Leuven Drug Research Institute

Woluwe, Belgium

Leuven Drug Research Institute

Woluwe, Belgium

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Deldicque L.,Institute of Neurosciences | Cani P.D.,Leuven Drug Research Institute | Philp A.,University of Dundee | Philp A.,University of California at Davis | And 7 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010

High-fat diets are known to decrease muscle protein synthesis, the adaptation to overload, and insulin sensitivity. Conditions that disrupt endoplasmic reticulum (ER) homeostasis lead to the activation of the unfolded protein response (UPR) that is associated with decreases in protein synthesis, chronic inflammation, and insulin resistance. The purpose of the present study was to establish whether ER stress is induced by a high-fat diet in skeletal muscle and whether ER stress can decrease mTORC1 activity and protein synthesis in muscle cells. Two independent protocols of high-fat feeding activated the UPR in mice. In the first study, mice consuming a high-fat diet containing 70% fat and <1% carbohydrates for 6 wk showed higher markers of the UPR (BiP, IRE1α, and MBTPS2) in the soleus and in the tibialis anterior muscles and ATF4 in the tibialis anterior (P < 0.05). In the second study, a 20-wk high-fat diet containing 46% fat and 36% carbohydrates also increased BiP, IRE1α, and phospho-PERK protein and the expression of ATF4, CHOP, and both the spliced and unspliced forms of XBP1 in the plantar flexors (P < 0.05). In C2C12 muscle cells, tunicamycin, thapsigargin, and palmitic acid all increased UPR markers and decreased phosphorylation of S6K1 (P < 0.05). Collectively, these data show that a high-fat diet activates the UPR in mouse skeletal muscle in vivo. In addition, in vitro studies indicate that palmitic acid, and other well-known ER stress inducers, triggered the UPR in myogenic cells and led to a decrease in protein synthesis and mTORC1 activity. Copyright © 2010 the American Physiological Society.


Sheridan P.O.,Rowett Institute of Nutrition and Health | Bindels L.B.,Leuven Drug Research Institute | Saulnier D.M.,NIZO Food Research | Reid G.,Lawson Health Research Institute | And 6 more authors.
Gut microbes | Year: 2014

It has become clear in recent years that the human intestinal microbiota plays an important role in maintaining health and thus is an attractive target for clinical interventions. Scientists and clinicians have become increasingly interested in assessing the ability of probiotics and prebiotics to enhance the nutritional status of malnourished children, pregnant women, the elderly, and individuals with non-communicable disease-associated malnutrition. A workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP), drawing on the knowledge of experts from industry, medicine, and academia, with the objective to assess the status of our understanding of the link between the microbiome and under-nutrition, specifically in relation to probiotic and prebiotic treatments for under-nourished individuals. These discussions led to four recommendations:   (1) The categories of malnourished individuals need to be differentiated To improve treatment outcomes, subjects should first be categorized based on the cause of malnutrition, additional health-concerns, differences in the gut microbiota, and sociological considerations. (2) Define a baseline "healthy" gut microbiota for each category Altered nutrient requirement (for example, in pregnancy and old age) and individual variation may change what constitutes a healthy gut microbiota for the individual. (3) Perform studies using model systems to test the effectiveness of potential probiotics and prebiotics against these specific categories These should illustrate how certain microbiota profiles can be altered, as members of different categories may respond differently to the same treatment. (4) Perform robust well-designed human studies with probiotics and/or prebiotics, with appropriate, defined primary outcomes and sample size These are critical to show efficacy and understand responder and non-responder outcomes. It is hoped that these recommendations will lead to new approaches that combat malnutrition. This report is the result of discussion during an expert workshop titled "How do the microbiota and probiotics and/or prebiotics influence poor nutritional status?" held during the 10th Meeting of the International Scientific Association for Probiotics and Prebiotics (ISAPP) in Cork, Ireland from October 1-3, 2012. The complete list of workshop attendees is shown in Table 1.


Lai T.N.H.,Institute Des Science Of La Vie | Lai T.N.H.,Hanoi University of Agriculture | Herent M.-F.,Leuven Drug Research Institute | Quetin-Leclercq J.,Leuven Drug Research Institute | And 4 more authors.
Food Chemistry | Year: 2013

The sim fruit (Rhodomyrtus tomentosa) has long been used in folk medicine to treat diarrhoea, dysentery, and to boost the immune system. The purpose of this work was to determine its phenolic profile and to evaluate the changes of content during maturation, as well as the variations induced by environmental conditions. Using HPLC-ESI-HR-MS, 19 phenolic compounds (PCs) were tentatively characterised and included stilbenes and ellagitannins as major components, followed by anthocyanins, flavonols, and gallic acid. PCs were then further quantified by HPLC-DAD. Piceatannol, a promising health-promoting stilbene component, was the major PC in the fruit with a concentration of 2.3 mg/g dry weight at full maturity stage. This concentration is 1000-2000 times higher than that of red grapes, a major source of stilbene in the human diet. During maturation, the contents in piceatannol and other stilbenes, ellagitannins, and flavonols decreased while the anthocyanin content increased. Shade-grown sim fruits showed significantly higher piceatannol levels than sun-exposed fruits. Taken together, these findings highlight the potential of sim, an under-utilised plant species from South-East Asia, as a source of health-promoting fruits. © 2012 Elsevier Ltd. All rights reserved.


Passo Tsamo C.V.,Institute Des Science Of La Vie | Passo Tsamo C.V.,Institute of Medical Research and Medicinal Plant Studies | Herent M.-F.,Leuven Drug Research Institute | Tomekpe K.,CIRAD - Agricultural Research for Development | And 5 more authors.
Food Chemistry | Year: 2015

The present study investigated the phenolic profiles of the pulp and peel of nine plantain cultivars and compared them to those of two dessert bananas of commercial interest (Grand Nain and Gros Michel), alongside a newly created hybrid, resistant to black sigatoka disease (F568). Identification and quantification of phenolic compounds were performed by means of HPLC-ESI-HR-MS and HPLC-DAD. Hydroxycinnamic acids, particularly ferulic acid-hexoside with 4.4-85.1 μg/g of dry weight, dominated in the plantain pulp and showed a large diversity among cultivars. Flavonol glycosides were predominant in plantain peels, rutin (242.2-618.7 μg/g of dry weight) being the most abundant. A principal component analysis on the whole data revealed that the phenolic profiles of the hybrid, the dessert bananas and the pure plantains differed from each other. Plantain pulps and peels appeared as good sources of phenolics, which could be involved in the health benefits associated with their current applications. © 2014 Elsevier Ltd. All rights reserved.


Evens N.,Laboratory for Radiopharmacy | Vandeputte C.,IMIR K.U. Leuven | Muccioli G.G.,Leuven Drug Research Institute | Lambert D.M.,Leuven Drug Research Institute | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

The type 2 cannabinoid receptor (CB2R) is part of the endocannabinoid system and is expressed in tissues related to the immune system. As the CB2R has a very low brain expression in non-pathological conditions, but is upregulated in activated microglia, it is an interesting target for visualization of neuroinflammation using positron emission tomography with a suitable radiolabeled CB2R ligand. In this study, we radiolabelled a fluoroethyl derivative of GW405833, a well known CB2R partial agonist, with fluorine-18 (half-life 109.8 min) by alkylation of the phenol precursor with 1-bromo-2-[18F]fluoroethane. In vitro studies showed that FE-GW405833 behaved as a selective high affinity (27 nM) inverse agonist for hCB2R. [18F]FE-GW405833 showed moderate initial brain uptake in mice and rats, but a slow washout from brain and plasma due to retention of a radiometabolite. Specific binding of the tracer to human CB2R was demonstrated in vivo in a rat model with local CB 2R overexpression in the brain. Optimized derivatives of GW405833 that are less susceptible to metabolism will need to be developed in order to provide a useful tracer for CB2R quantification with PET. © 2011 Elsevier Ltd. All rights reserved.


Pachikian B.D.,Leuven Drug Research Institute | Neyrinck A.M.,Leuven Drug Research Institute | Deldicque L.,Catholic University of Louvain | De Backer F.C.,Leuven Drug Research Institute | And 9 more authors.
Journal of Nutrition | Year: 2010

Magnesium (Mg) deficiency is a common nutritional disorder that is linked to an inflammatory state characterized by increased plasma acute phase protein and proinflammatory cytokine concentrations. Recent studies have shown that changes in the composition of gut microbiota composition participate in systemic inflammation. In this study, therefore, we assessed the potential role of gut microbiota in intestinal and systemic inflammation associated with Mg deficiency in mice. For this purpose, mice were fed a control or Mg-deficient diet (500 mg vs. 70 mg Mg/kg) for 4 or 21 d. Compared with the mice fed the control diet, mice fed the Mg-deficient diet for 4 d had a lower gut bifidobacteria content (-1.5 log), a 36-50% lower mRNA content of factors controlling gut barrier function in the ileum (zonula occludens-1, occludin, proglucagon), and a higher mRNA content (by ∼2-fold) in the liver and/or intestine of tumor necrosis factor-a, interleukin-6, CCAAT/enhancer binding protein homologous protein, and activating transcription factor 4, reflecting inflammatory and cellular stress. In contrast, mice fed the Mg-deficient diet for 21 d had a higher cecal bifidobacteria content compared with the control group, a phenomenon accompanied by restoration of the intestinal barrier and the absence of inflammation. In conclusion, we show that Mg deficiency, independently of any other changes in nutrient intake, modulates the concentration of bifidobacteria in the gut, a phenomenon that may time-dependently affect inflammation and metabolic disorders in mice. © 2010 American Society for Nutrition.


Lobysheva I.I.,Catholic University of Louvain | Biller P.,Catholic University of Louvain | Gallez B.,Leuven Drug Research Institute | Beauloye C.,Catholic University of Louvain | Balligand J.-L.,Catholic University of Louvain
PLoS ONE | Year: 2013

Impaired nitric oxide (NO)-dependent endothelial function is associated with the development of cardiovascular diseases. We hypothesized that erythrocyte levels of nitrosylated hemoglobin (HbNO-heme) may reflect vascular endothelial function in vivo. We developed a modified subtraction method using Electron Paramagnetic Resonance (EPR) spectroscopy to identify the 5-coordinate α-HbNO (HbNO) concentration in human erythrocytes and examined its correlation with endothelial function assessed by peripheral arterial tonometry (PAT). Changes in digital pulse amplitude were measured by PAT during reactive hyperemia following brachial arterial occlusion in a group of healthy volunteers (50 subjects). Erythrocyte HbNO levels were measured at baseline and at the peak of hyperemia. We digitally subtracted an individual model EPR signal of erythrocyte free radicals from the whole EPR spectrum to unmask and quantitate the HbNO EPR signals.Results:Mean erythrocyte HbNO concentration at baseline was 219+/-12 nmol/L (n = 50). HbNO levels and reactive hyperemia (RH) indexes were higher in female (free of contraceptive pills) than male subjects. We observed a dynamic increase of HbNO levels in erythrocytes isolated at 1-2 min of post-occlusion hyperemia (120+/-8% of basal levels); post-occlusion HbNO levels were correlated with basal levels. Both basal and post-occlusion HbNO levels were significantly correlated with reactive hyperemia (RH) indexes (r = 0.58; P<0.0001 for basal HbNO).Conclusion:The study demonstrates quantitative measurements of 5-coordinate α-HbNO in human venous erythrocytes, its dynamic physiologic regulation and correlation with endothelial function measured by tonometry during hyperemia. This opens the way to further understanding of in vivo determinants of NO bioavailability in human circulation. © 2013 Lobysheva et al.


Hage S.,Leuven Drug Research Institute | Marinangeli C.,Catholic University of Louvain | Stanga S.,Catholic University of Louvain | Octave J.-N.,Catholic University of Louvain | And 2 more authors.
Neurodegenerative Diseases | Year: 2014

Background: Accumulation of β-amyloid peptides (Aβ) and its progressive deposition into amyloid plaques are key events in the aetiology of Alzheimer's disease (AD). To date, AD treatment is symptomatic and consists of drugs treating the cognitive decline. Objective: Identifying molecules specifically targeting Aβ production or aggregation represents a huge challenge in the development of specific AD treatments. Several molecules reported as γ-secretase inhibitors or modulators have been evaluated, but so far none of them have proven to be selective or fully efficient. We have previously investigated the potential interest of plant extracts and we reported that Pterocarpus erinaceus stem-bark extract was active on Aβ release. Our aim here was to characterize the mechanisms by which this extract reduces Aβ levels. Methods: We tested P. erinaceus extract at non-toxic concentrations on cells expressing the human amyloid precursor protein (APP695) or its amyloidogenic β-cleaved C-terminal fragment (C99), as well as on neuronal cell lines. P. erinaceus extract was found to inhibit Aβ release. We further showed that this extract inhibited γ-secretase activity in cell-free and in vitro assays, strongly suggesting that P. erinaceus extract is a natural γ-secretase inhibitor. Importantly, this extract did not inhibit γ-secretase-dependent Notch intracellular domain release. Conclusion: P. erinaceus extract appears as a new potent γ-secretase inhibitor selective towards APP processing. © 2013 S. Karger AG, Basel.


Geurts L.,Leuven Drug Research Institute | Geurts L.,Catholic University of Louvain | Neyrinck A.M.,Catholic University of Louvain | Delzenne N.M.,Catholic University of Louvain | And 4 more authors.
Beneficial Microbes | Year: 2014

Crosstalk between organs is crucial for controlling numerous homeostatic systems (e.g. energy balance, glucose metabolism and immunity). Several pathological conditions, such as obesity and type 2 diabetes, are characterised by a loss of or excessive inter-organ communication that contributes to the development of disease. Recently, we and others have identified several mechanisms linking the gut microbiota with the development of obesity and associated disorders (e.g. insulin resistance, type 2 diabetes, hepatic steatosis). Among these, we described the concept of metabolic endotoxaemia (increase in plasma lipopolysaccharide levels) as one of the triggering factors leading to the development of metabolic inflammation and insulin resistance. Growing evidence suggests that gut microbes contribute to the onset of low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. We have demonstrated that enteroendocrine cells (producing glucagon-like peptide-1, peptide YY and glucagon-like peptide-2) and the endocannabinoid system control gut permeability and metabolic endotoxaemia. Recently, we hypothesised that specific metabolic dysregulations occurring at the level of numerous organs (e.g. gut, adipose tissue, muscles, liver and brain) rely from gut microbiota modifications. In this review, we discuss the mechanisms linking gut permeability, adipose tissue metabolism, and glucose homeostasis, and recent findings that show interactions between the gut microbiota, the endocannabinoid system and the apelinergic system. These specific systems are discussed in the context of the gut-to-peripheral organ axis (intestine, adipose tissue and brain) and impacts on metabolic regulation. In the present review, we also briefly describe the impact of a variety of non-digestible nutrients (i.e. inulin-type fructans, arabinoxylans, chitin glucans and polyphenols). Their effects on the composition of the gut microbiota and activity are discussed in the context of obesity and type 2 diabetes. © 2014 Wageningen Academic Publishers.


PubMed | Catholic University of Louvain and Leuven Drug Research Institute
Type: | Journal: Neuroscience research | Year: 2015

Spinal glial reactivity has been strongly implicated in pain that follows peripheral nerve injury. Among the many therapeutic agents that have been tested for anti-allodynia through immune modulation is the atypical methylxanthine propentofylline. While propentofylline shows a potent anti-allodynia effect after nerve transection injury, we here demonstrate that, when propentofylline is used intrathecally at the effective immune-modulatory dose, allodynia after rat nerve crush injury is completely preserved. Microglial/macrophage Iba-1 and astrocytic GFAP expression, increased in the dorsal horn of nerve crushed animals, was, however, effectively attenuated by propentofylline. Effective modulation of spinal glial reactivity is, thus, no assurance for anti-allodynia.

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