Post-translational regulation of RORγt—A therapeutic target for the modulation of interleukin-17-mediated responses in autoimmune diseases

AbstractRetinoic acid-related orphan receptor gamma t (RORγt) is a nuclear receptor, which is selectively expressed by various lymphocytes. RORγt is critical for the development of secondary and tertiary lymphoid organs, and for the thymic development of the T cell lineage. RORγt has been extensively studied as the master transcription factor of IL-17 expression and Th17 cells, which are strongly associated with various inflammatory and autoimmune conditions. Given its essential role in promoting pro-inflammatory responses, it is not surprising that the expression of RORγt is tightly controlled. By its nature as a nuclear receptor, RORγt activity is also regulated in a ligand-dependent manner, which makes it an attractive drug target. In addition, multiple post-translational mechanisms, including post-translational modifications, such as acetylation and ubiquitinylation, as well as interactions with various co-factors, modulate RORγt function. Here we attempt a comprehensive review of the post-translational regulation of RORγt, an area that holds the potential to transform the way we target the RORγt/IL-17 pathway, by enabling the development of safe and highly selective modulators of RORγt activity

Mature oligodendrocytes bordering lesions limit demyelination and favor myelin repair via heparan sulphate production

International audienceMyelin destruction is followed by resident glia activation and mobilization of endogenous progenitors (OPC) which participate in myelin repair. Here we show that in response to demyelination, mature oligodendrocytes (OLG) bordering the lesion express Ndst1, a key enzyme for heparan sulfates (HS) synthesis. Ndst1+ OLG form a belt that demarcates lesioned from intact white matter. Mice with selective inactivation of Ndst1 in the OLG lineage display increased lesion size, sustained microglia and OPC reactivity. HS production around the lesion allows Sonic hedgehog (Shh) binding and favors the local enrichment of this morphogen involved in myelin regeneration. In MS patients, Ndst1 is also found overexpressed in oligodendroglia and the number of Ndst1-expressing oligodendroglia is inversely correlated with lesion size and positively correlated with remyelination potential. Our study suggests that mature OLG surrounding demyelinated lesions are not passive witnesses but contribute to protection and regeneration by producing HS

Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis

The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10−6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed

Modulation of Cerebral Activity Induced by α-casozepine, a Benzodiazepine-like Peptide Derived from Bovine Casein

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Optimizing chain alignment and preserving the pristine structure of single-ether based PBTTT helps improve thermoelectric properties in sequentially doped thin films

International audienceDoped polymer semi-conductors are of central interest in material science for their interesting charge transport and thermoelectric properties. Polymer alignment and crystallization are two means to enhance thermoelectric parameters (charge..

Binding of divalent metal ions to 1–25 β-caseinophosphopeptide: An isothermal titration calorimetry study

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Evaluating the Critical Roles of Precursor Nature and Water Content When Tailoring Magnetic Nanoparticles for Specific Applications

Because of the broad range of application of iron oxide nanoparticles (NPs), the control of their size and shape on demand remains a great challenge, as these parameters are of upmost importance to provide NPs with magnetic properties tailored to the targeted application. One promising synthesis process to tune their size and shape is the thermal decomposition one, for which a lot of parameters were investigated. But two crucial issues were scarcely addressed: the precursors nature and water content. Two in house iron stearates with two or three stearate chains were synthesized, dehydrated, and then tested in standard synthesis conditions of spherical and cubic NPs. Investigations combined with modeling showed that the precursors nature and hydration rate strongly affect the thermal decomposition kinetics and yields, which, in turn, influence the NP size. The cubic shape depends on the decomposition kinetics but also crucially on the water content. A microscopic insight was provided by first-principles simulation showing an iron reduction along the reaction pathway and a participation of water molecules to the building unit formation

Bioconjugation studies of an EGF-R targeting ligand on dendronized iron oxide nanoparticles to target head and neck cancer cells

A major challenge in nanomedicine is designing nanoplatforms (NPFs) to selectively target abnormal cells to ensure early diagnosis and targeted therapy. Among developed NPFs, iron oxide nanoparticles (IONPs) are good MRI contrast agents and can be used for therapy by hyperthermia and as radio-sensitizing agents. Active targeting is a promising method for selective IONPs accumulation in cancer tissues and is generally performed by using targeting ligands (TL). Here, a TL specific for the epidermal growth factor receptor (EGFR) is bound to the surface of dendronized IONPs to produce nanostructures able to specifically recognize EGFR-positive FaDu and 93-Vu head and neck cancer cell lines. Several parameters were optimized to ensure a high coupling yield and to adequately quantify the amount of TL per nanoparticle. Nanostructures with variable amounts of TL on the surface were produced and evaluated for their potential to specifically target and be thereafter internalized by cells. Compared to the bare NPs, the presence of the TL at the surface was shown to be effective to enhance their internalization and to play a role in the total amount of iron present per cell. Keywords: Active targeting, head cancer; Bioconjugation; Coupling; Iron oxide; Magnetic Nanoparticles; Neck cancer; Peptide 22

Unravelling the Thermal Decomposition Parameters for The Synthesis of Anisotropic Iron Oxide Nanoparticles

Iron oxide nanoparticles are widely used as a contrast agent in magnetic resonance imaging (MRI), and may be used as therapeutic agent for magnetic hyperthermia if they display in particular high magnetic anisotropy. Considering the effect of nanoparticles shape on anisotropy, a reproducible shape control of nanoparticles is a current synthesis challenge. By investigating reaction parameters, such as the iron precursor structure, its water content, but also the amount of the surfactant (sodium oleate) reported to control the shape, iron oxide nanoparticles with different shape and composition were obtained, in particular, iron oxide nanoplates. The effect of the surfactant coming from precursor was taking into account by using in house iron stearates bearing either two or three stearate chains and the negative effect of water on shape was confirmed by considering these precursors after their dehydration. Iron stearates with three chains in presence of a ratio sodium oleate/oleic acid 1:1 led mainly to nanocubes presenting a core-shell Fe1-xO@Fe3-xO4 composition. Nanocubes with straight faces were only obtained with dehydrated precursors. Meanwhile, iron stearates with two chains led preferentially to the formation of nanoplates with a ratio sodium oleate/oleic acid 4:1. The rarely reported flat shape of the plates was confirmed with 3D transmission electronic microscopy (TEM) tomography. The investigation of the synthesis mechanisms confirmed the major role of chelating ligand and of the heating rate to drive the cubic shape of nanoparticles and showed that the nanoplate formation would depend mainly on the nucleation step and possibly on the presence of a given ratio of oleic acid and chelating ligand (oleate and/or stearate)