HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

Effects of sildenafil on maximum walking time in patients with arterial claudication: The ARTERIOFIL study

BACKGROUND: Patients with lower extremity peripheral artery disease (PAD) frequently experience claudication, a clinical symptom indicative of reduced walking capacity. Recommended care consists of exercise rehabilitation combined with optimal medical treatment and surgery. The effects of a single oral dose of sildenafil, a phosphodiesterase type-5 inhibitor, on patients with claudication are discussed. The aim of this study was to test the efficacy of a single 100 mg dose of sildenafil compared to placebo in terms of maximal walking time (MWT) in patients with claudication. METHODS: The ARTERIOFIL study is a crossover, double-blind, prospective, randomized, single-center study conducted at Angers University Hospital in France. MWT (primary endpoint) was assessed using a treadmill test (10% incline; 3.2 km/h). Secondary endpoints (pain-free walking time (PFWT), transcutaneous oximetry during exercise and redox cycle parameters and safety) were also studied. RESULTS: Fourteen patients were included of whom two were ultimately excluded. In the 12 remaining patients, the MWT was significantly improved during the sildenafil period compared with the placebo period (300 s [95% CI 172 s-428 s] vs 402 s [95% CI 274 s-529 s] p < 0.01). Sildenafil had no significant effect on pain-free walking time or skin tissue oxygenation during exercise. According to redox cycle parameters, sildenafil significantly reduced blood glucose and pyruvate levels and the 3-hydroxybutyrate/acetoacetate ratio, while there was no significant effect on lactate, 3-hydroxybutyrate, acetoacetate and free fatty acid levels. Symptomatic transient hypotension was observed in two women. CONCLUSIONS: The ARTERIOFIL study has shown that a single 100 mg oral dose of sildenafil had a significant effect on increase in MWT but had no significant effects on PFWT and oxygenation parameters in patients with claudication. A double-blind, prospective, randomized, multicenter study (VIRTUOSE©) is ongoing to evaluate the chronic effect of six month-long sildenafil treatment on MWT in PAD patients with claudication. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at clinicaltrials.gov, registration. number: NCT02832570, (https://clinicaltrials.gov/ct2/show/NCT02832570)

Internal Carotid Artery Hypoplasia: A New Clinical Feature in Pseudoxanthoma Elasticum

International audienc

Simple Shared Motifs (SSM) in conserved region of promoters: a new approach to identify co-regulation patterns

<p>Abstract</p> <p>Background</p> <p>Regulation of gene expression plays a pivotal role in cellular functions. However, understanding the dynamics of transcription remains a challenging task. A host of computational approaches have been developed to identify regulatory motifs, mainly based on the recognition of DNA sequences for transcription factor binding sites. Recent integration of additional data from genomic analyses or phylogenetic footprinting has significantly improved these methods.</p> <p>Results</p> <p>Here, we propose a different approach based on the compilation of Simple Shared Motifs (SSM), groups of sequences defined by their length and similarity and present in conserved sequences of gene promoters. We developed an original algorithm to search and count SSM in pairs of genes. An exceptional number of SSM is considered as a common regulatory pattern. The SSM approach is applied to a sample set of genes and validated using functional gene-set enrichment analyses. We demonstrate that the SSM approach selects genes that are over-represented in specific biological categories (Ontology and Pathways) and are enriched in co-expressed genes. Finally we show that genes co-expressed in the same tissue or involved in the same biological pathway have increased SSM values.</p> <p>Conclusions</p> <p>Using unbiased clustering of genes, Simple Shared Motifs analysis constitutes an original contribution to provide a clearer definition of expression networks.</p

A genome-wide association scan implicates <i>DCHS2, RUNX2, GLI3, PAX1</i> and <i>EDAR</i> in human facial variation

We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values−8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar function

L’insuffisance de masse musculaire mesurée par bioimpédancemétrie chez le patient obèse : prévalence, facteurs associés et comparaison de deux méthodes

National audienceL’évaluation de la composition corporelle chez le patient obèse et l’obésité sarcopénique (OS) sont des sujets d’actualité avec un récent consensus international d’experts établis par Société européenne nutrition clinique métabolisme (ESPEN) l’Association pour l’étude (EASO) ayant but d’unifier nos pratiques en proposant une démarche diagnostique claire l’OS. Ce propose mesurer l’augmentation masse grasse (FM) associée à l’insuffisance musculaire squelettique (SMM) rapportée au poids (W) (SMM/W) (méthode 1). Précédemment, ratio index (FMI)/index maigre (FFMI) 2) avait été proposé. Les objectifs étaient déterminer comparer prévalence (IMM) ses facteurs associés entre ces deux méthodes, dans population patients souffrant d’obésité sévère début prise charge notre centre spécialisé. nutritionnelle, incluant poids, taille, indice (IMC) bioimpédancemétrie monofréquence (BIA) (Bodystat) (mais pas force serrement), recherche risque sarcopénie accord réalisées tous les patients. méthodes ont appliquées utilisant, méthode 1, l’équation SMM Janssen, FMI/FFMI, données indiqués directement l’appareil BIA. La concordance 2 a déterminée coefficient kappa. recherchés analyse multivariée. Au total, 253 inclus 01/2017 12/2019 : 204 femmes (80,6 %) 49 hommes (19,4 %), d’âge moyen 44,4 ± 13 années, BMI 43 6,8 kg/m2. l’IMM était 89,7 % (227/253) 35,2 (83/253) 2. faible (kappa = 0,10). Peu communs mis évidence. Avec l’âge (odds 1,05, [intervalle confiance 95 %, 1,0

Le partage et l’application des connaissances en santé publique : résultats d’une étude préliminaire auprès d’élus et techniciens locaux [Note de synthèse n°4]

En France, de récentes propositions ont été faites en santé publique en faveur du partage et de l’application des connaissances (PAC) entre les chercheurs et les acteurs liés à la décision publique : d’une part, pour renforcer les liens entre ces acteurs et, d’autre part, pour favoriser une prise de décision éclairée par l’ensemble des connaissances disponibles en santé publique [1]. Ces connaissances peuvent être issues de la recherche, de bases de données, ou de l’expérience [2]. Cependant, peu d’informations sont disponibles sur les besoins et les contraintes des décideurs locaux en matière de PAC.Cette note de synthèse présente les résultats d’une étude préliminaire dont les objectifs étaient de savoir de quelles façons les élus et techniciens de communes et intercommunalités : (1) s’informent sur la santé ; (2) entrent en relation avec des chercheurs ; et (3) envisagent les stratégies pour développer ou renforcer les connaissances et compétences en santé de leur collectivité.Cette étude a été faite en collaboration avec le réseau français des Villes-Santé de l’OMS (RFVS-OMS) et l’association Elus, santé publique et territoires (ESPT)

Le partage et l’application des connaissances en santé publique : résultats d’une étude préliminaire auprès d’élus et techniciens locaux

National audienc

Digestive enzyme ratios are good indicators of hatchling yolk reserve and digestive gland maturation in early life stages of cuttlefish Sepia officinalis L.: application of these new tools in ecology and aquaculture

International audienceIn Sepia officinalis (Linnaeus, 1758), the digestive gland matures during the first month post-hatching, while a shift from intracellular acid to extracellular alkaline digestion occurs. The purpose of this study was to investigate the possibility of using enzymatic ratios for the description of digestive system maturation in early life stages of S. officinalis. Second, it is intended to apply these new tools as eco-physiological indicators for understanding the impact of cuttlefish eggs’ life history from different spawning sites of the English Channel on digestive performance of juveniles. An experimental rearing was performed over 35 days after hatching (DAH) on juveniles from wild collected eggs in 2010 and 2011. Four digestive enzyme activities and their ratios [i.e., trypsin, cathepsin, acid (ACP), and alkaline (ALP) phosphatase, ALP/ACP, and trypsin/cathepsin] were studied along with histological features (e.g., internal yolk surface and digestive gland development). The two enzyme ratios were good indicators of digestive system maturation allowing the study of the digestive gland’s development. They were highly correlated to juveniles’ weight increase and histological features of the gland in early DAH. These ratios described more accurately the shift occurring between the intracellular acid and the extracellular alkaline modes of digestion in S. officinalis and were more specific than separated enzyme activities. Their application as eco-physiological tools revealed that enzyme ratios reflected yolk content and digestive gland development in new hatching juveniles. Finally, ALP/ACP ratio was shown to be a powerful tool to describe growth performance of S. officinalis which is useful for aquaculture optimization