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Background To analyze the relationship between the transcriptional expression of lactate dehydrogenase A (LDHA) and the disease control in patients with a head and squamous cell carcinoma (HNSCC). Methods We determined the transcriptional expression of LDHA in 110 HNSCC patients treated with surgery. Results Five-year disease-free survival for patients with a high transcriptional expression of LDHA (n = 51) was 39.2% (95% confidence interval [CI]: 25.3%-53.1%), and for patients with a low expression (n = 59), it was 63.6% (95% CI: 51.1%-76.1%) (p = 0.004). According to the results of a multivariate analysis, patients with a high transcriptional expression of LDHA had a 3.4-fold increased risk of tumor recurrence. Patients with a high transcriptional expression of LDHA tended to show a higher intensity of immunohistochemical expression of LDHA at the tumor cells (p = 0.086). Conclusion In HNSCC patients treated with surgery, a high transcriptional expression of LDHA was associated with a significant decrease in disease-free survival. more...

The impact that healthy aging can have on society has raised great interest in understanding aging mechanisms. However, the effects this biological process may have on the gastrointestinal tract (GIT) have not yet been fully described. Results in relation to changes observed in the enteroendocrine system along the GIT are controversial. Grape seed proanthocyanidin extracts (GSPE) have been shown to protect against several pathologies associated with aging. Based on previous results, we hypothesized that a GSPE pre-treatment could prevent the aging processes that affect the enteroendocrine system. To test this hypothesis, we treated 21-month-old female rats with GSPE for 10 days. Eleven weeks after the treatment, we analyzed the effects of GSPE by comparing these aged animals with young animals. Aging induced a greater endocrine response to stimulation in the upper GIT segments (cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1)), a decrease in the mRNA abundance of GLP-1, peptide YY (PYY) and chromogranin A (ChgA) in the colon, and an increase in colonic butyrate. GSPE-treated rats were protected against a decrease in enterohormone expression in the colon. This effect is not directly related to the abundance of microbiome or short-chain fatty acids (SCFA) at this location. GSPE may therefore be effective in preventing a decrease in the colonic abundance of enterohormone expression induced by aging. more...

It has been previously shown that acutely administered insect Alphitobius diaperinus protein increases food intake in rats and modifies the ex vivo enterohormone secretory profile differently than beef or almond proteins. In this study, we aimed to evaluate whether these effects could be maintained for a longer period and determine the underlying mechanisms.We administered two different insect species to rats for 26 days and measured food intake at different time points. Both insect species increased food intake in the first week, but the effect was later lost. Glucagon-like peptide 1 (GLP-1) and ghrelin were measured in plasma and ex vivo, and no chronic effects on their secretion or desensitization were found. Nevertheless, digested A. diaperinus acutely modified GLP-1 and ghrelin secretion ex vivo.Our results suggest that increases in food intake could be explained by a local ghrelin reduction acting in the small intestine. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John WileySons Ltd on behalf of Society of Chemical Industry. more...

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. more...

The identification of prognostic non-invasive biomarkers is a priority for cancer patients’ care. Circulating microRNA (miRNAs) have been described in numerous human malignancies as diagnostic, prognostic, and therapeutic cancer biomarkers. The aim of our study was to analyze the expression profile of a set of miRNAs, involved in the modulation of the glycolytic pathway, as prognostic factors in human head and neck squamous cell carcinomas (HNSCC). Serum samples of 54 patients with untreated HNSCC were obtained at the time of diagnosis. The prognostic value of circulating miR-26b, miR-124, miR-155 and miR-375 was evaluated towards disease-free survival. We found that there were optimal miRNAs cut-off values for lower risk of recurrence in HNSCC patients. Kaplan–Meier curves showed that higher levels of miR-26b and lower levels of miR-155 were associated with better disease-free survival rates. In the multivariate analysis, patients with serum miR-26b > 0.062 and miR-155 more...

Western-style diet is an obesogenic diet for rodents and humans due to its content of saturated fat and refined sugars, mainly sucrose and, in consequence, sucrose-derived fructose. This type of diets relates with intestinal disturbances when consumed regularly. The aim of this work was to analyse the adaptive morphologic and functional changes at intestinal level derived from the unhealthy components of a Cafeteria diet in rats. The effect of grape seed proanthocyanidin extract (GSPE) in the prevention of diet-induced intestinal dysfunction was also analysed. Rats were fed a 17-week cafeteria diet (CAF) without or with oral-GSPE supplementation, either intermittent GSPE administration (SIT-CAF); last 10-day GSPE supplementation at doses of 100 mg/kg and 500 mg/kg day (CORR-100) and (CORR-500) or pre-supplementation with 500 mg/kg GSPE (PRE-CAF). GSPE-CAF supplemented groups showed similar results to CAF diet group regarding morphology and inflammatory score in the duodenum. As an adaptive response to diet, CAF increased intestinal absorptive surface (1.24-fold) all along the intestinal tract and specifically in the small intestine, duodenum, due to increase villus height and a higher villus/crypt ratio, in addition to increase in Goblet cell percentage and inflammatory index. Animals fed GSPE at the current doses and times had higher villus heights and absorptive surface similar to Cafeteria diet group. In the duodenum, villus height correlated with body weight at 17 week and negatively with MLCK gene expression. In the colon, villus height correlated with the percentage of goblet cells. In conclusion, the CAF diet produced adaptive modifications of the intestine by increasing the absorptive area of the small intestine, the percentage of goblet cells and the inflammatory index at the duodenal level. GSPE supplementation can partially reverse the intestinal morphological changes induced by the high fat/sucrose diet when administered intermittently. more...

Simple Summary The presence of lymph neck node metastasis is the most important clinical prognostic factor in patients with head and neck squamous cell carcinoma. The expression of the semaphorin-3F and neuropilin-2 proteins is involved in the regulation of lymphangiogenesis. We analized the transcriptional expression of semaphorin-3F and neuropilin-2 in head and neck squamous cell carcinoma tumors of patients without clinical or radiology evidence of lymph node involvement treated with elective neck dissection. We found that patients with high semaphorin-3F and low neuropilin-2 had a lower risk of occult lymph node metastasis than the ones who had low semaphorin-3F or high semaphorin-3F and high neuropilin-2. If our results are validated, the expression of the SEMA3F-NRP2 axis could be used as a biomarker predicting the risk of occult lymph node metastasis, with elective neck dissections being indicated exclusively for patients at higher risk. The availability of a biomarker with the capacity to predict the presence of occult lymph node metastases would make it possible to avoid elective neck dissections in low-risk patients, with the consequent decrease in surgical time and morbidity of the treatment without impairing the oncologic outcome. The expression of the semaphorin-3F (SEMA3F) and neuropilin-2 (NRP2) is involved in the regulation of lymphangiogenesis. The present study analyzes the relationship between the transcriptional expression of the SEMA3F-NRP2 genes and the presence of occult lymph node metastases in patients with cN0 head and neck squamous cell carcinomas. We analyzed the transcriptional expression of SEMA3F and NRP2 in a cohort of 53 patients with cN0 squamous cell carcinoma treated with an elective neck dissection. Occult lymph node metastases were found in 37.7% of the patients. Patients with occult lymph node metastases (cN0/pN+) had significantly lower SEMA3F expression values than patients without lymph node involvement (cN0/pN0). Considering the expression of the SEMA3F-NRP2 genes, patients were classified into two groups according to the risk of occult nodal metastasis: Group 1 (n = 34), high SEMA3F/low NRP2 expression, with a low risk of occult nodal involvement (14.7% cN0/pN+); Group 2 (n = 19), low SEMA3F or high SEMA3F/high NRP2 expression, with a high risk of occult nodal involvement (78.9% cN0/pN+). Multivariate analysis showed that patients in Group 2 had a 26.2 higher risk of lymph node involvement than patients in Group 1. There was a significant relationship between the transcriptional expression values of the SEMA3F-NRP2 genes and the risk of occult nodal metastases. more...

Current demand of consumers for healthy and sustainable food products has led the industry to search for different sources of plant protein isolates and concentrates. Legumes represent an excellent nonanimal protein source with high-protein content. Legume species are distributed in a wide range of ecological conditions, including regions with drought conditions, making them a sustainable crop in a context of global warming. However, their use as human food is limited by the presence of antinutritional factors, such as protease inhibitors, lectins, phytates, and alkaloids, which have adverse nutritional effects. Antitechnological factors, such as fiber, tannins, and lipids, can affect the purity and protein extraction yield. Although most are removed or reduced during alkaline solubilization and isoelectric precipitation processes, some remain in the resulting protein isolates. Selection of appropriate legume genotypes and different emerging and sustainable facilitating technologies, such as high-power ultrasound, pulsed electric fields, high hydrostatic pressure, microwave, and supercritical fluids, can be applied to increase the removal of unwanted compounds. Some technologies can be used to increase protein yield. The technologies can also modify protein structure to improve digestibility, reduce allergenicity, and tune technological properties. This review summarizes recent findings regarding the use of emerging technologies to obtain high-purity protein isolates and the effects on techno-functional properties and health. info:eu-repo/semantics/acceptedVersion more...

Protein is considered the most satiating macronutrient, and its effect on satiety and food intake is source-dependent. For the first time, we compared the effect of the administration of an insect or almond preload, both containing 20 g of protein, on appetite and food intake in human subjects. Participants consumed both foods and a vehicle as a liquid preload on three separate days. They were then offered a breakfast and lunch buffet meal at which food intake was measured. Visual analogue scale (VAS) questionnaires were completed following the three preloads to assess appetite and other sensations. At breakfast, reduced energy intake was observed for both preloads compared with vehicle. At lunch, food intake only differed in the insect group, which consumed more than the vehicle. Insect preload increased the total amount of protein ingested with a slight increase in total energy consumed, differently than almond, which significantly increased total protein and energy consumed. There was no correlation between indigestion-sensation ratings and food intake. Moreover, the insect preload resulted in lower sleepiness and tiredness ratings compared with the almond preload. Thus, insect-derived protein may be suitable as a safe ingredient for snacks intended for elderly or infirm patients who require increased protein intake. more...

The cytokine signature present in COVID-19 could provide information on the pathogenic mechanisms of the disease and could identify possible prognostic biomarkers and possible therapeutic targets. In this longitudinal work, we studied the clinical and biochemical parameters and circulating cytokine levels of 146 patients at the time of admission for COVID-19 and 4–6 weeks later. The main objective of this study was to determine whether basal cytokines could be early prognostic biomarkers of COVID-19, and also to analyze the impact of comorbidities, such as obesity or metabolic syndrome (MS), in the cytokine profile. The levels of most inflammatory cytokines were elevated on admission in relation to the level that was reached 4–6 weeks later, except for IL-1β, which was lower on admission; these levels were irrespective of the presence of obesity or MS since the cytokine storm masks these inflammatory processes. Among the cytokines analyzed, those that correlated with a worse prognosis of COVID-19 were resistin, IL-6, IL-8, IL-15, MCP-1 and TNF-α. Specifically, resistin and IL-15 are the best early predictors of requiring invasive ventilation. Therefore, resistin and IL-15 should be included in the personalized treatment decision algorithm of patients with COVID-19. more...

Bitterness is perceived in humans by 25 subtypes of bitter taste receptors (hTAS2R) that range from broadly tuned to more narrowly tuned receptors. hTAS2R5 is one of the most narrowly tuned bitter taste receptors in humans. In this study, we review the literature on this receptor and show there is no consensus about its role. We then compare the possible role of hTAS2R5 with that of the proteins of the TAS2R family in rat, mouse, and pig. A phylogenetic tree of all mammalian TAS2R domain-containing proteins showed that human hTAS2R5 has no ortholog in pig, mouse, or rat genomes. By comparing the agonists that are common to hTAS2R5 and other members of the family, we observed that hTAS2R39 is the receptor that shares most agonists with hTAS2R5. In mouse, some of these agonists activate mTas2r105 and mTas2r144, which are distant paralogs of hTAS2R5. mTas2r144 seems to be the receptor that is most similar to hTAS2R5 because they are both activated by the same agonists and have affinities in the same range of values. Then, we can conclude that hTAS2R5 has a unique functional specificity in humans as it is activated by selective agonists and that its closest functional homolog in mouse is the phylogenetically distant mTas2r144. This research was funded by MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa”, grant number AGL2017-83477-R, C. Grau-Bové received a doctoral research grant from the Martí Franqués program of the Universitat Rovira i Virgili. M. Pinent and X. Terra are Serra Húnter fellows. We would like to express our thanks to Judith Pérez for her contribution to this work. more...

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/publishedVersion more...

The current production of meat presents many disadvantages for the environment and much research focuses on alternative protein sources. Insects are novel protein sources highly valued for their nutritional and sustainable potential. However, many aspects concerning biological and nutritional properties of the insects after digestion, in comparison with other protein sources, are still overlooked. In this work, a comparative study on three different protein sources, namely almond, lean beef and insect Alphitobius diaperinus (lesser mealworm), was performed after in vitro simulated gastrointestinal digestion. An in-depth characterization of the chemical composition of the solubilized protein and lipid fractions of the digesta was performed by applying different analytical techniques, including chromatographic methods coupled to mass spectrometry and more...

The endocrine pancreas plays a key role in metabolism. Procyanidins (GSPE) targets β-cells and glucagon-like peptide-1 (GLP-1)-producing cells, however, there is no information on the effects of GSPE on glucagon. We performed GSPE preventive treatments administered to Wistar rats before or at the same time as they were fed a cafeteria diet during 12 or 17 weeks. We then measured the pancreatic function and GLP-1 production. We found that glucagonemia remains modified by GSPE pre-treatment several weeks after the treatment has finished. The animals showed a higher GLP-1 response to glucose stimulation, together with a trend towards a higher GLP-1 receptor expression in the pancreas. When the GSPE treatment was administered every second week, the endocrine pancreas behaved differently. We show here that glucagon is a more sensitive parameter than insulin to GSPE treatments, with a secretion that is highly linked to GLP-1 ileal functionality and dependent on the type of treatment. more...

Background The aim of this study is to evaluate the relationship between the aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) ratio and local disease control in patients with head and neck squamous cell carcinomas (HNSCC) treated with radiotherapy/chemoradiotherapy. Methods We calculated the pre-treatment AST/ALT ratio in 670 patients with HNSCC treated with radiotherapy (n = 309, 46.1%) or chemoradiotherapy (n = 361, 53.9%). Results Five-year local recurrence-free survival for patients with a low AST/ALT ratio value (n = 529, 79.0%) was 75.0% (95% CI: 71.1-78.9), and for patients with a high value (n = 141, 21.0%) it was 53.4% (CI 95: 44.4-62.4) (p = 0.0001). In a multivariable analysis, patients with a high ratio had nearly twice the risk of having a local tumor recurrence (HR 1.97, 95% CI 1.42-2.75, p = 0.0001). Conclusion The AST/ALT ratio was independently associated with the risk of local recurrence in patients with HNSCC treated with radiotherapy or chemoradiotherapy. more...

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. more...

Adaptive homeostasis declines with age and this leads to, among other things, the appearance of chronic age-related pathologies such as cancer, neurodegeneration, osteoporosis, sarcopenia, cardiovascular disease and diabetes. Grape seed-derived procyanidins (GSPE) have been shown to be effective against several of these pathologies, mainly in young animal models. Here we test their effectiveness in aged animals: 21-month-old female rats were treated with 500 mg GSPE/kg of body weight for ten days. Afterwards they were kept on a chow diet for eleven weeks. Food intake, body weight, metabolic plasma parameters and tumor incidence were measured. The GSPE administered to aged rats had an effect on food intake during the treatment and after eleven weeks continued to have an effect on visceral adiposity. It prevented pancreas dysfunction induced by ageing and maintained a higher glucagon/insulin ratio together with a lower decrease in ketonemia. It was very effective in preventing age-related tumor development. All in all, this study supports the positive effect of GSPE on preventing some age-related pathologies. more...

In this study we compare the interaction of three protein sources—insect, beef, and almond—with the gastrointestinal tract. We measured the enterohormone secretion ex vivo in human and pig intestine treated with in vitro digestions of these foods. Insect and beef were the most effective in inducing the secretion of CCK, while almond was the most effective in inducing PYY in pig duodenum. In the human colon, almond was also the most effective in inducing PYY, and GLP-1 levels were increased by insect and beef. The three digested proteins reduced ghrelin secretion in pig duodenum, while only insect reduced ghrelin secretion in human colon. We also found that food intake in rats increased in groups fed a raw insect pre-load and decreased when fed raw almond. In conclusion, the insect Alphitobius diaperinus modulates duodenal and colonic enterohormone release and increases food intake in rats. These effects differ from beef and almond. more...

Grape seed proanthocyanidin extract (GSPE) modulates several parameters involved in metabolic syndrome. GSPE is a mixture of compounds, some which are rapidly absorbed, while others remain in the lumen where they might have effects that are translated to the whole organism. Our aim was to decipher if the 8-day treatment of GSPE, previously shown to reduce food intake, induces changes in the microbiota and enterohormone secretion. The ratio of Firmicutes : Bacteroidetes was lower in the microbiota of GSPE-treated rats compared to controls, and differences in several taxonomic families and genera were observed. Such modulation led to a reduction in cecal butyrate content. GSPE also increased plasma glucagon-like-peptide-1 (GLP-1). Gallic acid did not induce major changes in the microbiota profile nor in GLP-1 secretion. Correlations between several microbiota taxa and plasma triacylglycerol, adiposity, and enterohormones were observed. Modulation of microbiota may be one of the mechanism by which GSPE impacts metabolic health. more...

Scope A grape-seed proanthocyanidin extract (GSPE) interacts at the intestinal level, enhancing glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) release, which modulate appetite and glucose homeostasis. Thus, enhancing L-cell numbers could be a strategy to promote hormone production, providing a potential strategy for obesity and type-2 diabetes mellitus (T2DM) treatment. Methods and results Mice ileum organoids are used to evaluate the long-term effects of GSPE and two of its main components, epicatechin (EC) and gallic acid (GA), on intestinal differentiation. Hormone levels are determined using RIA and ELISA kits, and gene expression of transcription factors involved in intestinal cell differentiation, as well as markers of different cell types, are assessed by real-time qPCR. GSPE upregulates enterohormone gene expression and content, as well as the pan-endocrine marker chromogranin A. GSPE also modulates the temporal gene expression profile of early and late transcription factors involved in L-cell differentiation. Furthermore, GSPE upregulates goblet cell (Muc2) and enterocyte (sucraseisomaltase) markers, while downregulating stem cell markers (Lgr5+). Although EC and GA modified enterohormone release, they do not reproduce GSPE effects on transcription factor's profile. Conclusions This study shows the potential role of GSPE in promoting enteroendocrine differentiation, effect that is not mediated by EC or GA. more...

The intestinal barrier is constantly exposed to potentially harmful environmental factors, including food components and bacterial endotoxins. When intestinal barrier function and immune homeostasis are compromised (intestinal dysfunction), inflammatory conditions may develop and impact overall health. Evidence from experimental animal and cell culture studies suggests that exposure of intestinal mucosa to proanthocyanidin (PAC)-rich plant products, such as grape seeds, may contribute to maintaining the barrier function and to ameliorating the pathological inflammation present in 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 intestinal dysfunction and in humans, and to provide insights into the underlying biochemical and molecular mechanisms. more...

Flavonoids have been shown to modulate GLP-1 in obesity. GLP-1 induces some of its effects through the intestinal GLP-1 receptor (GLP-1R), though no data exist on how flavonoids affect this receptor. Here, we examine how a dose of grape seed proanthocyanidin extract (GSPE) with anti-obesity activity affects intestinal GLP-1R and analyze whether epigenetics play a role in the long-lasting effects of GSPE. We found that 10-day GSPE administration prior to the cafeteria diet upregulated GLP-1R mRNA in the ileum 17 weeks after the GSPE treatment. This was associated with a hypomethylation of the GLP-1R promoter near the region where the SP1 transcription factor binds. In the colon, the cafeteria diet upregulated GLP-1R without showing any GSPE effect. In conclusion, we have identified long-lasting GSPE effects on GLP-1R gene expression in the ileum that are partly mediated by hypomethylation at the gene promoter and may affect the SP1 binding factor. more...

Anti-inflammatory and barrier-protective properties have been attributed to proanthocyanidins in the context of intestinal dysfunction, however little information is available about the impact of these phytochemicals on intestinal barrier integrity and immune response in the human. Here we assessed the putative protective properties of a grape-seed proanthocyanidin extract (GSPE) against dextran sodium sulfate (DSS)-induced acute dysfunction of the human colon in an Ussing chamber system. Human proximal and distal colon tissues from colectomized patients were submitted ex vivo for a 30-min preventive GSPE treatment (50 or 200 µg mL−1) followed by 1-h incubation with DSS (12% w v−1). Transepithelial electrical resistance (TEER), permeation of a fluorescently-labeled dextran (FD4) and proinflammatory cytokine release [tumor necrosis factor (TNF)-α and interleukin (IL)-1β] of colonic tissues were determined. DSS reduced TEER (45–52%) in both the proximal and distal colon; however, significant increments in FD4 permeation (fourfold) and TNF-α release (61%) were observed only in the proximal colon. The preventive GSPE treatment decreased DSS-induced TEER loss (20–32%), FD4 permeation (66–73%) and TNF-α release (22–33%) of the proximal colon dose-dependently. The distal colon was not responsive to the preventive treatment but showed a reduction in IL-1β release below basal levels with the highest GSPE concentration. Our results demonstrate potential preventive effects of GSPE on human colon dysfunction. Further studies are required to test whether administering GSPE could be a complementary therapeutic approach in colonic dysfunction associated with metabolic disorders and inflammatory bowel disease. more...

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle. more...

Obesity and ageing are current issues of global concern. Adaptive homeostasis is compromised in the elderly, who are more likely to suffer age-related health issues, such as obesity, metabolic syndrome, and cardiovascular disease. The current worldwide prevalence of obesity and higher life expectancy call for new strategies for treating metabolic disorders. Grape-seed proanthocyanidin extract (GSPE) is reported to be effective in ameliorating these pathologies, especially in young animal models. In this study, we aimed to test the effectiveness of GSPE in modulating obesity-related pathologies in aged rats fed an obesogenic diet. To do so, 21-month-old rats were fed a high-fat/high-sucrose diet (cafeteria diet) for 11 weeks. Two time points for GSPE administration (500 mg/kg body weight), i.e., a 10-day preventive GSPE treatment prior to cafeteria diet intervention and a simultaneous GSPE treatment with the cafeteria diet, were assayed. Body weight, metabolic parameters, liver steatosis, and systemic inflammation were analysed. GSPE administered simultaneously with the cafeteria diet was effective in reducing body weight, total adiposity, and liver steatosis. However, the preventive treatment was effective in reducing only mesenteric adiposity in these obese, aged rats. Our results confirm that the simultaneous administration of GSPE improves metabolic disruptions caused by the cafeteria diet also in aged rats. more...

The gastrointestinal alterations associated with the consumption of an obesogenic diet, such as inflammation, permeability impairment and oxidative stress, have been poorly explored in both diet-induced obesity (DIO) and genetic obesity. The aim of the present study was to examine the impact of an obesogenic diet on the gut health status of DIO rats in comparison with the Zucker (fa/fa) rat leptin receptor-deficient model of genetic obesity over time. For this purpose, female Wistar rats (n 48) were administered a standard or a cafeteria diet (CAF diet) for 12, 14·5 or 17 weeks and were compared with fa/fa Zucker rats fed a standard diet for 10 weeks. Morphometric variables, plasma biochemical parameters, myeloperoxidase (MPO) activity and reactive oxygen species (ROS) levels in the ileum were assessed, as well as the expressions of proinflammatory genes (TNF-α and inducible nitric oxide synthase (iNOS)) and intestinal permeability genes (zonula occludens-1, claudin-1 and occludin). Both the nutritional model and the genetic obesity model showed increased body weight and metabolic alterations at the final time point. An increase in intestinal ROS production and MPO activity was observed in the gastrointestinal tracts of rats fed a CAF diet but not in the genetic obesity model. TNF-α was overexpressed in the ileum of both CAF diet and fa/fa groups, and ileal inflammation was associated with the degree of obesity and metabolic alterations. Interestingly, the 17-week CAF group and the fa/fa rats exhibited alterations in the expressions of permeability genes. Relevantly, in the hyperlipidic refined sugar diet model of obesity, the responses to chronic energy overload led to time-dependent increases in gut inflammation and oxidative stress. more...

cope : 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. Methods and results : GSPE produced a short-term increase in plasma ghrelin in rats after an acute treatment. A mouse ghrelinoma cell line was used to test the effects of the main pure grape-seed phenolic compounds on ghrelin release. Monomeric flavanols stimulated ghrelin secretion by activating bitter taste receptors. In contrast, gallic acid (GA) and oligomeric flavanols inhibited ghrelin release. The ghrelin-inhibiting effects of GA were confirmed in rats and in rat duodenal segments. One day after the last dose of a subchronic treatment, GSPE decreased plasma ghrelin in rats, ghrelin secretion in intestinal segments and ghrelin mRNA expression in stomach. Conclusion : The sustained satiating effects of GSPE are related to a long-term decrease in ghrelin expression. GA and oligomeric flavanols play a ghrelin-inhibiting role in this process. This article is protected by copyright. All rights reserved more...

In SARS-CoV-2-infected patients, obesity, hypertension, and diabetes are dangerous factors that may result in death. Priority in detection and specific therapies for these patients are necessary. We wanted to investigate the impact of obesity and metabolic syndrome (MS) on the clinical course of COVID-19 and whether prognostic biomarkers described are useful to predict the evolution of COVID-19 in patients with obesity or MS. This prospective cohort study included 303 patients hospitalized for COVID-19. Participants were first classified according to the presence of obesity, then, they were classified according to the presence of MS. Clinical, radiologic, and analytical parameters were collected. We reported that patients with obesity presented moderate COVID-19 symptoms and pneumonia, bilateral pulmonary infiltrates, and needed tocilizumab more frequently. Meanwhile, patients with MS presented severe pneumonia and respiratory failure more frequently, they have a higher mortality rate, and they also showed higher creatinine and troponin levels. The main findings of this study are that IL-6 is a potential predictor of COVID-19 severity in patients with obesity, while troponin and LDH can be used as predictive biomarkers of COVID-19 severity in MS patients. Therefore, treatment for COVID-19 in patients with obesity or MS should probably be intensified and personalized. more...

In this study we compare the interaction of three protein sources&mdash, insect, beef, and almond&mdash, with the gastrointestinal tract. We measured the enterohormone secretion ex vivo in human and pig intestine treated with in vitro digestions of these foods. Insect and beef were the most effective in inducing the secretion of CCK, while almond was the most effective in inducing PYY in pig duodenum. In the human colon, almond was also the most effective in inducing PYY, and GLP-1 levels were increased by insect and beef. The three digested proteins reduced ghrelin secretion in pig duodenum, while only insect reduced ghrelin secretion in human colon. We also found that food intake in rats increased in groups fed a raw insect pre-load and decreased when fed raw almond. In conclusion, the insect Alphitobius diaperinus modulates duodenal and colonic enterohormone release and increases food intake in rats. These effects differ from beef and almond. more...

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe the molecular targets and the duration of the effects. We treated rats with 500 mg GSPE/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on cafeteria diet, we used RT-PCR to measure the mRNA of the key energy metabolism enzymes from liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. Liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, fatty oxidation (Oxct1 and Cpt1b mRNA) was increased in muscle. However, after seventeen weeks, there was a completely different gene expression pattern. As conclusion, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle more...

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/acceptedVersion more...

Flavonoids have been shown to modulate GLP-1 in obesity. GLP-1 induces some of its effects through the intestinal GLP-1 receptor (GLP-1R), though no data exist on how flavonoids affect this receptor. Here, we examine how a dose of grape seed proanthocyanidin extract (GSPE) with anti-obesity activity affects intestinal GLP-1R and analyze whether epigenetics play a role in the long-lasting effects of GSPE. We found that 10-day GSPE administration prior to the cafeteria diet upregulated GLP-1R mRNA in the ileum 17 weeks after the GSPE treatment. This was associated with a hypomethylation of the GLP-1R promoter near the region where the SP1 transcription factor binds. In the colon, the cafeteria diet upregulated GLP-1R without showing any GSPE effect. In conclusion, we have identified long-lasting GSPE effects on GLP-1R gene expression in the ileum that are partly mediated by hypomethylation at the gene promoter and may affect the SP1 binding factor. more...

The enteroendocrine system coordinates gastrointestinal (GI) tract functionality and the whole organism. However, the scarcity of enteroendocrine cells and their scattered distribution make them difficult to study. Here, we glued segments of the GI wall of pigs to a silicon tube, keeping the apical and the basolateral sides separate. The fact that there was less than 1% of 70-kDa fluorescein isothiocyanate (FITC)-dextran on the basolateral side proved that the gluing was efficient. Since the lactate dehydrogenase leakage at basolateral side was lower than 0.1% (1.40 ± 0.17 nKatals) it proved that the tissue was viable. The intestinal barrier function was maintained as it is in segments mounted in Ussing chambers (the amount of Lucifer Yellow crossing it, was similar between them; respectively, % LY, 0.48 ± 0.13; 0.52 ± 0.09; p > 0.05). Finally, apical treatments with two different extract produced differential basolateral enterohormone secretions (basolateral PYY secretion vs control; animal extract, 0.35 ± 0.16; plant extract, 2.5 ± 0.74; p < 0.05). In conclusion, we report an ex vivo system called "Ap-to-Bas" for assaying vectorial transepithelial processes that makes it possible to work with several samples at the same time. It is an optimal device for enterohormone studies in the intestine. more...

Grape-seed proanthocyanidins' role as stimulators of active GLP-1 in rats suggests that they could be effective as satiating agents. Wistar rats were used to study the effects of proanthocyanidins on food intake with different doses, administration times and proanthocyanidin extract compositions. A dose of 423 mg of phenolics per kg body weight (BW) of grape-seed proanthocyanidin extract (GSPE) was necessary to decrease the 12-hour cumulative food intake by 18.7 ± 3.4%. Proanthocyanidins were effective when delivered directly into the gastrointestinal tract one hour before, or simultaneously at the start of the feeding period. Proanthocyanidins without galloyl forms, such as those from cocoa extract, were not as effective as grape-seed derived forms. GSPE increased the portal levels of active GLP-1 and total ghrelin and decreased the CCK levels, simultaneously with a decrease in gastric emptying. In conclusion, grape-seed proanthocyanidins could be useful as a satiating agent under the conditions defined in this study. more...