Non-alcoholic fatty liver disease, and the underlying altered fatty acid metabolism, reveals brain hypoperfusion and contributes to the cognitive decline in APP/PS1 mice

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, is associated with cognitive decline in middle-aged adults, but the mechanisms underlying this association are not clear. We hypothesized that NAFLD would unveil the appearance of brain hypoperfusion in association with altered plasma and brain lipid metabolism. To test our hypothesis, amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were fed a standard diet or a high-fat, cholesterol and cholate diet, inducing NAFLD without obesity and hyperglycemia. The diet-induced NAFLD disturbed monounsaturated and polyunsaturated fatty acid (MUFAs, PUFAs) metabolism in the plasma, liver, and brain, and particularly reduced n-3 PUFAs levels. These alterations in lipid homeostasis were associated in the brain with an increased expression of Tnfalpha, Cox2, p21, and Nox2, reminiscent of brain inflammation, senescence, and oxidative stress. In addition, compared to wild-type (WT) mice, while brain perfusion was similar in APP/PS1 mice fed with a chow diet, NAFLD in APP/PS1 mice reveals cerebral hypoperfusion and furthered cognitive decline. NAFLD reduced plasma beta40- and beta42-amyloid levels and altered hepatic but not brain expression of genes involved in beta-amyloid peptide production and clearance. Altogether, our results suggest that in a mouse model of Alzheimer disease (AD) diet-induced NAFLD contributes to the development and progression of brain abnormalities through unbalanced brain MUFAs and PUFAs metabolism and cerebral hypoperfusion, irrespective of brain amyloid pathology that may ultimately contribute to the pathogenesis of AD

Âge et stress oxydant

Différents mécanismes cellulaires de réparation, de défense et de maintien de l’homéostasie sont continuellement activés au cours de la vie. Ils permettent d’établir un équilibre temporaire face aux agressions successives endogènes et exogènes. Le principe d’hormesis

Étude crâniométrique des bovins de l'île Amsterdam : modélisation du dimorphisme sexuel.

The cattle from Amsterdam Island (South of Indian Ocean) had been initially introduced as domesticated animals into the island during the XVII century. Later abandoned, the cattle reverted to the wild state (feral animals). This old and hardy livestock has proved to be a reference population on which to do an osteometric study. The skulls of 91 adults (SO females and 41 males) were collected and measured by the anatomy laboratory of the Nantes Veterinary Faculty - France. The data allowed us to do a uni-and multivaried statistical study (single statistics, principal component analysis, disciminate analysis). This study permitted us to define osteomorphometric characteristics of the Amsterdam Island cattle skull : a small long- horned head with a sub-concave profile. A method to a global and comparative approach and a sexual dimorphism study has been proposed thanks to this large skull sample. For the most discriminant variables, a logistic regression allows us to modelise the sexual dimorphism.Les bovins de l'île Amsterdam (Sud de l'Océan indien) ont été initialement introduits domestiqués dans l'île au XVIIème siècle, puis suite à l'abandon du troupeau, sont retournés à l'état sauvage (animaux dits harets ou marrons). Ce cheptel rustique et ancien s'avère être une population de référence pour une étude ostéométrique. Les têtes osseuses de 91 individus adultes (50 femelles et 41 mâles) ont été récupérées par le laboratoire d'Anatomie Comparée de l'Ecole Nationale Vétérinaire et ont été mesurées. Les données acquises ont fait l'objet d'une étude statistique uni-et multivariée (statistiques simples, analyse en composantes principales, analyse discriminante). Cette étude a permis de définir les caractères ostéo-morphométriques de la tête osseuse du bovin de l'île Amsterdam : une tête à profil sub-concave de petite taille avec de grandes cornes. Grâce à un échantillon de taille assez importante, une méthodologie pour une approche ostéométrique globale et ainsi que pour une étude du dimorphisme sexuel a été proposée. Pour les variables les plus discriminantes, une régression logistique a permis une modélisation du dimorphisme sexuel.Guintard Claude, Betti Éric, Thorin Savarit Chantal, Antonot Philippe. Étude crâniométrique des bovins de l'île Amsterdam : modélisation du dimorphisme sexuel.. In: Revue d'Archéométrie, n°25, 2001. pp. 157-177

A single Mediterranean meal does not impair postprandial flow-mediated dilatation in healthy men with sub-clinical metabolic dysregulations

Introduction: Cardiovascular risk factors are known to exacerbate high-saturated fatty acid meal (HSFAM)-induced endothelial dysfunction but the influence of sub-clinical metabolic dysregulations and the acute impact of a single mixed Mediterranean-type meal (MMM) remains unknown and could especially benefit such individuals. Thus, this study has the objective to evaluate the metabolic and vascular effect of such meals in healthy subjects with or without sub-clinical fasting metabolic dysregulations. Material and Methods: Twenty-eight (28) healthy males without overt cardiovascular risk factors randomly ingested one of two isocaloric meals on separate days. Plasma metabolic markers, fatty acid (FA) profile and endothelial function (Flow-mediated dilatation; FMD) were assessed at baseline and 2 and 4 hours after meal ingestion. Unsupervised hierarchical clustering identified two subgroups of participants (n=11 and 17) differing by their baseline metabolic profiles. Results: The MMM did not significantly alter postprandial endothelial function in all subjects, irrespectively of baseline metabolic parameters. In contrast, the HSFAM induced postprandial endothelial dysfunction (Î %FMDabsolute = -5.28 Âą 2.54, p-valueThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Angiopoietin-like 2 is essential to aortic valve development in mice

Aortic valve (AoV) abnormalities during embryogenesis are a major risk for the development of aortic valve stenosis (AVS) and cardiac events later in life. Here, we identify an unexpected role for Angiopoietin-like 2 (ANGPTL2), a pro-inflammatory protein secreted by senescent cells, in valvulogenesis. At late embryonic stage, mice knocked-down for Angptl2 (Angptl2-KD) exhibit a premature thickening of AoV leaflets associated with a dysregulation of the fine balance between cell apoptosis, senescence and proliferation during AoV remodeling and a decrease in the crucial Notch signalling. These structural and molecular abnormalities lead toward spontaneous AVS with elevated trans-aortic gradient in adult mice of both sexes. Consistently, ANGPTL2 expression is detected in human fetal semilunar valves and associated with pathways involved in cell cycle and senescence. Altogether, these findings suggest that Angptl2 is essential for valvulogenesis, and identify Angptl2-KD mice as an animal model to study spontaneous AVS, a disease with unmet medical need

NTPDase1 (CD39) controls nucleotide-dependent vasoconstriction in mouse.

AIMS: Extracellular nucleotides are vasoactive molecules. The concentrations of these molecules are regulated by ectonucleotidases. In this study, we investigated the role of the blood vessel ectonucleotidase NTPDase1, in the vasoconstrictor effect of nucleotides using Entpd1(-/-) mice. METHODS AND RESULTS: Immunofluorescence, enzyme histochemistry, and HPLC analysis were used to evaluate both NTPDase expression and activity in arteries and isolated vascular smooth muscle cells (VSMCs). Vascular reactivity was evaluated in vitro and mean arterial blood pressure was recorded in anesthetized mice after nucleotide i.v. infusion. Expression of nucleotide receptors in VSMCs was determined by RT-PCR. Entpd1(-/-) mice displayed a dramatic deficit of nucleotidase activity in blood vessel wall in situ and in VSMCs in comparison to control mice. In aortic rings from Entpd1(-/-) mice, UDP and UTP induced a potent and long-lasting constriction contrasting with the weak response obtained in wild-type rings. This constriction occurred through activation of P2Y(6) receptor and was independent of other uracil nucleotide-responding receptors (P2Y(2) and P2Y(4)). UDP infusion in vivo increased blood pressure and this effect was potentiated in Entpd1(-/-) mice. In addition, pressurized mesenteric arteries from Entpd1(-/-) mice displayed an enhanced myogenic response, consistent with higher local concentrations of endogenously released nucleotides. This effect was inhibited by the P2 receptor antagonist RB-2. CONCLUSION: NTPDase1 is the major enzyme regulating nucleotide metabolism at the surface of VSMCs and thus contributes to the local regulation of vascular tone by nucleotides.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe