Modulation of microtubule assembly by the HIV-1 Tat protein is strongly dependent on zinc binding to Tat

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Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells

[EN] Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin β receptor (LTβR, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LTβR/HVEM pathway was associated with delayed downregulation of interleukin-7Rα and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LTβR/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival.SIThis work has been supported by grants of the Spanish Ministry of Health (Fondo de Investigaciones Sanitarias, PI13/00029), Department of Education of Castilla and Leon Regional Government (Grant# LE093U13) and Mutua Madrile~na Foundation (Basic research grants 2012) to J.I.R.B; by Miguel Servet National Grant (Health National Organization Research Program) CP12/03063 and by Gerencia Regional de Salud GRS963/A/2014 and GRS1142/A/2015 to M.L.R.G; and by the Swiss National Science Foundation to PS

Highly Sensitive Electrochemiluminescent Nanobiosensor for the Detection of Palytoxin

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The HIV-1 transcriptional activator Tat has potent nucleic acid chaperoning activities in vitro

The human immunodeficiency virus type 1 (HIV-1) is a primate lentivirus that causes the acquired immunodeficiency syndrome (AIDS). In addition to the virion structural proteins and enzyme precursors, that are Gag, Env and Pol, HIV-1 encodes several regulatory proteins, notably a small nuclear transcriptional activator named Tat. The Tat protein is absolutely required for virus replication since it controls proviral DNA transcription to generate the full-length viral mRNA. Tat can also regulate mRNA capping and splicing and was recently found to interfere with the cellular mi- and siRNA machinery. Because of its extensive interplay with nucleic acids, and its basic and disordered nature we speculated that Tat had nucleic acid-chaperoning properties. This prompted us to examine in vitro the nucleic acid-chaperoning activities of Tat and Tat peptides made by chemical synthesis. Here we report that Tat has potent nucleic acid-chaperoning activities according to the standard DNA annealing, DNA and RNA strand exchange, RNA ribozyme cleavage and trans-splicing assays. The active Tat(44–61) peptide identified here corresponds to the smallest known sequence with DNA/RNA chaperoning properties

Design and synthesis of intrinsically cell-penetrating nucleopeptides.

International audienceNucleopeptides, which are constituted of alpha-amino acids bearing nucleobases at their side chains, are able to penetrate into cells and to reach the nucleus without cytotoxic effects

Synthesis of Novel Mannoside Glycolipid Conjugates for Inhibition of HIV-1 Trans-Infection

International audienc

PBPK modeling of irbesartan: incorporation of hepatic uptake

International audienc

Aromatic Dipeptide Homologue-Based Hydrogels for Photocontrolled Drug Release

Peptide-based hydrogels are considered of special importance due to their biocompatibility and biodegradability. They have a wide range of applications in the biomedical field, such as drug delivery, tissue engineering, wound healing, cell culture media, and biosensing. Nevertheless, peptide-based hydrogels composed of natural α-amino acids are limited for in vivo applications because of the possible degradation by proteolytic enzymes. To circumvent this issue, the incorporation of extra methylene groups within the peptide sequence and the protection of the terminal amino group can increase the enzymatic stability. In this context, we investigated the self-assembly capacity of aromatic dipeptides (Boc-α-diphenylalanine and Boc-α-dityrosine) and their β- and γ-homologues and developed stable hydrogels. Surprisingly, only the Boc-diphenylalanine analogues were able to self-assemble and form hydrogels. A model drug, l-ascorbic acid, and oxidized carbon nanotubes (CNTs) or graphene oxide were then incorporated into the hydrogels. Under near-infrared light irradiation, the photothermal effect of the carbon nanomaterials induced the destabilization of the gel structure, which caused the release of a high amount of drug, thus providing opportunities for photocontrolled on-demand drug release

Controlled Chemical Derivatisation of Carbon Nanotubes with Imaging, Targeting, and Therapeutic Capabilities.

In drug delivery, carbon nanotubes (CNTs) hold a great potential as carriers because of their ability to easily cross biological barriers and be internalised into cells. Their high aspect ratio allows multi-functionalisation and their development as a multimodal platform for targeted therapy. In this article, we report the controlled covalent derivatisation of triple-functionalised CNTs with the anticancer drug gemcitabine, folic acid as a targeting ligand and fluorescein as a probe. The anticancer activity of gemcitabine was maintained after covalent grafting onto the CNTs. The functionalised nanotubes were internalised into both folate-positive and negative cells, suggesting the passive diffusion of CNTs. Overall, our approach is versatile and offers a precise chemical control of the sidewall functionalisation of CNTs and the possibility to manoeuvre the types of functionalities required on the nanotubes for a multimodal therapeutic strategy.journal article2015 Oct 122015 09 02importe

Multifunctionalised cationic fullerene adducts for gene transfer: Design, synthesis and DNA complexation

Cationic poly-N,N-dimethylfulleropyrrolidinium derivatives have been designed and synthesised to complex plasmid DNA for gene delivery