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Branched fatty acid esters of hydroxy fatty acids are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Recently, we showed that 9-palmitic acid esters of hydroxypalmitic acid (9-PAHPA) and 9-oleic acid esters of hydroxypalmitic acid increased insulin sensitivity in mice when incorporated to a chow diet or to a high fat and high sucrose diet. However, preventive supplementation with 9-PAHPA and 9-oleic acid esters of hydroxypalmitic acid in high fat and high sucrose diet mice did not impair significant weight gain or the development of hyperglycemia. The aim of this work was therefore to study whether in two animal models of obesity, namely the classical diet-induced obesity (DIO) and the db/db mice, 9-PAHPA may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. In DIO mice, we observed that 9-PAHPA increased body weight and fat mass. In line with this observation, we found that 9-PAHPA supplementation decreased energy expenditure. In liver and in skeletal muscle, mitochondrial activities and oxidative stress parameters were not modified by 9-PAHPA supplementation. In db/db mice, 9-PAHPA had no effect on the dramatic weight gain and hyperglycemia. In addition, 9-PAHPA supplementation did not correct either the hepatomegaly and hepatic steatosis or the severe muscle atrophy recorded compared with db/+ animals. Likewise, supplementation with 9-PAHPA did not impact the different metabolic parameters analyzed, either in the liver or in the skeletal muscles. However, it decreased insulin resistance in DIO and db/db mice. In conclusion, our study indicated that a long-term intake of 9-PAHPA in DIO and db/db mice improved insulin sensitivity but had only few effects on obesity and associated metabolic disorders.

Palm olein (PO) and olive oil (OO) are widely consumed in the world. PO is considered harmful to health, whereas OO is considered healthy. The aim of the study was to compare the effects of consumption of these oils on antioxidant status and inflammation in rats. This was an experimental study in male wistar rats fed a diet containing 30% of each oil. Rats had free access to food and water. After being fed for 12 weeks, animals were sacrificed and liver and aortic blood were collected. Plasma was used for the determination of interleukin-6 (IL-6) and oxidative stress parameters (Superoxide dismutase -SOD; Gluthation peroxidase - GPx; Thiobarbituric acid reactive substances - TBARS; Thiol groups and isoprostane). The inflammation and oxidative stress status as well as the expression of several genes/proteins were also analyzed in liver homogenate. No significant differences were observed between PO and OO in plasma and liver levels of the studied inflammation and oxidative stress parameters. This study showed that the consumption of PO induces an antioxidant status superimposable to that of OO. Key words : Palm olein - Olive oil - Oxidative stress - Inflammation - High fat diet

International audience; Furan fatty acids (FuFAs) are a group of fatty acids containing a furan ring on their aliphatic chain. They are present in small quantities in plants, microorganisms, and animals. The biosynthesis of FuFAs in plants and microorganisms is not fully described and their presence in animals is thought to be exclusively due to food with a high concentration in seafood products, which are themselves consumed by humans. The presence of the furan cycle makes FuFAs highly reactive with reactive oxygen derivatives. The three major biological effects of FuFAs are antioxidant, antimicrobial and anti-inflammatory. More specific studies on health effects have been conducted in recent years: FuFAs and their catabolic degradation products (e.g. CMPF) may influence lipid metabolism, insulin resistance and diabetes, cardiovascular diseases, and neurodegenerative diseases. FuFAs could thus be biomarkers of exposure to a healthy, seafood-rich diet, and also bioactive compounds in our diet capable of modulating signalling pathways with potential beneficial effects against metabolic disorders associated with a Western-style diet.

Overweight and obesity adversely affect health-related quality of life (HRQOL) through day-to-day impairments of both mental and physical functioning. It is assumed that polyphenols within the Mediterranean diet may contribute to improving HRQOL. This investigation aimed at studying the effects of a polyphenol-rich ingredient on HRQOL in overweight and obese but otherwise healthy individuals. A randomized, double-blind, placebo-controlled study including 72 volunteers was conducted. Subjects were randomly assigned to receive for a 16-week period either 900 mg/day of the supplement or a placebo. Dietary recommendations were individually determined and intakes were recorded. Daily physical mobility was also monitored. Improvement of HRQOL was set as the primary outcome and assessed at baseline and at the end of the investigation using the Short-Form 36 (SF-36) health survey. Body composition was analyzed using dual-energy X-ray absorptiometry (DXA). Physical activity was calculated using the International Physical Activity Questionnaire (IPAQ). After 16 weeks, despite there being no adherence to the Mediterranean Diet Serving Score (MDSS), supplemented individuals experienced significant HRQOL improvement (+5.3%, p = 0.001), including enhanced perceived physical (+11.2%, p = 0.002) and mental health (+4.1%, p = 0.021) components, with bodily pain, vitality, and general health being the greatest contributors. Body fat mass significantly decreased (−1.2 kg, p = 0.033), mainly within the trunk area (−1.0 kg, p = 0.002). Engagement in physical activity significantly increased (+1308 Met-min (Metabolic Equivalent Task minutes)/week, p = 0.050). Hence, chronic supplementation with nutritional diversity and dosing of a Mediterranean diet-inspired, polyphenol-rich ingredient resulted in significant amelioration in both perceived physical and mental health, concomitant with the improvement of body composition, in healthy subjects with excessive adiposity.

Overweight and obesity adversely affect health-related quality of life (HRQOL) through day-to-day impairments of both mental and physical functioning. It is assumed that polyphenols within the Mediterranean diet may contribute to improve HRQOL. This investigation aimed at studying the effects of a polyphenol-rich ingredient on HRQOL in overweight and obese but otherwise healthy individuals. A randomized, double-blind, placebo-controlled study including 72 volunteers was conducted. Subjects were randomly assigned to receive for a 16-week period either 900 mg/day of the supplement or a placebo. Dietary recommendations were individually determined, and intakes were recorded; daily physical mobility was monitored. Improvement of HRQOL was set as the primary outcome and assessed at baseline and at the end of the investigation, using the Short-Form 36 (SF-36) Health survey. Body composition was analyzed using dual-energy X-ray absorptiometry (DXA). Physical activity level was calculated using International Physical Activity Questionnaire (IPAQ). After 16 weeks, despite there was no adherence to the Mediterranean Diet Serving Score (MDSS), supplemented individuals experienced significant HRQOL improvement (+5.3%; P=0.001), including enhanced perceived physical (+11.2%; P=0.002) and mental health (+4.1%; P=0.021) components; bodily pain, vitality, and general health, being the greatest contributors. Besides, body fat mass significantly decreased (-1.2 kg; P=0.033), mainly within trunk area (-1.0 kg; P=0.002). Engagement in physical activity significantly increased (+1308 Met-min/week; P=0.050). Hence, chronic supplementation with a nutritional diversity and dose of a Mediterranean diet-inspired polyphenol-rich ingredient resulted in a significant amelioration in both perceived physical and mental health, concomitant with the improvement of body composition, in healthy subjects with excessive adiposity.

Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Since skeletal muscle is a major target for insulin, the aim of this study is to explore for the first time the influence of several FAHFAs in C2C12 myoblasts and in skeletal muscle phenotype in mice. Here, we show that eleven FAHFAs belonging to different families inhibit C2C12 myoblast proliferation. In addition, all FAHFAs decreased mitochondrial cytochrome c oxidase activity without affecting reactive oxygen species production and the mitochondrial network. During C2C12 myoblasts differentiation, we found that two of the most active lipids, 9-PAHPA and 9-OAHPA, did not significantly affect the fusion index and the expression of myosin heavy chains. However, we found that three months&rsquo, intake of 9-PAHPA or 9-OAHPA in mice increased the expression of more oxidative myosin in skeletal muscle without affecting skeletal muscle mass, number, and mean fiber area, mitochondrial activity, and oxidative stress parameters. In conclusion, our study indicated that the eleven FAHFAs tested decreased the proliferation rate of C2C12 myoblasts, probably through the inhibition of mitochondrial activity. In addition, we found that 9-PAHPA or 9-OAHPA supplementation in mice induced a switch toward a more oxidative contractile phenotype of skeletal muscle. These data suggest that the increase in insulin sensitivity previously described for these two FAHFAs is of muscular origin.

Introduction et but de l’etude Les FAHFAs, des acides gras esterifies par des acides gras hydroxyles, sont une famille de lipides endogenes bioactifs. A ce jour, la plupart des FAHFAs ramifies etudies sont des regioisomeres du PAHSA qui auraient une activite antidiabetique et anti-inflammatoire chez l’Homme et les rongeurs. Recemment, nous avons demontre que la prise de 9-PAHPA ou de 9-OAHPA augmentait le metabolisme basal et la sensibilite a l’insuline chez des souris C57BL/6 nourries avec un regime controle, mais qu’elle provoquait des lesions hepatiques chez certaines souris. Cette etude vise a determiner si un apport a long terme de 9-PAHPA ou de 9-OAHPA a les memes effets chez les souris nourries avec un regime obesogene. Materiel et methodes Des souris C57BL/6 ont ete nourries pendant douze semaines soit avec un regime temoin soit avec un regime riche en graisse et en sucre (HFHS) et supplemente ou non en 9-PAHPA ou 9-OAHPA. Le metabolisme basal a ete explore. Le metabolisme du glucose et des lipides ainsi que l’activite mitochondriale et le stress oxydant ont ete analyses. Resultats et analyse statistique La consommation du regime HFHS a induit une obesite, une resistance a l’insuline et une hyperglycemie a jeun, sans effets majeurs sur les parametres hepatiques. Le 9-PAHPA ou le 9-OAHPA a module le metabolisme basal et a ameliore la sensibilite a l’insuline. Contrairement a ce que nous avons observe precedemment chez des souris saines, aucun effet deletere de ces FAHFAs n’a ete observe sur le foie des souris obeses. Conclusion Ce travail indique que le 9-PAHPA et le 9-OAHPA peuvent tous deux avoir des effets interessants de sensibilisation a l’insuline chez les souris obeses et resistantes a l’insuline.

International audience; Purpose: Fatty acid esters of hydroxy fatty acids (FAHFAs) are a large family of endogenous bioactive lipids. To date, most of the studied FAHFAs are branched regioisomers of Palmitic Acid Hydroxyl Stearic Acid (PAHSA) that were reported to possess anti-diabetic and anti-inflammatory activity in humans and rodents. Recently, we have demonstrated that 9-PAHPA or 9-OAHPA intake increased basal metabolism and enhanced insulin sensitivity in healthy control diet-fed mice but induced liver damage in some mice. The present work aims to explore whether a long-term intake of 9-PAHPA or 9-OAHPA may have similar effects in obesogenic diet-fed mice. Methods: C57Bl6 mice were fed with a control or high fat-high sugar (HFHS) diets for 12 weeks. The HFHS diet was supplemented or not with 9-PAHPA or 9-OAHPA. Whole-body metabolism was explored. Glucose and lipid metabolism as well as mitochondrial activity and oxidative stress status were analyzed. Results: As expected, the intake of HFHS diet led to obesity and lower insulin sensitivity with minor effects on liver parameters. The long-term intake of 9-PAHPA or 9-OAHPA modulated favorably the basal metabolism and improved insulin sensitivity as measured by insulin tolerance test. On the contrary to what we have reported previously in healthy mice, no marked effect for these FAHFAs was observed on liver metabolism of obese diabetic mice. Conclusion: This study indicates that both 9-PAHPA and 9-OAHPA may have interesting insulin-sensitizing effects in obese mice with lower insulin sensitivity.

International audience; This study explored plasma levels and urinary and fecal excretion of metabolites and microbial-derived catabolites over a 24 h period following the ingestion of red wine (RWP) or grape seed (GSP) proanthocyanidin-rich extracts by rats. In total, 35 structurally-related (epi)catechin metabolites (SREMs) and 5-carbon side chain ring fission metabolites (5C-RFMs) (phenyl-γ-valerolactones and phenylvaleric acids), and 50 phenolic acid and aromatic catabolites were detected after intakes of both extracts. The consumption of the RWP extract, but not the GSP extract, led to the appearance of a ∼200 nmol L-1 peak plasma concentration of SREMs formed from flavan-3-ol monomers. In contrast, ingestion of the GSPs, but not the RWPs, resulted in a substantial increase in microbiota-derived 5-carbon side chain ring fission metabolites (5C-RFMs) in plasma. 5C-RFMs, along with low molecular weight phenolic catabolites were detected in urine after ingestion of both extracts. The GSP and RWP extracts had respective mean degrees of polymerisation 5.9 and 6.5 subunits, and the RWP extract had an upper polymer size of 21 subunits compared to 44 subunits for the GSP extract. The differences in plasma metabolite profiles might, therefore, be a consequence of this polydispersity impacting on the microbiota-mediated rates of cleavage of the proanthocyanidin subunits and their subsequent metabolism and absorption. Urinary excretion of phenolic catabolites indicated that 11% of RWPs and 7% for GSPs were subjected to microbial degradation. In all probability these figures, rather than representing the percentage of proanthocyanidins that are completely degraded, indicate partial cleavage of monomer subunits producing a much higher percentage of shortened proanthocyanidin chains. Obtaining more detailed information on the in vivo fate of proanthocyanidins is challenging because of the difficulties in analysing unabsorbed parent proanthocyanidins and their partially degraded flavan-3-ol subunit chains in feces. Further progress awaits the development of improved purification and analytical techniques for proanthocyanidins and their use in feeding studies, and in vitro fecal and bacterial incubations, with radio and/or stable isotope-labelled substrates.

International audience; Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a new family of endogenous lipids recently discovered. Several studies reported that some FAHFAs have antidiabetic and anti-inflammatory effects. The objective of this study was to explore the impact of two FAHFAs, 9-PAHPA or 9-OAHPA, on the metabolism of mice. C57Bl/6J male mice, 6 weeks old, were divided into 3 groups of 10 mice each. One group received a control diet and the two others groups received the control diet supplemented with 9-PAHPA or 9-OAHPA for 12 weeks. Mouse weight and body composition were monitored throughout the study. Some days before euthanasia, energy expenditure, glucose tolerance and insulin sensitivity were also determined. After sacrifice, blood and organs were collected for relevant molecular, biochemical and histological analyses. Although high intake of 9-PAHPA or 9-OAHPA increased basal metabolism, it had no direct effect on body weight. Interestingly, the 9-PAHPA or 9-OAHPA intake increased insulin sensitivity but without modifying glucose tolerance. Nevertheless, 9-PAHPA intake induced a loss of glucose-stimulated insulin secretion. Surprisingly, both studied FAHFAs induced hepatic steatosis and fibrosis in some mice, which were more marked with 9-PAHPA. Finally, a slight remodeling of white adipose tissue was also observed with 9-PAHPA intake. In conclusion, the long-term high intake of 9-PAHPA or 9-OAHPA increased basal metabolism and insulin sensitivity in healthy mice. However, this effect, highly likely beneficial in a diabetic state, was accompanied by manifest liver damage in certain mice that should deserve special attention in both healthy and pathological studies.

High-intensity exercises are known to provoke delayed onset muscle soreness (DOMS). Delayed onset muscle soreness typically occurs within the first 24 h, peaks between 24 and 72 h, and can last as long as 5-7 days post-exercise. Delayed onset muscle soreness is a multifactorial process involving both mechanical and biochemical components, associated with clinical features that may limit range of motion, and athletes seek for effective recovery strategies to optimize future training sessions. TensLess® is a food supplement developed to help manage post-exercise recovery. The supplement has been investigated on 13 recreationally active athletes of both sex, during a randomized, double-blind, and crossover clinical investigation, including a 3-week washout period. The clinical investigation was based on the study of TensLess® effects for DOMS management and on the reduction of associated muscle damages following an eccentric exercise protocol. Supplementation with TensLess® induced significant decrease in DOMS perception (-33%; p = 0.008) as of the first 24 h; this was significantly correlated with a lowered release of muscle damage-associated biomarkers, namely myoglobin, creatinine, and creatine kinase, for the whole length of the recovery period. Taken together, these positive results clearly indicate that post-exercise supplementation with TensLess® may preserve myocytes and reduce soreness following eccentric exercise-induced damages, and, accordingly, significantly shorten muscle recovery. Copyright © 2017 John Wiley & Sons, Ltd.

International audience; Inflammation and oxidative stress are thought to be involved in, or associated with, the development of obesity, dyslipidemia, hepatic steatosis, and insulin resistance. This work was designed to determine the evolution of inflammation and oxidative stress during onset and progression of hepatic steatosis and glucose intolerance. Seventy-five male Wistar rats were divided to control and high-fat high-fructose (HFHFr) groups. A subgroup of each group was sacrificed at 4, 8, 12, 16, and 20 weeks. HFHFr-fed rats exhibited overweight, glucose intolerance, and hepatic steatosis with increased contents of hepatic diacylglycerols and ceramides. The HFHFr diet increased hepatic interleukin 6 (IL-6) protein and adipose tissue CCL5 gene expression and hepatic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity but not mitochondrial reactive oxygen species (ROS) production. The HFHFr diet decreased plasma and liver levels of isoprostanoid metabolites as well as plasma thiobarbituric acid-reactive substance (TBARS) levels. Hepatic glutathione content was decreased with a moderate decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) with the HFHFr diet. Overall, HFHFr diet led to hepatic lipid accumulation and glucose intolerance, which were accompanied by only moderate inflammation and oxidative stress. Most of these changes occurred at the same time and as early as 8 or 12 weeks of diet treatment. This implies that oxidative stress may be the result, not the cause, of these metabolic alterations, and suggests that marked hepatic oxidative stress should probably occur at the end of the steatotic stage to result in frank insulin resistance and steatohepatitis. These findings need to be further evaluated in other animal species as well as in human studies.

Metabolic syndrome components, including obesity, dyslipidemia and impaired glucose homeostasis, become a major public health issue. Muscles play a predominant role in insulin-mediated glucose uptake, and high fat diets may negatively affect muscle function and homeostasis. This work aimed to study the time-course of muscle lipid accumulation, oxidative stress and mitochondrial dysfunction and their association to impaired glucose homeostasis in rats fed an obesogenic diet. Male Wistar rats were fed with a standard or a high fat/high fructose (HFHFr) diet and sacrificed on 4, 8, 12, 16, 20 weeks. Rats fed the HFHFr diet developed mild overweight, increased liver and adipose tissue weights and glucose intolerance. The impaired glucose homeostasis increased gradually with the HFHFr diet to become significant on the 12th and 16th weeks of diet. In parallel, the muscle lipid composition showed an increase in the saturated fatty acids and the monounsaturated fatty acids with a marked decrease in the polyunsaturated fatty acids. The HFHFr diet also increased muscle contents of both diacylglycerols and Ceramides. Surprisingly, HFHFr diet did not induce major muscle mitochondrial dysfunction or oxidative stress. These results indicate that muscle lipid alterations, as well as impaired glucose homeostasis occur as early as the 8th week of HFHFr diet, increase to reach a plateau around the 12th-16th weeks of diet, and then attenuate towards the end of study. At these diet treatment durations, muscle mitochondrial activity and oxidative stress remained unchanged and do not seem to have a major role in the observed impaired glucose homeostasis.

International audience; Purpose Palm (PO) and olive oils (OO) are the two most consumed and/or used oils in the world for food elaboration. These oils should not be confused with the solid palm stearin which is widely used in pastry making. Large number of studies was reported dealing with adverse/beneficial cardiovascular effects of PO and OO, whereas few studies were conducted to compare their potential effects on hepatic steatosis and liver lipid metabolism. The aim of this study was to compare the metabolic effects of high intake of POs (both crude and refined) and virgin OO on surrogate parameters of glucose tolerance, hepatic lipid metabolism and liver integrity. Methods Thirty-two young male Wistar rats were divided into four equal groups and fed either control diet (11% energy from fat) or three high-fat diets rich in crude or refined POs or in OO (56% energy from fat), during 12 weeks. Systemic blood and liver biochemical parameters linked to glucose and lipid metabolism as well as hepatic steatosis and liver fatty acid composition were explored. The inflammation and oxidative stress status as well as the expression of several genes/proteins were also analyzed. ResultsThe major effects of POs intake concerned glucose metabolism and liver fatty acid composition, whereas the major effects of OO intake concerned hepatic TG accumulation, inflammation, and cytolysis. Conclusions In conclusion, high dietary intake of PO compromises glucose tolerance whereas high dietary intake of OO compromises hepatic lipid composition and liver integrity. However, adverse hepatic effects of OO observed in this study may not be transposed to human since, (a) the rodent model could lead to different effects than those observed in humans and (b) the average normal OO amounts ingested in the population are lower than those corresponding to a high-fat diet. So, further studies are needed to determine a maximum non-invasive dietary intake of OO.

The development of nutraceutical ingredients has risen as a nutritional solution for health prevention. This study evaluated the effects of Oleactiv&reg, an ingredient developed for the prevention of atherogenesis, in hypercholesterolemic hamsters. Oleactiv&reg, is a polyphenol-rich ingredient obtained from artichoke, olive and grape extracts as part of fruit and vegetables commonly consumed within the Mediterranean diet. A total of 21 Golden Syrian hamsters were divided into three groups. The standard group (STD) was fed a normolipidemic diet for 12 weeks, while the control group (CTRL) and Oleactiv&reg, goup (OLE) were fed a high-fat diet. After sacrifice, the aortic fatty streak area (AFSA), plasmatic total cholesterol (TC), high-density lipoproteins (HDL-C), non-HDL-C and triglycerides (TG), were assessed. The cholesterol efflux capacity (CEC) of hamster plasma was quantified using a radiolabeled technique in murine macrophages J774. OLE administration induced a significant reduction of AFSA (&minus, 69%, p &lt, 0.0001). Hamsters of the OLE group showed a significant decrease of both non-HDL-C (&minus, 173 mmol/L, p &lt, 0.05) and TG (&minus, 154 mmol/L, p &lt, 0.05). Interestingly, OLE induced a significant increase of total CEC (+17,33%, p &lt, 0,05). Oleactiv&reg, supplementation prevented atheroma development and had positive effects on the lipid profile of hypercholesterolemic hamsters. The increased CEC underlines the anti-atherosclerotic mechanism at the root of the atheroma reduction observed.

The incidence of obesity and its metabolic complications are rapidly increasing and become a major public health issue. This trend is associated with an increase in the prevalence of non-alcoholic fatty liver disease (NAFLD), insulin resistance and diabetes. The sequence of events leading to NAFLD progression and mitochondrial dysfunction and their interrelation remains to be elucidated. This study aimed to explore the installation and progression of NAFLD and its association with the liver mitochondrial structure and activity changes in rats fed an obesogenic diet up to 20 weeks. Male Wistar rats were fed either a standard or high-fat–high-fructose (HFHFR) diet and killed on 4, 8, 12, 16 and 20 weeks of diet intake. Rats fed the HFHFR diet developed mildly overweight, associated with increased adipose tissue weight, hepatic steatosis, hyperglycaemia and hyperinsulinaemia after 8 weeks of HFHFR diet. Hepatic steatosis and many biochemical modifications plateaued at 8–12 weeks of HFHFR diet with slight amelioration afterwards. Interestingly, several biochemical and physiological parameters of mitochondrial function, as well as its phospholipid composition, in particular cardiolipin content, were tightly related to hepatic steatosis installation. These results showed once again the interrelation between hepatic steatosis development and mitochondrial activity alterations without being able to say whether the mitochondrial alterations preceded or followed the installation/progression of hepatic steatosis. Because both hepatic steatosis and mitochondrial alterations occurred as early as 4 weeks of diet, future studies should consider these four 1st weeks to reveal the exact interconnection between these major consequences of obesogenic diet intake.

This study developed, optimized and validated an ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) method to identify and quantify metabolites and microbial-derived catabolites in urine, plasma and feces of rats following ingestion of 50 mg of a red wine proanthocyanidin-rich extract. The method was validated for specificity, linearity, limit of detection (LD) and quantification (LQ), intra-day and inter-day precision, recovery and matrix effects, which were determined for 34 compounds in the three biological matrices. After method validation, three parent flavan-3-ols, four 5-carbon side chain ring fission metabolites, and 27 phenolic acid and aromatic catabolites were quantified in plasma, urine and feces after red wine proanthocyanidin intake. These results establish the value of the UHPLC-HRMS protocol in obtaining a detailed picture of proanthocyanidin metabolites and their microbial-derived catabolites, along with their phase II metabolites, in biological fluids of rat, and potentially in human clinical studies designed to evaluate the bioavailability of dietary flavan-3-ols.

Fatty acid hydroxylated fatty acid esters (FAHFAs) are a family of endogenous lipids recently rediscovered by Professor Kahn's team (Yore et al., 2014). Several studies have shown that FAHFAs improve glucose tolerance, sensitivity to and secretion of insulin and have anti-inflammatory effects. FAHFAs are found in blood and many tissues in humans and in rodents, as well as in breast milk and in food. They are synthesized de novo in tissues, however the biosynthesis and degradation pathways of these bioactive lipids are not yet elucidated. Several studies show that the levels of FAHFAs are regulated in mice and humans by physiological and physiopathological conditions such as fasting, obesity and insulin resistance. In this review, we will present the current state of the art concerning FAHFAs and in particular, the biological effects of these bioactive lipids.; Les esters d’acides gras hydroxylés (FAHFAs) sont une famille de lipides endogènes récemment découverts par l’équipe du Pr Kahn (Yore et al., 2014). Plusieurs travaux montrent que les FAHFAs améliorent la tolérance au glucose, la sensibilité à l’insuline et sa sécrétion, et possèdent des effets anti-inflammatoires. Les FAHFAs sont présents dans le sang et dans de nombreux tissus chez l’homme et chez le rongeur, mais également dans le lait maternel et dans les aliments. Les FAHFAs sont synthétisés de novo dans les tissus, cependant leurs voies de biosynthèse et de dégradation ne sont pas élucidées à ce jour. Les taux de FAHFAs dans l’organisme seraient modifiés par des altérations physiologiques et physiopathologiques tels le jeûne, l’obésité et l’insulinorésistance. Dans cette revue, nous ferons un bilan sur l’état des connaissances concernant les FAHFAs et présenterons en particulier les effets biologiques de ces lipides bioactifs connus à l’heure actuelle

International audience; The prevalence of metabolic syndrome components, such as obesity, glucose intolerance and hepatic steatosis, is rapidly increasing and becoming a major issue of public health. The present work was designed to determine the effects of Spirulina platensis (Sp) algae and silicon-enriched Sp on major metabolic syndrome components in obesogenic diet-fed rats. Forty male Wistar rats were divided into 4 groups. Ten rats were fed a control diet and 30 rats were fed a high fat (HF) diet. The HF groups were divided into three groups and supplemented with placebo or Sp or Si-enriched Sp for 12 weeks. Dietary intake and body weight were recorded. Oral glucose tolerance test and surrogate metabolic syndrome (insulin, leptin, adiponectin and lipids), mitochondrial function (enzymatic activity of respiratory chain complexes and β-hydroxyacyl-CoA dehydrogenase), NADPH oxidase activity and several long-established oxidative stress markers were measured in the blood and liver. The HF diet induced obesity, glucose intolerance, hepatic steatosis and huge metabolic alterations, associated with higher NADPH oxidase activity and lower hepatic sulfhydryl group and glutathione contents. Otherwise, the Sp and Sp + Si supplements showed some interesting effects on rat characteristics and particularly on blood and hepatic metabolic parameters. Indeed, the intake of Sp or Sp + Si mainly improved glucose tolerance and decreased the enzymatic activity of hepatic NADPH oxidase. Overall, Si supplementation of spirulina does not appear to have more beneficial effects than spirulina alone. Other experiments with different species of rats/mice, different diets or different durations of diet intake should be undertaken to confirm or invalidate these results.

Because of their antimicrobial properties, the use of silver nanoparticles (AgNPs) is increasing fast in industry, food, and medicine. In the food industry, nanoparticles are used in packaging to enable better conservation products such as sensors to track their lifetime, and as food additives, such as anti-caking agents and clarifying agents for fruit juices. Nanoemulsions, used to encapsulate, protect and deliver additives are also actively developed. Nanomaterials in foods will be ingested and passed through the digestive tract. Those incorporated in food packaging may also be released unintentionally into food, ending up in the gastrointestinal tract. It is therefore important to make a risk assessment of nanomaterials to the consumer. Thus, exposure to AgNPs is increasing in quantity and it is imperative to know their adverse effects in man. However, controversies still remain with respect to their toxic effects and their mechanisms. Understanding the toxic effects and the interactions of AgNPs with biological systems is necessary to handle these nanoparticles and their use. They usually generate reactive oxygen species resulting in increased pro-inflammatory reactions and oxidative stress via intracellular signalling pathways. Here, we mainly focus on the routes of exposure of AgNPs, toxic effects and the mechanisms underlying the induced toxicity.

Workout capacity is energy-production driven. To produce peak metabolic power outputs, the organism predominantly relies more on anaerobic metabolism, but this undoubtedly has a negative and limiting impact on muscle function and performance. The aim of the study was to evaluate if an innovative polyphenol-based food supplement, PerfLoad®, was able to improve metabolic homeostasis and physical performance during high-intensity exercises under anaerobic conditions. The effect of a supplementation has been investigated on fifteen recreationally-active male athletes during a randomized, double-blind and crossover clinical investigation. The Wingate test, an inducer of an unbalanced metabolism associated to oxidative stress, was used to assess maximum anaerobic power during a high-intensity exercise on a cycle ergometer. Supplementation with PerfLoad® correlated with a significant increase in total power output (5%), maximal peak power output (3.7%), and average power developed (5%), without inducing more fatigue or greater heart rate. Instead, oxidative homeostasis was stabilized in supplemented subjects. Such results demonstrated that PerfLoad® is a natural and efficient solution capable of, similarly to training benefits, helping athletes to improve their physical performance, while balancing their metabolism and reducing exercise-induced oxidative stress. Actividad Física y Deporte

High-intensity exercises are known to provoke delayed onset muscle soreness (DOMS). Delayed onset muscle soreness typically occurs within the first 24 h, peaks between 24 and 72 h, and can last as long as 5-7 days post-exercise. Delayed onset muscle soreness is a multifactorial process involving both mechanical and biochemical components, associated with clinical features that may limit range of motion, and athletes seek for effective recovery strategies to optimize future training sessions. TensLess

International audience; A comprehensive study of the bioavailability of orally administered silver nanoparticles (AgNPs) was carried out using a rat model. The silver uptake was monitored in liver and kidney tissues, as well as in urine and in feces. Significant accumulation of silver was found in both organs, the liver being the principal target of AgNPs. A significant (∼50%) fraction of silver was found in feces whereas the fraction excreted via urine was negligible (\textless0.01%). Intact silver nanoparticles were found in feces by asymmetric flow field-flow fractionation (AsFlFFF) coupled with UV-Vis analysis. Laser ablation-ICP MS imaging showed that AgNPs were able to penetrate into the liver, in contrast to kidneys where they were retained in the cortex. Silver speciation analysis in cytosols from kidneys showed the metallothionein complex as the major species whereas in the liver the majority of silver was bound to high-molecular (70-25 kDa) proteins. These findings demonstrate the presence of Ag(i), released by the oxidation of AgNPs in the biological environment.

Workout capacity is energy-production driven. To produce peak metabolic power outputs, the organism predominantly relies more on anaerobic metabolism, but this undoubtedly has a negative and limiting impact on muscle function and performance. The aim of the study was to evaluate if an innovative polyphenol-based food supplement, PerfLoad®, was able to improve metabolic homeostasis and physical performance during high-intensity exercises under anaerobic conditions. The effect of a supplementation has been investigated on fifteen recreationally-active male athletes during a randomized, double-blind and crossover clinical investigation. The Wingate test, an inducer of an unbalanced metabolism associated to oxidative stress, was used to assess maximum anaerobic power during a high-intensity exercise on a cycle ergometer. Supplementation with PerfLoad® correlated with a significant increase in total power output (5%), maximal peak power output (3.7%), and average power developed (5%), without inducing more fatigue or greater heart rate. Instead, oxidative homeostasis was stabilized in supplemented subjects. Such results demonstrated that PerfLoad® is a natural and efficient solution capable of, similarly to training benefits, helping athletes to improve their physical performance, while balancing their metabolism and reducing exercise-induced oxidative stress.

Oxidative stress is involved in obesity. However, dietary antioxidants could prevent oxidative stress-induced damage. We have previously shown the preventive effects of a melon superoxide dismutase.(SODB) on oxidative stress. However, the mechanism of action of SODB is still unknown. Here, we evaluated the effects of a 1-month curative supplementation with SODB on the liver of obese hamsters. Golden Syrian hamsters received either a standard diet or a cafeteria diet composed of high-fat, high-sugar, and high-salt supermarket products, for 15 weeks. This diet resulted in insulin resistance and in increased oxidative stress in the liver. However, inflammatory markers (IL-6, TNF-alpha, and NF-kappa B) were not enhanced and no liver steatosis was detected, although these are usually described in obesity-induced insulin resistance models. After the 1-month supplementation with SODB, body weight and insulin resistance induced by the cafeteria diet were reduced and hepatic oxidative stress was corrected. This could be due to the increased expression of the liver antioxidant defense proteins (manganese and copper/zinc superoxide dismutase, catalase, and glutathione peroxidase). Even though no inflammation was detected in the obese hamsters, inflammatory Markers were decreased after SODB supplementation, probably through the reduction of oxidative stress. These findings suggest for the first time that SODB could exert its antioxidant properties by inducing the endogenous antioxidant defense. The mechanisms underlying this induction need to be further investigated. (C) 2013 Elsevier Inc. All rights reserved.

The aim of this study was to investigate the effects of dietary silicon-enriched spirulina (SES) on atherosclerosis.Hamsters (six per group) on a high-fat (HF) diet received SES or non-enriched spirulina (both at 57 mg/kg body weight) daily. This corresponded to 0.57 mg silicon/kg body weight daily.The HF diet induced dyslipidemia, insulin resistance, oxidative stress, and vascular dysfunction. Compared with the HF group, SES attenuated increases of lipemia and prevented insulin resistance (IR) (P = 0.001). SES protected against oxidative stress through a reduction of heart (P = 0.006) and liver (P0.0001) nicotinamide adenine dinucleotide phosphate-oxidase activity and by sparing the activity of superoxide dismutase (P = 0.0017) and glutathione peroxidase (P = 0.01861). SES decreased inflammation, lowering tumor necrosis factor-α (P = 0.0006) and interleukin-6 levels (P = 0.0112), decreasing polymorphonuclear cells and preventing nuclear factor-κB activity (P = 0.0259). SES corrected plasma level of monocyte chemoattractant protein-1 (P = 0.0380), which was increased by the HF diet. Finally, SES supplementation prevented vascular and endothelial functions assessed respectively by the contractile response to the agonist phenylephrine and the relaxation induced by acetylcholine.SES protects against metabolic imbalance, inflammation, oxidative stress, and vascular dysfunction induced by an HF diet, and could prevent the atherogenic processes. Synergistic effects between spirulina and silicon were observed.

International audience; Silicon has beneficial effects especially on bones and skin and is important in cardiovascular pathophysiology. Furthermore, in spontaneously hypertensive rats, it reduces hypertension and increases antihypertensive and antiatherogenic gene expressions in the aorta. Thus, incorporating silicon into spirulina could be a way to produce a bioavailable food supplement. The potential toxic effects of silicon-rich spirulina (SES) through haematological and biochemical parameters and inflammatory and oxidative status were evaluated in rats' blood and liver tissue. The study consisted in a 90-day experiment on female and male rats supplemented with three doses (28.5, 57 and 285 mg/kg BW/day) of SES. No mortality, abnormal clinical signs, behavioural changes or macroscopic findings were observed whatever the groups. Haematological parameters were not modified in SES treated-groups. No marked change was recorded in biochemical parameters The liver endogenous antioxidant enzymes (SOD, GPx, catalase) activities were not modified whatever the gender and the dose, just as markers of oxidative stress (O2°(-), TBARS, thiols) and inflammation such as IL-6 and TNF-alpha. Our findings indicate that dietary supplementation of silicon-rich spirulina on rats has no harmful side nor toxic effects and could be beneficial especially in the case of suspicion or installation of pathologies due to oxidative stress.

We have shown previously that noradrenaline (NA) stimulated or inhibited the release of corticotropin-releasing hormone (CRH) according to the availability of adrenal steroids. The aim of the present work was to examine whether the changes in the NA modulation of CRH release from hypothalamic neurons result from a steroid-induced plasticity of the adrenergic transduction pathways. From anterior hypothalamic slices cultured in standard medium (i.e., containing adrenal steroids at a final dilution of 61 +/- 9 ng/ml), (a) the stimulatory effect of NA on CRH release was reversed in a dose-dependent manner by increasing concentrations of the alpha1-adrenoreceptor antagonist prazosin, (b) activation of protein kinase C by acute treatment with phorbol 12-myristate 13-acetate (0.5 microM, 1 h) mimicked NA stimulation of CRH secretion, and (c) the activation of L-type Ca2+ channels by Bay K 8644 also produce an increased CRH secretion. In contrast, the inhibitory effect of NA on CRH secretion from slices cultured in steroid-free medium was markedly reversed by the alpha2-adrenoreceptor antagonist yohimbine, by pretreatment with pertussin toxin, or by the addition of 4-aminopyridine, a K+-channel blocker. Acute treatment with phorbol 12-myristate 13-acetate did not change the inhibitory NA effect. Moreover, all these effects were reversed by daily corticosterone supplementation, for as long as they were tested. These results are consistent with a steroid-dependent change in the nature of adrenergic receptors and its associated transduction pathways involved in the regulation of CRH secretion in the hypothalamus.

International audience; beta,beta-Carotene 15-15 ' mono-oxygenase 1 (BCMO1) is a key enzyme in vitamin A (VitA) metabolism in mammals. Dietary compounds, such as carotenoids and polyphenols, were reported to influence BCMO1 activity. The aim of this study was to evaluate the effect of hesperidin (Hes), on the VitA bioefficacy of beta-carotene (Bc) from orange-fleshed sweet potato, using Mongolian gerbils, focussing on BCMO1 activity. Gerbils (n = 50) depleted in VitA were divided into five groups fed with basal diet containing 3% white-or orange-fleshed sweet potatoes supplemented or not with Hes. Liver BCMO1 activity was low, with no significant differences between groups. Interestingly, intestinal mucosal BCMO1 activity was significantly higher in the gerbils fed without Bc or VitA than those fed with a VitA/Bc-supplemented diet. Finally, our results show that, under a low VitA status, Hes dramatically stimulated intestinal BCMO1 activity, an effect that could possibly be related to its action as an agonist of PPAR gamma.

Scope High-fat (HF) diets contribute to the development of cardiovascular diseases and the metabolic syndrome. This study was undertaken to investigate the beneficial effects of Vineatrol®-enriched red wines on blood lipids, oxidative stress and inflammation, and the role of some metabolic pathway regulatory proteins. Methods and results Golden Syrian hamsters received an HF diet for 13 wk, in the presence or absence of red wines supplemented with Vineatrol® (RWV) or not. The HF diet increased plasma cholesterol, triglycerides, glucose, and insulin, which were attenuated by RWV treatment. RWV protected against the HF-induced increase in liver nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and spared antioxidant enzyme activities. RWV did not reduce either liver steatosis or increased plasma leptin due to the HF diet, but greatly improved adiponectinemia. In the liver, RWV affected the inflammatory response by decreasing polymorphonuclear cell number and lowering TNF-α and IL-6 levels. Moreover, the increase in NF-κB activity in the HF group liver was prevented by RWV. Finally, RWV partially corrected low SIRT1 levels due to the HF diet but had no influence on SIRT3 or p-AMPK protein levels. Conclusion Our studies suggest that RWV is capable of reversing the atherogenic process induced by an HF diet in hamster tissues.

Due to undesirable hazardous interactions with biological systems, we evaluated the effect of silver nanoparticles (AgNPs) intake on oxidative stress and inflammation. Rats received for 81 days a standard diet (Controls) or a standard diet plus 500 mg/d/kg BW AgNPs. We assayed plasma lipids, and oxidative stress was assessed by measuring liver and heart superoxide anion production (O₂°⁻) and liver malondialdehyde levels (MDA). Antioxidant status was appraised using plasma paraoxonase activity (PON), plasma antioxidant capacity (PAC) and liver superoxide dismutase activity (SOD). Liver inflammatory cytokines TNFα and IL-6 levels and plasma alanine aminotransferase (ALT) were assayed. Compared with Controls, AgNPs raised cholesterolemia (9.5%), LDL-cholesterol (30%), and lowered triglycerides (41%). They also increased liver (30%) and cardiac (41%) O₂°⁻ production, reduced PON activity (15%) and raised liver TNFα (9%) and IL-6 (∼12%). Plasma ALT activity rose (12%) after treatment with AgNPs. However, PAC and liver MDA and SOD activity were unchanged. These features indicate that exposure to 500 mg/d/kg BW of AgNPs results in liver damage by a dysregulation of lipid metabolism, highlighting liver and heart as the most sensitive organs to the deleterious effects. Our findings also demonstrate for the first time the oxidative and inflammatory effects of dietary AgNPs.

We evaluated the effect of the intake of a grapevine-shoot phenolic extract (Vineatrol 30) on early atherosclerosis in hamsters fed a hyperlipidic diet. Golden Syrian hamsters received for 13 weeks either a standard diet, a high-fat (HF) diet, or the HF diet plus Vineatrol 30 at 0.04, 0.2, or 1.0 mg/(kg body weight/d). We measured plasma lipids and glucose, insulin, leptin and adiponectin, as well as liver TNF-α and IL-6 levels. Oxidative stress was assessed by measuring plasma paraoxonase activity (PON) and liver superoxide anion production (O(2)(•-)). The aortic fatty streak area (AFSA) was also determined. In comparison with HF group, we demonstrated that the highest dose of Vineatrol 30 was capable of decreasing AFSA (67%), insulinemia (40%), and leptinemia (8.7%), which were increased by the HF diet. We also showed increased O(2)(•-) production (35%) and a rise in levels of the liver proinflammatory cytokines TNF-α (22%) and IL-6 (21%), accompanied by a fall in PON activity (56%) due to the HF diet versus the standard diet. In contrast, except plasma adiponectin levels that are not changed, Vineatrol 30 treatment lowered AFSA (67%), O(2)(•-) production (36%), insulin resistance (42%), leptinemia (9%), liver TNF-α (18%) and IL-6 (15%), while it rose PON activity (29%). These findings demonstrate the preventive effects of polyphenols present in Vineatrol 30 in managing cardiovascular, metabolic, and inflammatory risk factors.

An organotypic culture system of anterior hypothalamic slices was developed for studying the secretory responses of corticotropin-releasing hormone (CRH) neurons to corticosteroid-catecholamine interactions. The standard culture medium included 5% horse serum containing 50 micrograms/l cortisol. In 1- to 3-day cultures, the tissue viability was demonstrated by the presence of arginine vasopressin immunolabeled perikarya and axons in the paraventricular nucleus and by sustained tissue concentrations of CRH (around 50 pg/mg protein). However, immunoreactive CRH neurons were not detectable in cultures in the standard medium. Exposure of cultures to high K+ (56 mM) in the medium induced a ten-fold increase in basal CRH release which was completely abolished in a Ca(2+)-free medium containing 2 mM EGTA. Noradrenaline (NA) triggered CRH release in a dose-dependent (1-20 microM) and time-dependent (0.5-6 h) manner. Removal of corticosteroids from the media by charcoal treatment led to (1) the visualization of immunolabelled CRH perikarya and fibers and a 55% rise in CRH content of the paraventricular nucleus tissue and (2) to a five-fold increase in CRH release. Both effects were reversed by supplementation of the culture medium with corticosterone (50 micrograms/l). Under steroid-free conditions, NA (1-10 microM) not only failed to induce CRH release, but strongly inhibited the consistent baseline in CRH release. This was reminiscent of a similar corticosteroid-dependent inversion of the NA effect on the hypothalamic-pituitary-adrenal axis described in vivo. Overall, these results are direct evidence of complex corticosteroid-catecholamine interrelationships as major regulatory factors of the hypothalamic-pituitary-adrenal axis.

Today, due to oxidative stress, the postulated involvement of lipid peroxidation in atherogenesis and obesity invoked intensive interest in the use of antioxidant nutritional supplements. Epidemiological evidence suggests that intake of some vitamins, minerals, and other food constituents may help to protect against heart disease, obesity, cancer and the aging process and that antioxidants may have a protective effect, in either preventing these diseases or lessening the severity of the diseases upon their onset.

This study evaluates and defines the histological and biochemical consequences of irradiation on the Hauer-Jensen intestinal model and investigates the potential effects of dietary polyphenols. Sprague–Dawley rats were orchiectomized, and an ileal loop was transposed to the left part of the scrotum, then irradiated 2 weeks after surgery with a single dose of 21 Gy (4.49 Gy/min). Four groups of rats received either phenolic extracts from grape seeds (EGS) and from red wine (ACYS, EGT), or pure quercetin 3-O-β-glucoside (Q3G), for 5 days before the irradiation and were sacrificed 2 weeks after. Antioxidant enzyme activities, i.e. superoxide dismutase (SOD) and glutathione peroxidase activity (GSHPx), and oxidative markers such as myeloperoxidase activity (MPO) and thiobarbituric acid reactive substances (MDA) were measured as well as cytokine-induced neutrophil chemoattractant level (CINC-1), a chemokine involved in inflammation. Irradiated rats exhibited a high radiation injury score (RIS) with a thickened serosa, mucosal loss and ulceration, and epithelial atypicality. Intestinal MPO activity and CINC-1 concentration were significantly increased in irradiated animals (60 and 66 %, respectively). Higher plasma MDA levels (58 %) and SOD activity (32 %) were accompanied by a reduced GSHPx activity (79 %). However, feeding phenolic extracts remarkably reduced levels of blood SOD activity (34 % on average), intestinal CINC-1 (25–75 % range) and MPO activity (36–84 %). Except for Q3G, phenolics preserved the intestinal structure. These findings show that irradiation triggers an inflammation, and an oxidative stress by disturbing the pro-oxidant/antioxidant balance and indicate that phenolics supply exerts preventive effects against radio-induced intestinal impairment.

International audience; This study explored major systems of reactive oxygen species (ROS) production and their consequences on oxidative stress, mitochondriogenesis and muscle metabolism in aged rats, and evaluated the efficiency of 30-day oral supplementation with a moderate dose of a red grape polyphenol extract (RGPE) on these parameters. In the liver of aged rats, NADPH oxidase activity was increased and mitochondrial respiratory chain complex activities were altered, while xanthine oxidase activity remained unchanged. In muscles, only mitochondrial activity was modified with aging. The oral intake of RGPE decreased liver NADPH oxidase activity in the aged rats without affecting global oxidative stress, suggesting that NADPH oxidase was probably not the dominant detrimental source of production of O(2)·(-) in the liver. Interestingly, RGPE supplementation increased mitochondrial biogenesis and improved antioxidant status in the gastrocnemius of aged rats, while it had no significant effect in soleus. RGPE supplementation also decreased age-dependent autophagy in gastrocnemius of aged rats. These results extended existing findings on the beneficial effects of RGPE on mitochondriogenesis and muscle metabolism in aged rats.

Following a series of investigations supporting the concept that the brain stem catecholaminergic (CA) system played a major stimulatory role on both basal and stress-triggered states of the hypothalamic-pituitary-adrenocortical (HPA) axis, across alpha 1 and beta receptors and also via alpha 2 receptors, the present study was designed to gain a deeper insight into the fine mechanism of functional interactions between the alpha 2 receptors mediated CA system and two peptidergic mechanisms, both shown to take part in the stimulatory control of the HPA axis: beta-endorphin and NPY. All experiments were conducted on rats whose noradrenergic bundles, which directly innervate the CRF neurons and are strongly implicated in the ether stress-induced corticotropic response, had been bilaterally obliterated by an intracerebral (i.c.) injection of 6-OHDA (NAB-X). Results showed that: (1) the blockade of the ether-stress induced ACTH response resulting from NAB-X was entirely reversed by an intraventricular (i.c.v.) infusion of the alpha 2 antagonist idazoxan (10 nmol), which appeared ineffective under basal conditions; (2) the restoration of a normal post-stress ACTH surge by i.c.v. idazoxan was itself blunted by an i.c.v. pretreatment with naloxone (10 nmol), whereas an i.c. pretreatment with an anti-NPY serum appeared ineffective. These data suggest that, in addition to a stimulatory control exerted by postsynaptic alpha 2 receptors directly on CRF neurons, other alpha 2 receptors participate, exclusively under the stress conditions above, in a tonic inhibitory control, indirectly mediated to the HPA axis across a stimulatory opioid, but not NPY regulatory component.

The effects of various stressors (restraint, ether, histamine and insulin-induced hypoglycemia stress) on the early time course activation of the different catecholaminergic (CA) cell groups A1/C1, A2/C2 and locus ceruleus (LC) from the brainstem were studied. The activity of the central noradrenergic neurons was assessed by measuring in tissue punches the 3,4-dihydroxyphenylacetic acid (DOPAC) level, a side metabolite of noradrenaline (NA) and adrenaline biosynthesis that is thought to reflect the activity of NA cells. Short 5 min restraint stress led to an immediate increase of DOPAC level in the three CA groups. In the A1/C1 and A2/C2 groups the maximal increase, respectively +75 and +50%, was already reached at the end of the application of the stress while for the LC the maximum (+84%) was obtained 15 min after the onset of the stress. Return to baseline level was achieved within 2 h. Continuous immobilization stress did not further alter the DOPAC concentration in the LC and the A1/C1 while a progressive increase up to 85% in the A2/C2 group was seen over 20 min. Following a 2-min exposure to ether, DOPAC was increased in all three structures within 5 min. At this time the maximum was already reached in the A1/C1 and LC, respectively +99 and +43%. After histamine or insulin injection DOPAC level increased in the A1/C1 and A2/C2 in the +25/+50% range but was not significantly affected in the LC. In all the stress situations studied the increase in DOPAC level, particularly in the A1/C1 group always preceded or was concomitant to the increase of plasma corticosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress during pregnancy results in neurochemical and behavioral alterations observed throughout adulthood and aging. We here examined the impact of prenatal stress (PS) on cognitive functions in juvenile-4-week-old-rats, focusing on putative sex differences. Dams received an unpredictable 90-min duration contention stress between gestational day E17 and E20. Locomotion and learning ability were examined in offsprings between day P24 and P29 using actimetry, spontaneous alternation in the Y-maze, delayed alternation in the T-maze, and passive avoidance. Both male and female PS rats showed increased activity. In the Y-maze, diminished spontaneous alternation (males: -20%; females: -29%) were seen for PS rats compared to non-PS rats. The number of arm entries was unchanged among groups. In the T-maze, PS rats failed to perform delayed alternation, as shown by equal time spent and number of entries in both the novel and previously explored arms. In the passive avoidance test, PS resulted in significant impairments for female offspring only of both step-through latency and percentage of animals to criterion. PS thus induced severe learning impairments affecting both short-term and long-term memories that could be observed early in lifetime, in 4-week-old, juvenile rats. In addition, marked sex differences were evidenced, particularly in the passive avoidance response that may reflect differential developmental neuroadaptations in precise brain structures.

The glial GLAST and GLT-1 glutamate transporters are transiently expressed in hippocampal neurons as shown by immunocytochemistry (Plachez et al., 2000. J. Neurosci. Res., 59, 587–593). In order to test if this transient expression is associated to a transient glutamate uptake activity, [3H]-glutamate uptake was studied during the in vitro development of embryonic hippocampal neurons cultured in a defined (serum free) medium. In these cultures, the ratio of the number of glial cells to the number of neurons increased from 1.7 to 11.3% during the first 10 days of culture, while 77% of the neurons died. The number of neurons then remains stable up to 23 days of culture. The initial glutamate uptake velocity at 20 and 200 μM [3H]-glutamate usually increased about five times between 1 and 10 days in vitro (DIV). Interestingly, at 2 μM [3H]-glutamate, the uptake initial velocity showed a biphasic pattern, with a transient peak between 1 and 6 DIV, the maximum being reached at 2 DIV and a delayed regular increase from 8 to 23 DIV. The concentration-dependent curves were best fitted with two saturable sites high and low affinities, at both 2 and 10 DIV. To pharmacologically characterize the transient increased glutamate uptake activity, four uptake inhibitors, l -threo-3-hydroxy-aspartic acid (THA), l -trans-pyrrolidine-2,4-dicarboxylic acid ( l -trans-2,4-PDC), dihydrokainate (DHK), and dl -threo-β-benzyloxyaspartate (TBOA) were tested. THA, l -trans-2,4-PDC and dl -TBOA inhibited glutamate uptake both at 2 and 10 DIV, while the GLT-1 selective uptake inhibitor DHK neither strongly affected the uptake at 2, nor at 10 DIV. These data indicated that, besides the regular increase in the glial-dependent glutamate uptake activity, a transient high-affinity, DHK insensitive, glutamate transport activity in hippocampal neurons in culture is present. This latter activity could potentially be related to the transient expression of the glial GLAST transporter in neurons.