pinecone/core-2020-05-10-deduplication huggingface dataset:
A role for peroxisome proliferator-activated receptor gamma in resveratrol-induced colon cancer cell apoptosis.

International audienceResveratrol may function as a chemopreventive agent. A recent clinical study demonstrates a reduction in tumor cell proliferation in colorectal patients receiving repeated oral ingestion of resveratrol. However, gaps remain in our knowledge of the molecular mechanisms by which resveratrol exerts its chemopreventive effect. We have previously demonstrated that resveratrol induces apoptosis in colon cancer cells and that resveratrol can sensitize chemoresistant colon cancer cells to various drugs. Based on its ability to activate peroxisome proliferator-activated receptor gamma (PPARγ) in colon cancer cells, we sought to determine the implication of this nuclear transcription factor in resveratrol-induced apoptosis. Transient transfection of cancer cells with a dominant-negative PPARγ mutant or treatment with a PPARγ antagonist (GW9662) reversed the inhibitory effect of resveratrol. Moreover, GW9662 prevented disruption of the cell cycle induced by resveratrol and consequently abrogated resveratrol-induced apoptosis. Tumor cell death was potentiated by combining resveratrol with rosiglitazone, a PPARγ agonist. The results show that PPARγ plays a role in resveratrol-induced apoptosis of colon carcinoma cells. The combination of resveratrol with a PPARγ agonist could be a promising pharmacological approach for treatment of colorectal cancer
A metabolomics-driven approach to predict cocoa product consumption by designing a multimetabolite biomarker model in free-living subjects from the PREDIMED study

SCOPE: The aim of the current study was to apply an untargeted metabolomics strategy to characterize a model of cocoa intake biomarkers in a free-living population. METHODS AND RESULTS: An untargeted HPLC-q-ToF-MS based metabolomics approach was applied to human urine from 32 consumers of cocoa or derived products (CC) and 32 matched control subjects with no consumption of cocoa products (NC). The multivariate statistical analysis (OSC-PLS-DA) showed clear differences between CC and NC groups. The discriminant biomarkers identified were mainly related to the metabolic pathways of theobromine and polyphenols, as well as to cocoa processing. Consumption of cocoa products was also associated with reduced urinary excretions of methylglutarylcarnitine, which could be related to effects of cocoa exposure on insulin resistance. To improve the prediction of cocoa consumption, a combined urinary metabolite model was constructed. ROC curves were constructed to evaluate the model and individual metabolites. The AUC values (95% CI) for the model were 95.7% (89.8-100%) and 92.6% (81.9-100%) in training and validation sets, respectively, whereas the AUCs for individual metabolites were <90%. CONCLUSIONS: The metabolic signature of cocoa consumption in free-living subjects reveals that combining different metabolites as biomarker models improves prediction of dietary exposure to cocoa
Zinc supplementation influences genomic stability biomarkers, antioxidant activity and zinc transporter genes in an elderly Australian population with low zinc status

An increased intake of Zinc (Zn) may reduce the risk of degenerative diseases but may prove to be toxic if taken in excess. This study aimed to investigate whether zinc carnosine supplement can improve Zn status, genome stability events, and Zn transporter gene expression in an elderly (65-85 years) South Australian cohort with low plasma Zn levels.A 12-week placebo-controlled intervention trial was performed with 84 volunteers completing the study, (placebo, n = 42) and (Zn group, n = 42). Plasma Zn was significantly increased (p < 0.05) by 5.69% in the Zn supplemented group after 12 weeks. A significant (p < 0.05) decrease in the micronucleus frequency (-24.18%) was observed for the Zn supplemented cohort relative to baseline compared to the placebo group. Reductions of -7.09% for tail moment and -8.76% for tail intensity were observed for the Zn group (relative to baseline) (p < 0.05). Telomere base damage was found to be also significantly decreased in the Zn group (p < 0.05). Both MT1A and ZIP1 expression showed a significant increase in the Zn supplemented group (p < 0.05).Zn supplementation may have a beneficial effect in an elderly population with low Zn levels by improving Zn status, antioxidant profile, and lowering DNA damage.Razinah Sharif, Philip Thomas, Peter Zalewski, and Michael Fenec
Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells

This study was supported by funding from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the BBSRC Diet and Health Research Industry Club (BBSRC-DRINC), including BB/H532059/1, BB/H004963/1, BB/I006028/1, BB/I005943/1 and BB/J004545/1. A.C. is a Royal Society Wolfson Research Merit Award Holder.Scope : In vitro and in vivo studies suggest that dietary anthocyanins modulate cardiovascular disease risk; however, given anthocyanins extensive metabolism, it is likely that their degradation products and conjugated metabolites are responsible for this reported bioactivity.  Methods and results : Human vascular endothelial cells were stimulated with either oxidized LDL (oxLDL) or cluster of differentiation 40 ligand (CD40L) and cotreated with cyanidin-3-glucoside and 11 of its recently identified metabolites, at 0.1, 1, and 10 μM concentrations. Protein and gene expression of IL-6 and VCAM-1 was quantified by ELISA and RT-qPCR. In oxLDL-stimulated cells the parent anthocyanin had no effect on IL-6 production, whereas numerous anthocyanin metabolites significantly reduced IL-6 protein levels; phase II conjugates of protocatechuic acid produced the greatest effects (>75% reduction, p ≤ 0.05). In CD40L-stimulated cells the anthocyanin and its phase II metabolites reduced IL-6 protein production, where protocatechuic acid-4-sulfate induced the greatest reduction (>96% reduction, p ≤ 0.03). Similarly, the anthocyanin and its metabolites reduced VCAM-1 protein production, with ferulic acid producing the greatest effect (>65% reduction, p ≤ 0.04).  Conclusion : These novel data provide evidence to suggest that anthocyanin metabolites are bioactive at physiologically relevant concentrations and have the potential to modulate cardiovascular disease progression by altering the expression of inflammatory mediators.Publisher PDFPeer reviewe
Ability of the gut microbiota to produce PUFA-derived bacterial metabolites: Proof of concept in germ-free versus conventionalized mice.

SCOPE: The gut microbiota is able to modulate host physiology through the production of bioactive metabolites. Our recent studies suggest that changes in gut microbiota composition upon prebiotics supplementation alter tissue levels of PUFA-derived metabolites in mice. However, in vivo evidence that gut microbes produces PUFA-derived metabolites is lacking. This study aimed to decipher the contribution of gut microbes versus that of the host in PUFA-derived metabolite production.
METHODS AND RESULTS: To achieve this goal, we compared the proportion of PUFA-derived metabolites and the expression of fatty acid desaturases in germ-free (GF) and conventionalized (CONV) mice fed either a low fat or Western diet. Higher concentrations of PUFA-derived metabolites were found in the colonic contents of conventionalized mice (CONV) mice compared to GF mice. The abundance of these metabolites in host tissues was modulated by dietary treatments but not by microbial status. Although microbial status did significantly influence desaturase expression, no correlations between host enzymes and tissue PUFA-derived metabolite levels were observed.
CONCLUSION: Together, these results highlight the ability of the gut microbiota to produce PUFA-derived metabolites from dietary PUFA. However, microbial production of these metabolites in colonic contents is not necessarily associated with modifications of their concentration in host tissues
Dose effect on the uptake and accumulation of hydroxytyrosol and its metabolites in target tissues in rats

Hydroxytyrosol (HT) is the most prominent phenolic compound of virgin olive oil and due to its scientifically validated biological activities it is entering to the market as a potentially useful supplement for cardiovascular disease prevention. The aim of the present study was to investigate the relationship between the HT dose intake and its tissue uptake in rats, and thus, providing complementary information in relation to the target-dose relationship. Rats were given a refined olive oil enriched with HT at different doses (1, 10, and 100 mg/kg) and they were sacrificed after 5 h to ensure the cell tissue uptake of HT and its metabolites. Plasma samples and different organs as liver, kidney, heart and brain were obtained, and HT metabolites were analyzed by UPLC-MS/MS. The results showed that HT and its metabolites could be accumulated in a dose-dependent manner basically in the liver, kidney, and brain and were detected in these tissues even at nutritionally relevant human doses. The detection of free HT in liver and kidney was noteworthy. To date, this appears to be the only biologically active form, and thus, it provides relevant information for optimizing the potential applications of HT to prevent certain hepatic and renal diseases. In recent years, HT and its derivatives have led to a great interest from the virgin olive oil producers and manufacturers of nutraceutical supplements. The increasing interest in HT is mainly due to the European Food Safety Agency (EFSA) Panel on Dietetic Products, Nutrition, and Allergies (NDA) scientific opinion that established a cause-and-effect relationship between the consumption of olive oil polyphenols and protection of LDL particles from oxidative damage [1]. Based on this positive opinion, the health claim “Olive oil polyphenols contribute to the protection of blood lipids from oxidative stress” was included in the list of health claims [2], being the only authorized health claim in the European Union regarding polyphenols and health.This study was supported by the Spanish Ministry of Education and Science (AGL2012-40144-C03-03, AGL2012-40144- C03-02 and AGL2012-40144-C03-01 projects), by the University of Lleida through the M.C. L´opez de las Hazas and L. Rubi´o grant. CIBERobn is an iniciative of Instituto de Salud Carlos III (ISCIII). The authors are grateful for the generous gift of hydroxytyrosol from Seprox Biotech, Madrid, Spai
Determination of the potential bioavailability of plant microRNAs using a simulated human digestion process

The “dietary xenomiR hypothesis” proposes that microRNAs (miRNAs) in foodstuffs survive transit through the mammalian gastrointestinal tract and pass into cells intact to affect gene regulation. However, debate continues as to whether dietary intake poses a feasible route for such exogenous gene regulators. Understanding on miRNA levels during pre-treatments of human diet is essential to test their bioavailability during digestion. This study makes the novel first use of an in vitro method to eliminate the inherent complexities and variability of in vivo approaches used to test this hypothesis. Plant miRNA levels in soybean and rice were measured during storage, processing, cooking, and early digestion using real-time PCR. We have demonstrated for the first time that storage, processing, and cooking does not abolish the plant miRNAs present in the foodstuffs. In addition, utilizing a simulated human digestion system revealed significant plant miRNA bioavailability after early stage digestion for 75 min. Attenuation of plant messenger RNA and synthetic miRNA was observed under these conditions. Even after an extensive pretreatment, plant-derived miRNA, delivered by typical dietary ingestion, has a robustness that could make them bioavailable for uptake during early digestion. The potential benefit of these regulatory molecules in pharma-nutrition could be explored further
Maternal obesity in females born small: pregnancy complications and offspring disease risk

Obesity is a major public health crisis, with 1.6 billion adults worldwide being classified as overweight or obese in 2014. Therefore, it is not surprising that the number of women who are overweight or obese at the time of conception is increasing. Obesity during pregnancy is associated with the development of gestational diabetes and preeclampsia. The developmental origins of health and disease hypothesis proposes that perturbations during critical stages of development can result in adverse fetal changes, which leads to an increased risk of developing diseases in adulthood. Of particular concern, children born to obese mothers are at a greater risk of developing cardiometabolic disease. One subset of the population who are predisposed to developing obesity are children born small for gestational age, which occurs in 10% of pregnancies worldwide. Epidemiological studies report that these growth restricted children have an increased susceptibility to type 2 diabetes, obesity and hypertension. Importantly during pregnancy, growth restricted females have a higher risk of developing cardiometabolic disease, indicating that they may have an exacerbated phenotype if they are also overweight or obese. Thus the development of early pregnancy interventions targeted to obese mothers may prevent their children from developing cardiometabolic disease in adulthood. This article is protected by copyright. All rights reserved
Protective effect of hydroxytyrosol and its predominant plasmatic human metabolites against endothelial dysfunction in human aortic endothelial cells

Scope

Hydroxytyrosol (HT) is the major phenolic compound in virgin olive oil (VOO) in free and conjugated forms that may exert health benefits against atherosclerosis. The native form of HT is undetectable in plasma due to an extensive first pass phase II metabolism. Therefore, it is necessary to find strategies to obtain HT metabolites and to demonstrate their protective role against the endothelial dysfunction.
Methods and results

Biosynthesis of the main plasmatic HT metabolites was performed through Caco-2 cells. The bioactivity of HT and the mixture of metabolites was tested at physiological concentrations (1, 2, 5, and 10 μM) in human aortic endothelial cells (HAEC) co-incubated with TNF-α (10 ng/mL) for 18 and 24 h. After the incubations, cells and media were analyzed to test possible deconjugation of metabolites or conjugation of HT. Both HT and metabolites significantly reduced the secretion of E-selectin, P-selectin, ICAM-1, and VCAM-1, but only HT metabolites further reduced MCP-1 at 24 h. HT underwent a conjugation process after incubation leading to its main metabolites in a dose-dependent manner.
Conclusion

Physiological HT metabolites, synthetized for the first time by using an intestinal cell model, might be responsible in part for the protection against endothelial dysfunction.This studywas supported by the Spanish Ministry of Education and Science, The MEFOPC Project (AGL2012-40144-C03-03, AGL2012-40144-C03-02 and AGL2012-40144-C03-01) and by the University of Lleida through the M-C. L´opez de las Hazas grant
Systematic analysis of the polyphenol metabolome using the Phenol-Explorer database

SCOPE: The Phenol-Explorer web database details 383 polyphenol metabolites identified in human and animal biofluids from 221 publications. Here we exploit these data to characterize and visualize the polyphenol metabolome, the set of all metabolites derived from phenolic food components. METHODS AND RESULTS: Qualitative and quantitative data on 383 polyphenol metabolites as described in 424 human and animal intervention studies were systematically analyzed. Of these metabolites, 301 were identified without prior enzymatic hydrolysis of biofluids, and included glucuronide and sulfate esters, glycosides, aglycones, and O-methyl ethers. Around one third of these compounds are also known as food constituents and corresponded to polyphenols absorbed without further metabolism. Many ring-cleavage metabolites formed by gut microbiota were noted, mostly derived from hydroxycinnamates, flavanols and flavonols. Median maximum plasma concentrations (Cmax ) of all human metabolites were 0.09 μM and 0.32 μM when consumed from foods or dietary supplements respectively. Median time to reach maximum plasma concentration in humans (Tmax ) was 2.18 h. CONCLUSION: These data show the complexity of the polyphenol metabolome and the need to take into account biotransformations to understand in vivo bioactivities and the role of dietary polyphenols in health and disease. This article is protected by copyright. All rights reserved
Changes in the human plasma and urinary metabolome associated with acute dietary exposure to sucrose and the identification of potential biomarkers of sucrose intake

This is the peer reviewed version of the following article: Beckmann, M., Joosen, A. M., Clarke, M. M., Mugridge, O., Frost, G., Engel, B., Talliart, K., Lloyd, A., Draper, J. & Lodge, J. K (2015).Changes in the human plasma and urinary metabolome associated with acute dietary exposure to sucrose and the identification of potential biomarkers of sucrose intake. Molecular Nutrition and Food Research , which has been published in final form at http://dx.doi.org/doi:10.1002/mnfr.201500495. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Scope The intake of sucrose is of public health concern but limited information is available on the metabolic effects of short-term exposure. Our aim was to use metabolomics to investigate the metabolic impact of acute sucrose exposure. Methods and results We performed a randomized, parallel, single-dose feeding study on healthy females (n = 90, aged 29.9 ? 4.7 years, BMI 23.3 ? 2.5 kg/m2) consuming either 0, 50, or 100 g sucrose in 500 mL water. Blood and urine samples were taken before and 24 h post sucrose intake. Urine and plasma samples underwent detailed metabolite profiling analysis using established protocols. Flow-injection electrospray MS fingerprinting analysis showed that 3 h after intake was the most informative time point in urine and plasma and out of 120 explanatory signals, highlighted 16 major metabolite signals in urine and 25 metabolite signals in plasma that were discriminatory and correlated with sucrose intake over time. The main confirmed metabolites positively correlated with intake were sucrose, fructose, and erythronic acid, while those negatively correlating with intake included fatty acids and derivatives, acyl-carnitines, and ketone bodies. GC-TOF-MS profiling analysis confirmed the fingerprinting data. Conclusion Acute exposure to sucrose identified a number of metabolites correlated with sucrose intake and several compounds attributed to metabolic fasting.authorsversionPeer reviewe
Plasma metabolomic biomarkers of mixed nuts exposure inversely correlate with severity of metabolic syndrome

SCOPE: To identify the most discriminant dietary biomarkers of nuts exposure in subjects with metabolic syndrome (MetS), and investigate the potential association between exposure and the severity of the MetS diagnostic traits. METHODS AND RESULTS: We applied the untargeted LC-ESI-qToF-MS-driven metabolomic workflow to explore the changes occurring in the plasma metabolome of MetS subjects following 12-week intake of mixed nuts (30 g/d) (nuts versus control groups). Urolithin A glucuronide was the most discriminative biomarker of nut exposure, showing the highest predictive capacity [ROC AUC = 89.6% (80.8-98.4)] despite the inter-individual variation expected for a host-microbial cometabolite. Furthermore, the detection of urolithin A glucuronide in plasma showed significant inverse correlation with basal abdominal adiposity (waist circumference: r = -0.550, p<0.01; waist-hip ratio: r = -0.409, p<0.05) and impaired glycemic control (fasting insuli & HOMA-IR: r = -0.417, p<0.05). Significant changes in medium-chain dicarboxylic acids, recognized as alternative energy substrates that are particularly relevant in the case of glycemic control impairment, were also associated with nut consumption. CONCLUSION: Higher levels of urolithin are reported in subjects with less severe MetS traits, especially in females. We believe that this inverse correlation may be related with profile of gut microbial dysbiosis, recently associated to subjects with MetS
Targeting pancreatic cancer using a combination of gemcitabine with the omega-3 polyunsaturated fatty acid emulsion, Lipidem™

Scope\ud
\ud
Pancreatic cancer remains a disease of poor prognosis, with alternate strategies being sought to improve therapeutic efficacy. Omega-3 fatty acids have shown clinical benefit, and mechanisms of action are under investigation.\ud
Methods and results\ud
\ud
Proliferation assays, flow cytometry, invasion assays, ELISA and western blotting were used to investigate efficacy of omega-3 fatty acids alone and in combination with gemcitabine. The docosahexanoic acid (DHA)/eicosapentanoic acid (EPA) combination, Lipidem™, in combination with gemcitabine inhibited growth in pancreatic cancer and pancreatic stellate cell (PSC) lines, with PSCs exhibiting greatest sensitivity to this combination. Invasion of pancreatic cancer cells and PSCs in a 3D spheroid model, was inhibited by combination of gemcitabine with Lipidem™. PSCs were required for cancer cell invasion in an organotypic co-culture model, with invasive capacity reduced by Lipidem™ alone. Platelet-derived growth factor (PDGF) is a key cytokine in pro-proliferative and invasion signalling, and thus a critical regulator of interactions between pancreatic cancer cells and adjacent stroma. Platelet-derived growth factor (PDGF-BB) secretion was completely inhibited by the combination of Lipidem™ with gemcitabine in cancer cells and PSCs.\ud
Conclusion\ud
\ud
Lipidem™ in combination with gemcitabine, has anti-proliferative and anti-invasive efficacy in vitro, with pancreatic stellate cells exhibiting the greatest sensitivity to this combination.Peer-reviewedPost-prin
Differential effects of Epigallocatechin-3-gallate containing supplements on correcting skeletal defects in a Down syndrome mouse model

SCOPE: Down syndrome (DS), caused by trisomy of human chromosome 21 (Hsa21), is characterized by a spectrum of phenotypes including skeletal abnormalities. The Ts65Dn DS mouse model exhibits similar skeletal phenotypes as humans with DS. DYRK1A, a kinase encoded on Hsa21, has been linked to deficiencies in bone homeostasis in DS mice and individuals with DS. Treatment with Epigallocatechin-3-gallate (EGCG), a known inhibitor of Dyrk1a, improves some skeletal abnormalities associated with DS in mice. EGCG supplements are widely available but the effectiveness of different EGCG-containing supplements has not been well studied.
METHODS AND RESULTS: Six commercially available supplements containing EGCG were analyzed, and two of these supplements were compared with pure EGCG for their impact on skeletal deficits in a DS mouse model. The results demonstrate differential effects of commercial supplements on correcting skeletal abnormalities in Ts65Dn mice. Different EGCG-containing supplements display differences in degradation, polyphenol content, and effects on trisomic bone.
CONCLUSION: This work suggests that the dose of EGCG and composition of EGCG-containing supplements may be important in correcting skeletal deficits associated with DS. Careful analyses of these parameters may lead to a better understanding of how to improve skeletal and other deficits that impair individuals with DS