up of at least three subunits. It is devoid of phospholipase A2, esterase, fibrinogenolytic and amidolytic activities. It inhibits aggregation of washed platelets, induced by either collagen, PAF acether or thrombin, with similar ic50 of 2.3 nM. Cerastatin also inhibits the thrombin-induced clot retraction of platelet-rich plasma. It does not inhibit the amidolytic or the procoagulant activities of thrombin. Cerastatin caused no lytic effect on platelet membranes since it did not cause release of lactate dehydrogenase. Pretreatment of platelets with cerastatin irreversibly inhibits the aggregation induced by thrombin. Also, cerastatin completely inhibits the fibrinogen-induced aggregation of a chymotrypsin-treated platelets. Cerastatin therefore inhibits platelet aggregation by interfering with the interaction of fibrinogen with fibrinogen receptors

The Catalytic Activity of Protein Disulfide Isomerase Is Involved in Human Immunodeficiency Virus Envelope–Mediated Membrane Fusion after CD4 Cell Binding

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SPC3, an anti-HIV peptide construct derived from the viral envelope, binds and enters HIV target cells

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An Anti-Human Immunodeficiency Virus Multiple Antigen Peptide Encompassing the Cleavage Region of the Env Precursor Interferes With Membrane Fusion at a Post-CD4 Binding Step

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Procoagulant and platelet-aggregating properties of cerastocytin from Cerastes cerastes venom.

International audienceCerastocytin is a thrombin-like serine protease with potent platelet-proaggregating properties. It is able to activate factor XIII but is less active than thrombin on plasma coagulation. The aggregation induced by cerastocytin resembles that induced by thrombin, since rabbit washed platelets desensitized by a pretreatment with thrombin do not aggregate in the presence of cerastocytin. Furthermore, preincubation of platelets with monoclonal antibodies specific for glycoproteins GPIb or GPIIbIIIa blocks receptor sites for thrombin and fibrinogen, respectively, and prevents their aggregation induced by thrombin or cerastocytin. A monoclonal antibody, inhibitor of von Willebrand factor (VWF)-dependent agglutination, blocks the aggregation induced by cerastocytin. After activation with cerastocytin, washed rabbit platelets degranulate and secrete ATP and phospholipase A2. However, cerastocytin is less potent in inducing the release of phospholipase A2 than in inducing ATP secretion

Glycosaminoglycans and protein disulfide isomerase-mediated reduction of HIV Env,

Conformational changes within the human immunodeficiency virus-1 (HIV-1) surface glycoprotein gp120 result from binding to the lymphocyte surface receptors and trigger gp41-mediated virus/cell membrane fusion. The triggering of fusion requires cleavage of two of the nine disulfide bonds of gp120 by a cell-surface protein disulfide-isomerase (PDI). Soluble glycosaminoglycans such as heparin and heparan sulfate bind gp120 via V3 and, possibly, a CD4-induced domain. They exert anti-HIV activity by interfering with the HIV envelope glycoprotein ( Env)/cell-surface interaction. Env also binds cell-surface glycosaminoglycans. Here, using surface plasmon resonance, we observed an inverse relationship between heparin binding by gp120 and its thiol content. In vitro, and in conditions in which gp120 could bind CD4, heparin and heparan sulfate reduced PDI-mediated gp120 reduction by approximately 80%. Interaction of Env with the surface of lymphocytes treated using sodium chlorate, an inhibitor of glycosaminoglycan synthesis, led to gp120 reduction. We conclude that besides their capacity to block Env/cell interaction, soluble glycosaminoglycans can effect anti-HIV activity via interference with PDI- mediated gp120 reduction. In contrast, their presence at the cell surface is dispensable for Env reduction during the course of interaction with the lymphocyte surface. This work suggests that the reduction of exofacial proteins in various diseases can be inhibited by compounds targeting the substrates ( not by targeting PDI, as is usually done), and that glycosaminoglycans that primarily protect proteins by preserving them from proteolysis also have a role in preventing reduction