Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis

Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTa, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions: FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis

Propriétés immunomodulatrices des protéines Core et ARFP du virus de l'hépatite C sur les cellules de la lignée monocytaire

LYON-ENS Sciences (693872304) / SudocSudocFranceF

Software Product Reliability Based on Basic Block Metrics Recomposition

International audienceIn the context of functional verification, the focus has always been on hardware and its ability to be both resilient to errors and to recover from them autonomously. In order to evaluate these characteristics, an extensive use of Fault Injection tools is made to achieve clear and granular results. These testing campaigns are carried out on the entire DUT and require a consistent amount of time and computational resources. The possibility of reducing these costs applying modern techniques as the study of the Dysfunctional State Machine or the proof of concept regarding the composability of single block fault injection campaigns to obtain a library of component of which the reliability metrics are well known, as already been extensively discussed and proven on hardware. In this work instead the application of this methodologies to software is presented for the first time. In order to do so, the software has been divided into basic block, atomic chunks of code having precise&nbsp;&nbsp;carachteristics that will ensure the possibility to study them singularly and then recompose them into a software product which reliability metrics are known, without the need for complete Fault injection campaign.</p

MBSA Approaches Applied to Next Decade Digital System-On-a-Chip Components

International audienc

MBSA Approaches Applied to Next Decade Digital Components

International audienceIn the field of automatic quality or safety assurance level evaluation, this paper proposes the first approach towards the automation of the modelling processes of both the valid and faulty state machines within a SoC (System-on-a-Chip). The choice of using the modelling framework of APSYS guarantees the possibility to model beyond the classical electromechanical systems, exploring the MBSA applied to SoC. Experimental results have been conducted on an I2C-AHB and SPI-AHB systems, laying the base for a more complete and extended analysis of complex digital systems, defining the basis to ensure the scalability of the model, crucial when approaching heavily interconnected systems as those belonging to the digital world.</p

MBSA Approaches Applied to Next Decade Digital System-On-a-Chip Components

International audienc

Targeting Integrin-Dependent Adhesion and Signaling with 3-Arylquinoline and 3-Aryl-2-Quinolone Derivatives: A new Class of Integrin Antagonists.

We previously reported the anti-migratory function of 3-aryl-2-quinolone derivatives, chemically close to flavonoids (Joseph et al., 2002). Herein we show that 3-arylquinoline or 3-aryl-2-quinolone derivatives disrupt cell adhesion in a dose dependent and reversible manner yet antagonized by artificial integrin activation such as manganese. Relying on this anti-adhesive activity, a Structure-Activity Relationship (SAR) study was established on 20 different compounds to throw the bases of future optimization strategies. Active drugs efficiently inhibit platelet spreading, aggregation, and clot retraction, processes that rely on αllbβ3 integrin activation and clustering. In vitro these derivatives interfere with β3 cytoplasmic tail interaction with kindlin-2 in pulldown assays albeit little effect was observed with pure proteins suggesting that the drugs may block an alternative integrin activation process that may not be directly related to kindlin recruitment. Ex vivo, these drugs blunt integrin signaling assayed using focal adhesion kinase auto-phosphorylation as a read-out. Hence, 3-arylquinoline and 3-aryl-2-quinolone series are a novel class of integrin activation and signaling antagonists

The activity of BJINT family members is closely related to their structure.

<p>Structure-activity relationship of 3-arylquinolines and 3-aryl-2-quinolones on cell spreading and attachment. BJINT003, BJINT006 and derivatives impair cell spreading and attachment mediated by focal adhesions. The activities have been estimated using at least three independent experiments where cells have been spread on fibronectin, fixed and stained with Crystal Violet.</p