Procainamide-SAHA Fused Inhibitors of hHDAC6 Tackle Multidrug-Resistant Malaria Parasites.

Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials.

Vector saliva controlled inflammatory response of the host may represent the Achilles heel during pathogen transmission.

Infection with vector-borne pathogens starts with the inoculation of these pathogens during blood feeding. In endemic regions, the population is regularly bitten by naive vectors, implicating a permanent stimulation of the immune system by the vector saliva itself (pre-immune context). Comparatively, the number of bites received by exposed individuals from non-infected vectors is much higher than the bites from infected ones.

DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Parasites.

Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites.

Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites.

Epigenetic control via reversible histone methylation regulates transcriptional activation throughout the malaria parasite genome, controls the repression of multi-copy virulence gene families and determines sexual stage commitment. Plasmodium falciparum encodes ten predicted SET domain-containing protein methyltransferases, six of which have been shown to be refractory to knock-out in blood stage parasites. We have expressed and purified the first recombinant malaria methyltransferase in sufficient quantities to perform a full enzymatic characterization and reveal the ill-defined PfSET7 is an AdoMet-dependent histone H3 lysine methyltransferase with highest activity towards lysines 4 and 9.

Disruption of Parasite hmgb2 Gene Attenuates Plasmodium berghei ANKA Pathogenicity.

Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that the Plasmodium genome encodes two genuine HMGB factors, Plasmodium HMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain.

Regulatory CD4+Foxp3+ T cells control the severity of anaphylaxis.

Objective: Anaphylaxis is a life-threatening outcome of immediate-type hypersensitivity to allergen, consecutive to mast cell degranulation by allergen-specific IgE. Regulatory T cells (Treg) can control allergic sensitization and mast cell degranulation, yet their clinical benefit on anaphylactic symptoms is poorly documented. Here we investigated whether Treg action during the effector arm of the allergic response alleviates anaphylaxis.

Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum.

Epigenetic factors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. We investigated Plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase.

Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH-GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging.

Antibodies normally do not cross the blood-brain barrier (BBB) and cannot bind an intracellular cerebral antigen. We demonstrate here for the first time that a new class of antibodies can cross the BBB without treatment. Camelids produce native homodimeric heavy-chain antibodies, the paratope being composed of a single-variable domain called VHH.

Impact of mosquito bites on asexual parasite density and gametocyte prevalence in asymptomatic chronic Plasmodium falciparum infections and correlation with IgE and IgG titers.

An immunomodulatory role of arthropod saliva has been well documented, but evidence for an effect on Plasmodium sp. infectiousness remains controversial. Mosquito saliva may orient the immune response toward a Th2 profile, thereby priming a Th2 response against subsequent antigens, including Plasmodium.

Downregulation of basophil-derived IL-4 and in vivo T(H)2 IgE responses by serotonin and other organic cation transporter 3 ligands.

Background: Murine basophils can contribute to the T(H)2 polarization of the immune response by providing rapidly large amounts of IL-4, which suggests that pharmacologic downregulation of this cytokine might provide a strategy to attenuate pathologies associated with excessive production.

Objective: We examined a number of physiological and pharmacologic ligands of the organic cation transporter 3 (OCT3), a membrane carrier of biogenic amines, for their inhibitory effect on IL-4 production by basophils, selecting the most efficient compounds for in vivo evaluation in basophil-dependent experimental models.

Methods: IL-4 production by basophils isolated ex vivo or from bone marrow cultures was assessed in response to various stimuli with or without biogenic monoamines or pharmacologic analogs.

[Role of histamine and histamine receptors in the pathogenesis of malaria].

A hallmark of the host response to Plasmodium parasite is an inflammatory reaction characterized by elevated histaminemia levels. Since histamine, which acts through four different receptors and which synthesis is under the control of the histidine decarboxylase (HDC), is endowed with pro-inflammatory and immunosuppressive activities, we hypothesized that this vaso-active amine may participe to malaria pathogenesis. Combining genetic and pharmacologic approaches by using H1R(-/-), H2R(-/-), H3R(-/-), HDC(-/-) mice and H1R, H2R-, and H3R-antagonists, respectively, we found that cerebral malaria-associated pathogenetic processes such as blood brain barrier disruption, and T lymphocyte sequestration to cerebral vascular endothelium in mice were associated with histamine production.

Total and functional parasite specific IgE responses in Plasmodium falciparum-infected patients exhibiting different clinical status.

Background: There is an increase of serum levels of IgE during Plasmodium falciparum infections in individuals living in endemic areas. These IgEs either protect against malaria or increase malaria pathogenesis. To get an insight into the exact role played by IgE in the outcome of P.

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation.

Immunoregulatory properties of mast cell-derived exosomes.

Transmission of information from mast cells to neighboring or distant cells must be established continuously in order to ensure homeostasis or to initiate immune and inflammatory responses. Owing to their strategic location in peripheral tissues and their prompt response to various stimuli, mast cells can be considered as the cell prototype to fulfill such a sentinel function. There are several ways for mast cells to communicate with other cells including cell-cell interactions via membrane-associated receptors, cytokines and other soluble mediators, and a newly described messenger which consists of membrane vesicles called exosomes carrying a number of immunoregulatory molecules.