Adipose cell metabolism modulation by red wine procyanidins

Flavonoids, and more specifically, red wine procyanidins, have many beneficial effectsagainst pathologies such as cardiovascular heart disease and related illnesses. Althoughadipose tissue has a central role in some of these pathologies, including obesity and diabetes,there is a lack of information about the effects of procyanidins on this tissue. This thesisaddresses this question. The effects of a grape seed procyanidin extract (GSPE) on the lipidand glucose metabolism of adipocytes were evaluated by taking the 3T3-L1 cell line as amodel of study. Results show that the GSPE has insulinomimetic effects, stimulating glucoseuptake, glycogen synthesis and trigliceride synthesis. To achieve this, the GSPE shares someof the mechanisms and intracellular mediators of the insulin-signalling pathways (such asGLUT-4 translocation, PI3K and p38 MAPK) but it must also use other, complementary,mechanisms. These results suggest that procyanidins have beneficial effects on diabetesand/or insulin resistance. This is partially proven by in vivo studies that show that GSPE hasantihyperglycemic properties on streptozotozin-induced diabetic rats. Also analyzed in thisthesis are the molecular mechanisms used by GSPE to explain the already described lipolyticeffects. Protein kinase A and PPARã are shown to be involved in these effects. Some ofthese results opened up another line of study into the effects of GSPE on the differentiationprocess of the 3T3-L1. These studies showed that procyanidins alter the differentiation ofpreadipocytes when added at the induction of differentiation. Since an increase in thenumber of adipocytes has a negative effect on obesity, this is a promising characteristic ofGSPE that should be taken into account when its possible antiobesity properties are studied.Als flavonoides, i més concretament a les procianidines del vi negre, se'ls han atribuït moltespropietats beneficioses contra diverses patologies, com les malalties cardiovasculars i altrespatologies relacionades. Tot i que el teixit adipós juga un paper important en algunesd'aquestes patologies, com la obesitat i la diabetis, la informació referent l'acció de lesprocianidines en aquest teixit és escassa. Aquesta tesis estudia els efectes de les procianidinesderivades de pinyol de raïm (GSPE) en l'adipòcit, i per a dur-ho a terme es pren com amodel d'estudi la línia cel.lular 3T3-L1. Per una banda es descriuen els efectes del GSPE enel metabolisme de lípids i glúcids de la cèl.lula adiposa. El GSPE fa un paperinsulinomimètic: estimula la captació de glucosa, la síntesi de glicògen i la síntesi de triacilglicerols. L'anàlisi dels mecanismes moleculars per exercir aquests efectes mostra que GSPEen part comparteix mecanismes i vies de senyalització propis de la insulina (translocació deGLUT-4, PI3K, p38 MAPK); tanmateix, s'observa que GSPE ha d'usar també altresmecanismes complementaris. Aquests resultats suggereixen que GSPE pot tenir efectespositius en situacions de diabetis i/o resistència a insulina, donat que a més a més, els estudisin vivo mostren que GSPE és antihiperglicèmic en condicions de diabetis induïda perestreptozotocina. En aquesta tesis també s'analitzen els mecanismes moleculars queexplicarien els efectes lipolítics de les procianidines descrits en estudis previs, i s'ha trobatque la proteina kinasa A i PPARã hi estan involucrats. Part d'aquests resultats han obert unaaltra via d'estudi sobre els efectes de la GSPE en el procés de diferenciació de la cèl.lulaadiposa on s'ha observat que el tractament amb procianidines a l'inici de la diferenciaciódificulta aquesta transformació. Donat que l'augment del nombre d'adipòcits afectanegativament la obesitat, aquest efecte de les procianidines és una característicaprometedora que caldrà tenir en compte en l'estudi del seu possible paper antiobesitat

Beneficial Effects of Proanthocyanidins on Intestinal Permeability and Its Relationship with Inflammation

The intestinal barrier is constantly exposed to potentially harmful environmental factors including food components and bacterial endotoxins. When the intestinal barrier function and immune homeostasis are compromised, inflammatory conditions may be developed and impact overall health. Evidence from experimental animal and cell-culture studies suggests that exposure of intestinal mucosa to proanthocyanidin-rich plant products may contribute to maintain the barrier function and to ameliorate the inflammation present in prevalent pathologies such as diet-induced obesity and inflammatory bowel disease. In this review, we aim to update the current knowledge on the bioactivity of PACs in experimental models of altered intestinal permeability and in humans, emphasizing the beneficial effects of grape-seed proanthocyanidin extracts in intestinal health and giving insights into the subjacent biochemical and molecular mechanism

Grape seed Proanthocyanidins target the Enteroendocrine system in cafeteria‐diet‐fed rats

Scope The effects on the enteroendocrine system of three different grape seed proanthocyanidin extract (GSPE) treatments are analyzed in rats on a cafeteria diet for 17 weeks. Methods and results GSPE is administered in a corrective manner (15 last days of the cafeteria diet) at two doses, 100 and 500 mg GSPE per kg bw. A third, longer treatment in which GSPE (500 mg kg–1 bw) is administered daily every other week during the 17 weeks of the cafeteria diet is also tested. Most GSPE treatments lead to ghrelin accumulation in the stomach, limited CCK secretion in the duodenum, and increased GLP‐1 and PYY mRNA in colon. GSPE also increases cecal hypertrophy and reduces butyrate content. When the treatment is administered daily every other week during 17 weeks, there is also an increase in colon size. These effects are accompanied by a reduced food intake at the end of the experiment when GSPE is administered at 500 mg GSPE kg–1 during the last 15 days, but not on the other treatments, despite an observed reduction in body weight in the longer treatment. Conclusion GSPE modulates the enteroendocrine system in models in which it also reduces food intake or body weight.info:eu-repo/semantics/acceptedVersio

Differential effects of a cafeteria diet and GSPE preventive treatments on the enterohormone secretions of aged vs. young female rats

Grape seed derived procyanidins (GSPE) have been shown to effectively prevent intestinal disarrangements induced by a cafeteria diet in young rats. However, little is known about the effects of procyanidins and cafeteria diet on enterohormone secretion in aged rats, as the ageing processes modify these effects. To study these effects in aged rats, we subjected 21-month-old and young 2-month-old female rats to two sub-chronic preventive GSPE treatments. After three months of cafeteria diet administration, we analysed the basal and stimulated secretion and mRNA expression of CCK, PYY and GLP-1, caecal SCFA and intestinal sizes. We found that the effects of a cafeteria diet on the basal duodenal CCK secretion are age dependent. GLP-1 in the ileum was not modified regardless of the rat's age, and GSPE preventive effects differed in the two age groups. GSPE pre-treatment reduced GLP-1, PYY and ChgA in mRNA in aged ileum tissue, while the cafeteria diet increased these in aged colon. The GSPE treatments only modified low-abundance SCFAs. The cafeteria diet in aged rats increases the caecum size differently from that in young rats and GSPE pre-treatment prevents this increase. Therefore, ageing modifies nutrient sensing, and the cafeteria diet acts mainly on the duodenum and colon, while procyanidins have a larger effect on the ileum.info:eu-repo/semantics/publishedVersio

Modulation of food intake by differential TAS2R stimulation in rat

Metabolic surgery modulates the enterohormone profile, which leads, among other effects, to changes in food intake. Bitter taste receptors (TAS2Rs) have been identified in the gastrointestinal tract and specific stimulation of these has been linked to the control of ghrelin secretion. We hypothesize that optimal stimulation of TAS2Rs could help to modulate enteroendocrine secretions and thus regulate food intake. To determine this, we have assayed the response to specific agonists for hTAS2R5, hTAS2R14 and hTAS2R39 on enteroendocrine secretions from intestinal segments and food intake in rats. We found that hTAS2R5 agonists stimulate glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), and reduce food intake. hTAS2R14 agonists induce GLP1, while hTASR39 agonists tend to increase peptide YY (PYY) but fail to reduce food intake. The effect of simultaneously activating several receptors is heterogeneous depending on the relative affinity of the agonists for each receptor. Although detailed mechanisms are not clear, bitter compounds can stimulate differentially enteroendocrine secretions that modulate food intake in rats

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

BACKGROUND: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. METHODOLOGY/PRINCIPAL FINDINGS: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. CONCLUSIONS/SIGNIFICANCE: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request

Defining Conditions for Optimal Inhibition of Food Intake in Rats by a Grape-Seed Derived Proanthocyanidin Extract

Food intake depends on homeostatic and non-homeostatic factors. In order to use grape seed proanthocyanidins (GSPE) as food intake limiting agents, it is important to define the key characteristics of their bioactivity within this complex function. We treated rats with acute and chronic treatments of GSPE at different doses to identify the importance of eating patterns and GSPE dose and the mechanistic aspects of GSPE. GSPE-induced food intake inhibition must be reproduced under non-stressful conditions and with a stable and synchronized feeding pattern. A minimum dose of around 350 mg GSPE/kg body weight (BW) is needed. GSPE components act by activating the Glucagon-like peptide-1 (GLP-1) receptor because their effect is blocked by Exendin 9-39. GSPE in turn acts on the hypothalamic center of food intake control probably because of increased GLP-1 production in the intestine. To conclude, GSPE inhibits food intake through GLP-1 signaling, but it needs to be dosed under optimal conditions to exert this effect

Subchronic treatment with grape-seed phenolics inhibits ghrelin production despite a short-term stimulation of ghrelin secretion produced by bitter-sensing flavanols

Grape-seed phenolic compounds have recently been described as satiating agents in rats when administered as a whole phenolic extract (GSPE). This satiating effect may involve the release of satiating gut hormones such as GLP-1, although a short-term increase in the orexigenic hormone ghrelin was also reported. In this study, we investigated the short- and long-term effects of GSPE in rats, focusing on the role of the main grape-seed phenolics in ghrelin secretion.status: publishe