Insulino-résistance et vieillissement cardiovasculaire (un traitement chronique par le resvératrol peut-il les améliorer ?)

Le vieillissement de la population est le résultat de l amélioration de la prise en charge des individus, en particulier des sujets âgés, conduisant à l apparition d une nouvelle catégorie démographique, le quatrième âge avec les plus de 75 ans. Cette population polypathologique présente de nombreuses spécificités, avec entre autres, une intolérance au glucose, un état de dénutrition et une altération des fonctions cardiovasculaires, les maladies cardiovasculaires restant la première cause de mortalité dans cette tranche d âge. Comme évoqué dès les années 50 par Harman, le stress oxydant pourrait jouer un rôle important dans l ensemble de ces comorbidités. Le resvératrol, un polyphénol anti-oxydant connu pour ses biens-faits cardiovasculaires pourrait ainsi être une molécule d intérêt dans ce contexte. Nos objectifs dans ce travail ont donc été d évaluer les effets d un traitement chronique par le resvératrol accompagné ou non d une prise en charge nutritionnelle chez la souris très âgée. Ces effets du resvératrol ont été étudiés aussi bien sur le plan métabolique que sur le phénotype cardiovasculaire. Nos résultats montrent qu un régime riche en protéines et pauvre en glucides a des effets variables en fonction de l âge. Sans effet sur la souris jeune, il devient délétère chez la souris adulte et très âgée avec une majoration de l altération de l homéostasie glucidique associée à une détérioration du bilan lipidique. Ces dysrégulations métaboliques ont pour conséquence une dégradation accrue des fonctions artérielles et cardiaques. Chez la souris très âgée, un traitement par le resvératrol amplifie les dommages liés à ce régime en accentuant les altérations métaboliques et cardiovasculaires, soulignant, et ce pour la première fois, de potentiels effets délétères du resvératrol dans le cadre du vieillissement. En revanche, chez la souris âgée dénutrie en l absence de prise en charge nutritionnelle, le resvératrol présente des effets bénéfiques avec une amélioration de l insulino-sensibilité et des fonctions artérielles, associée à une modification d expression de TXNIP, protéine à l interface de la régulation de l homéostasie du glucose et de la balance oxydative, faisant d elle une piste à explorer tant pour expliquer certains mécanismes impliqués dans le vieillissement que dans les effets du resvératrol.The aging of the population is the result of the improvement of the care of individuals, especially the elderly, leading to the emergence of a new demographic category, the fourth age with people more than 75 years old. This polypathological population has many specificities, with among other things, glucose intolerance, a state of malnutrition and impaired cardiovascular function. Cardiovascular disease remains the leading cause of death in this age group. As mentioned in the 50s by Harman, oxidative stress may play an important role in all of these diseases. Resveratrol, an antioxidant polyphenol known for its properties on cardiovascular events could thus be a molecule of interest in this context. Our objectives in this study were therefore to assess the effects of chronic treatment with resveratrol with or without a nutritional care in the very old mice. These metabolic and cardiovascular effects of resveratrol have been studied. Our results show that a high protein and low carbohydrate diet has different effects depending on age. Despite no effect have been observed on young mice, this diet becomes deleterious in adult and very old mice with an increase of impaired glucose homeostasis associated with a deterioration of the lipid profile. These metabolic dysregulations result in a further deterioration of arterial and cardiac function. In the very old mice, treatment with resveratrol boosts the damage related to this plan by increasing the metabolic and cardiovascular alterations, highlighting, for the first time, potential deleterious effects of resveratrol in aging. However, in elderly malnourished mice in the absence of nutritional care, resveratrol has beneficial effects with improved insulin sensitivity and arterial functions associated with altered expression of TXNIP, protein regulating glucose homeostasis and oxidative balance, making it worth exploring as to explain some of the mechanisms involved in aging and in the effects of resveratrol.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

La démence fronto-temporale (de la notion de démence à la prise en charge multidisciplinaire)

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude des polymorphismes du gène de la catalase dans la dénutrition des sujets âgés

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude des effets protecteurs du trans-resvératrol sur les lésions induites par une ischémie-reperfusion hépatique chez le rat

Liver ischemia-reperfusion (IR) occurs in many clinical conditions; including liver surgery and transplantation. Early phase of reprfusion is associated with excessive production of reactive oxygen species and proinflammatory cytokines. We investigated the effects of trans-resveratrol (T-res) (molecule reported to have multiple effects, of wich antioxidant and antiinflammatory properties) on liver injury induced by IR. After 1 hour of ischemia, administered 5 minutes prior to 3 hours of reperfusion, T-res was hepatoprotective at low doses (0.2 and 0.02 mg/Kg) by decreasing plasmatic aminotransferase levels and improving sinusoidal dilatation. T-res preserved antioxidant defense by preventing total and reduced glutathion depletion caused by IR. At 0.2 mg/kg, T-res significantly increased glutathione reductase, Cu/Zn superoxide dismutase, and catalase activities. We also found that T-res, at low doses (0.02 and 0.2 mg/Kg) was able to decrease IL-1b and TNF-a hepatic mRNA expression induced by IR, with a reduction in plasma concentrations of IL-6 and IL-1b. T-res did not modify mRNA and protein expression of NOS III, DDAH activity or plasma concentrations of nitrites. NOSII protein or mRNA were undetected after IR or after T-res treatment. T-res decreased HO1 transcription without altering HSP-70 transcription induced by hepatic IR. In conclusion, a prereperfusion treatment by T-res only at low doses decreases liver injury induced by IR by protecting against antioxidant defense failure and by inhibiting proinflammatory cytokines induction. Our data present T-res as a molecule with potential therapeutic use against lesions secondary to liver surgery or hepatic allograftLiver ischemia-reperfusion (IR) occurs in many clinical conditions; including liver surgery and transplantation. Early phase of reprfusion is associated with excessive production of reactive oxygen species and proinflammatory cytokines. We investigated the effects of trans-resveratrol (T-res) (molecule reported to have multiple effects, of wich antioxidant and antiinflammatory properties) on liver injury induced by IR. After 1 hour of ischemia, administered 5 minutes prior to 3 hours of reperfusion, T-res was hepatoprotective at low doses (0.2 and 0.02 mg/Kg) by decreasing plasmatic aminotransferase levels and improving sinusoidal dilatation. T-res preserved antioxidant defense by preventing total and reduced glutathion depletion caused by IR. At 0.2 mg/kg, T-res significantly increased glutathione reductase, Cu/Zn superoxide dismutase, and catalase activities. We also found that T-res, at low doses (0.02 and 0.2 mg/Kg) was able to decrease IL-1b and TNF-a hepatic mRNA expression induced by IR, with a reduction in plasma concentrations of IL-6 and IL-1b. T-res did not modify mRNA and protein expression of NOS III, DDAH activity or plasma concentrations of nitrites. NOSII protein or mRNA were undetected after IR or after T-res treatment. T-res decreased HO1 transcription without altering HSP-70 transcription induced by hepatic IR. In conclusion, a prereperfusion treatment by T-res only at low doses decreases liver injury induced by IR by protecting against antioxidant defense failure and by inhibiting proinflammatory cytokines induction. Our data present T-res as a molecule with potential therapeutic use against lesions secondary to liver surgery or hepatic allograftPARIS-BIUP (751062107) / SudocSudocFranceF

The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

International audienceThioredoxin interacting protein (TXNIP) is a metabolism-oxidative-and inflammationrelated marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases

Le resvératrol peut-il par son effet anti-oxydant protéger contre le vieillissement ?

International audienceD'après la théorie de Harman, le vieillissement vasculaire est dû notamment au stress oxydant, déséquilibre entre les systèmes anti-oxydants et pro-oxydants de l'organisme. L'accumulation de collagène et la calcification artérielle engendrées vont conduire à la formation de plaques d'athéromes et à l'artériosclérose. Les vaisseaux vont alors se rigidifier et s'épaissir. L'un des systèmes oxydants est l'enzyme NADPH-oxydase, comprenant la sous-unité p47phox. La thiorédoxine, quant à elle, est une enzyme anti oxydante. Dans cette étude, afin de prévenir la dégradation vasculaire, le resvératrol, polyphénol retrouvé en quantité notable dans le vin, est administré à des souris. Des données d'épaisseur, de distensibilité, de concentration en collagène et en calcium ainsi que les quantités de p47phox et de thiorédoxine sont étudiés au niveau de l'aorte. La comparaison entre des souris jeunes et des souris âgées ne recevant aucun traitement permet d'observer, lors d'un vieillissement aortique physiologique, une augmentation de l'épaisseur, une diminution de la distensibilité, une augmentation des teneurs en collagène et en calcium associés à une augmentation de la concentration en NADPH-oxydase et une diminution de celle de la thiorédoxine. D'après cette étude, le resvératrol permettrait de diminuer la concentration en p47phox et donc de diminuer le stress oxydant, sans pour autant influer sur la concentration en thiorédoxine. Les souris âgées traitées par resvératrol ont également, au niveau aortique, une épaisseur non-augmentée, une distensibilité conservée et une concentration en collagène inchangée par rapport aux souris jeunes. Le polyphénol ne semble pas influer sur la concentration aortique en calcium. Le resvératrol semble donc être une piste intéressante pour la prévention du vieillissement vasculaire

Relationship between catalase haplotype and arterial aging

International audienceBackgroundAlthough many conventional factors have been associated with the development of arterial aging, cardiovascular diseases remain the first cause of death in old age. Therefore, identification of new risk factors may prove promising for monitoring this serious health problem. Oxidative stress and particularly catalase (CAT), an antioxidant enzyme, play an important role in endothelial cell pathophysiology, in shear stress response and ultimately in arterial aging.ObjectiveExamine the relationships between CAT haplotypes and phenotypes of arterial aging (mean internal diameter, mean intima–media thickness of the common carotid arteries (CCA), presence of atheromatous plaques) in two French cohorts.Methods and results564 middle-aged French individuals (mean age 53 ± 12 years) from two cohorts (ERA and STANISLAS cohorts) were included in the study. Blood pressure, CCA intima–media thickness, CCA internal diameter and number of atheromatous plaques were measured. Catalase rs769214 SNP genotyping was performed. We identified a CAT haplotype that influences arterial aging. Individuals carrying the CAT2 haplotype had a higher mean internal diameter of CCA with aging and/or with an SBP ≥140 mmHg and were associated with a greater number of atheromatous plaques than CAT1 haplotypes carriers. This CAT2 haplotype appeared as an independent risk factor of arterial aging, similarly to previously identified factors such as age, systolic blood pressure, male, sex, tobacco use, hs-CRP, BMI and diabetes.ConclusionThe present study highlights the roles of CAT haplotypes in arterial aging and underlines the beneficial impact of the CAT1 haplotype on mean internal diameter of the CCA and atheromatous plaque number as well as on potential associated diseases

Resveratrol metabolism in a non-human primate, the grey mouse lemur (Microcebus murinus), using ultra-high-performance liquid chromatography-quadrupole time of flight.

The grey mouse lemur (Microcebus murinus) is a non-human primate used to study the ageing process. Resveratrol is a polyphenol that may increase lifespan by delaying age-associated pathologies. However, no information about resveratrol absorption and metabolism is available for this primate. Resveratrol and its metabolites were qualitatively and quantitatively analyzed in male mouse-lemur plasma (after 200 mg.kg-1 of oral resveratrol) by ultra-high performance liquid chromatography (UHPLC), coupled to a quadrupole-time-of-flight (Q-TOF) mass spectrometer used in full-scan mode. Data analyses showed, in MSE mode, an ion common to resveratrol and all its metabolites: m/z 227.072, and an ion common to dihydro-resveratrol metabolites: m/z 229.08. A semi-targeted study enabled us to identify six hydrophilic resveratrol metabolites (one diglucurono-conjugated, two monoglucurono-conjugated, one monosulfo-conjugated and two both sulfo- and glucurono-conjugated derivatives) and three hydrophilic metabolites of dihydro-resveratrol (one monoglucurono-conjugated, one monosulfo-conjugated, and one both sulfo- and glucurono-conjugated derivatives). The presence of such metabolites has been already detected in the mouse, rat, pig, and humans. Free resveratrol was measurable for several hours in mouse-lemur plasma, and its two main metabolites were trans-resveratrol-3-O-glucuronide and trans-resveratrol-3-sulfate. Free dihydro-resveratrol was not measurable whatever the time of plasma collection, while its hydrophilic metabolites were present at 24 h after intake. These data will help us interpret the effect of resveratrol in mouse lemurs and provide further information on the inter-species characteristics of resveratrol metabolism

Pre-Hospital Lactatemia Predicts 30-Day Mortality in Patients with Septic Shock-Preliminary Results from the LAPHSUS Study

International audienceBackground: Assessment of disease severity in patients with septic shock (SS) is crucial in determining optimal level of care. In both pre- and in-hospital settings, the clinical picture alone is not sufficient for assessing disease severity and outcomes. Because blood lactate level is included in the clinical criteria of SS it should be considered to improve the assessment of its severity. This study aims to investigate the relationship between pre-hospital blood lactate level and 30-day mortality in patients with SS. Methods: From 15 April 2017 to 15 April 2019, patients with SS requiring pre-hospital Mobile Intensive Care Unit intervention (MICU) were prospectively included in the LAPHSUS study, an observational, non-randomized controlled study. Pre-hospital blood lactate levels were measured at the time of first contact between the patients and the MICU. Results: Among the 183 patients with septic shock requiring action by the MICU drawn at random from LAPHSUS study patients, six (3%) were lost to follow-up on the 30th day and thus 177 (97%) were analyzed for blood lactate levels (mean age 70 ± 14 years). Pulmonary, urinary and digestive infections were probably the cause of the SS in respectively 58%, 21% and 11% of the cases. The 30-day overall mortality was 32%. Mean pre-hospital lactatemia was significantly different between patients who died and those who survived (respectively 7.1 ± 4.0 mmol/L vs. 5.9 ± 3.5 mmol/L, p < 10−3). Using Cox regression analysis adjusted for potential confounders we showed that a pre-hospital blood lactate level ≥ 4 mmol/L significantly predicted 30-day mortality in patients with SS (adjusted hazard ratio = 2.37, 95%CI (1.01–5.57), p = 0.04). Conclusion: In this study, we showed that pre-hospital lactatemia predicts 30-day mortality in patients with septic shock handled by the MICU. Further studies will be needed to evaluate if pre-hospital lactatemia alone or combined with clinical scores could affect the triage decision-making process for those patients