Mediterranean diet enriched in extra-virgin olive oil or nuts modulates circulating exosomal non-coding RNAs.

PURPOSE: Exosomes are extracellular vesicles secreted by cells, which can transport different molecules, including nucleic acids. Dietary habits may induce gene regulation through the modulation of exosomal RNAs. We aimed at characterizing exosomal lncRNAs, mRNA and miRNAs modulation after a 1-year adherence to a low-fat diet (LFD) or to Mediterranean-based diets enriched in extra-virgin olive oil (MedDiet + EVOO) or in a mixture of nuts (MedDiet + Nuts). METHODS: Plasma samples were collected, at baseline and after 1 year of dietary interventions, from 150 participants included in the PREDIMED study (Reus Center). LncRNAs, mRNAs and miRNAs were isolated from plasma exosomes and screened. RT-qPCR validation was performed for miRNAs. RESULTS: Compared with LFD, 413 lncRNAs and 188 mRNAs, and 476 lncRNAs and 235 mRNAs were differentially modulated in response to the MedDiet + EVOO and MedDiet + Nuts interventions, respectively. In addition, after 1 year of dietary interventions, 26 circulating miRNAs were identified as differentially expressed between groups. After 1 year of intervention, 11 miRNAs significantly changed in LFD group, while 8 and 21 were modulated in response to the MedDiet enriched with EVOO or nuts, respectively. Bioinformatic analyses of differentially expressed miRNAs and their validated target genes suggest certain metabolic pathways are modulated by LFD (PI3K-Akt and AMPK), MedDiet + EVOO (PI3K-Akt, NF-kappa B, HIF-1, and insulin resistance), and MedDiet-Nuts (FoxO, PI3K-Akt, AMPK, p53 and HIF-1) interventions. CONCLUSION: Results show that 1-year MedDiet + Nuts and MedDiet + EVOO dietary interventions modulate exosomal RNA content, with the former affecting a higher number of miRNAs. The modulation of exosomal RNAs could help explain how the adherence to a Mediterranean diet may lead to beneficial effects and deserves further investigation.

Comparative Transcriptomes of the Body Wall of Wild and Farmed Sea Cucumber Isostichopus badionotus.

Overfishing of sea cucumber Isostichopus badionotus from Yucatan has led to a major population decline. They are being captured as an alternative to traditional species despite a paucity of information about their health-promoting properties. The transcriptome of the body wall of wild and farmed I. badionotus has now been studied for the first time by an RNA-Seq approach. The functional profile of wild I. badionotus was comparable with data in the literature for other regularly captured species. In contrast, the metabolism of first generation farmed I. badionotus was impaired. This had multiple possible causes including a sub-optimal growth environment and impaired nutrient utilization. Several key metabolic pathways that are important in effective handling and accretion of nutrients and energy, or clearance of harmful cellular metabolites, were disrupted or dysregulated. For instance, collagen mRNAs were greatly reduced and deposition of collagen proteins impaired. Wild I. badionotus is, therefore, a suitable alternative to other widely used species but, at present, the potential of farmed I. badionotus is unclear. The environmental or nutritional factors responsible for their impaired function in culture remain unknown, but the present data gives useful pointers to the underlying problems associated with their aquaculture.

Sirt1 protects from K-Ras-driven lung carcinogenesis.

The NAD+-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-RasG12V-driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs.

Exercise dose affects the circulating microRNA profile in response to acute endurance exercise in male amateur runners.

The systemic response to exercise is dose-dependent and involves a complex gene expression regulation and cross-talk between tissues. This context ARISES the need for analyzing the influence of exercise dose on the profile of circulating microRNAs (c-miRNAs), as emerging posttranscriptional regulators and intercellular communicators. Thus, we hypothesized that different exercise doses will determine specific c-miRNA signatures that will highlight its potential as exercise dose biomarker. Nine active middle-aged males completed a 10-km race (10K), a half-marathon (HM), and a marathon (M). Blood samples were collected immediately before and after races. Plasma RNA was extracted, and a global screening of 752 microRNAs was analyzed using RT-qPCR. Three different c-miRNA profiles were defined according to the three doses. In 10K, 14 c-miRNAs were found to be differentially expressed between pre- and post-exercise, 13 upregulated and 1 downregulated. Regarding HM, 13 c-miRNAs were found to be differentially modulated, in all the cases upregulated. A total of 28 c-miRNAs were found to be differentially expressed in M, 21 overexpressed and 7 repressed after this race. We had also found 3 common c-miRNAs between 10K and M and 2 common c-miRNAs between 10K and HM. In silico analysis supported a close association between exercise dose c-miRNA profiles and cellular pathways linked to energy metabolism and cell cycle. In conclusion, we have observed that different exercise doses induced specific c-miRNA profiles. So, our results point to c-miRNAs as emerging exercise dose biomarkers and as one of regulatory mechanisms modulating the response to endurance exercise.

Targeting the lipid metabolic axis ACSL/SCD in colorectal cancer progression by therapeutic miRNAs: miR-19b-1 role.

An abnormal acyl-CoA synthetase/stearoyl-CoA desaturase (ACSL/SCD) lipid network fuels colon cancer progression, endowing cells with invasive and migratory properties. Therapies against this metabolic network may be useful to improve clinical outcomes. Because micro-RNAs (miRNAs/miRs) are important epigenetic regulators, we investigated novel miRNAs targeting this pro-tumorigenic axis; hence to be used as therapeutic or prognostic miRNAs. Thirty-one putative common miRNAs were predicted to simultaneously target the three enzymes comprising the ACSL/SCD network. Target validation by quantitative RT-PCR, Western blotting, and luciferase assays showed miR-544a, miR-142, and miR-19b-1 as major regulators of the metabolic axis, ACSL/SCD Importantly, lower miR-19b-1 expression was associated with a decreased survival rate in colorectal cancer (CRC) patients, accordingly with ACSL/SCD involvement in patient relapse. Finally, miR-19b-1 regulated the pro-tumorigenic axis, ACSL/SCD, being able to inhibit invasion in colon cancer cells. Because its expression correlated with an increased survival rate in CRC patients, we propose miR-19b-1 as a potential noninvasive biomarker of disease-free survival and a promising therapeutic miRNA in CRC.

Olive Oil, Palm Oil, and Hybrid Palm Oil Distinctly Modulate Liver Transcriptome and Induce NAFLD in Mice Fed a High-Fat Diet.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. The most severe form is nonalcoholic steatohepatitis (NASH). Among risk factors for the development of NAFLD is excessive lipid intake. Since palm (P) oil is the most consumed oil in the world, we aimed to investigate the effects of high-fat diets made with P oil, hybrid palm (HP) oil, or olive (O) oil in liver. Twenty-four male mice (C57Bl/6J) were fed a high-fat diet (41% fat) containing P, HP, or O oils for 8 weeks and compared to a control (C) group fed a chow diet. Adiposity was measured with computed tomography. Body, adipose tissue, and liver weights, as well as liver fat (Bligh⁻Dyer), blood lipid profile, glucose, and liver enzymes were measured. Liver histology (hematoxylin⁻eosin) and transcriptome (microarray-based) were performed. ANOVA tests with Newman⁻Keuls were used. Body weight was increased in the P group (p < 0.001) and body fat in the O group (C vs. O p ≤ 0.01, P vs. O p ≤ 0.05, HP vs. O p ≤ 0.05). All high-fat diets disturbed the blood lipid profile and glucose, with marked effects of HP on very low-density lipoprotein cholesterol (VLDL), triglycerides, and alkaline phosphatase (p ≤ 0.001). HP had the highest liver fat (42.76 ± 1.58), followed by P (33.94 ± 1.13). O had a fat amount comparable to C (16.46 ± 0.34, 14.71 ± 0.70, respectively). P and HP oils induced hepatocyte ballooning. Transcriptome alterations of the O group were related to amino acid metabolism and fatty acid (FA) metabolism, the P group to calcium ion homeostasis, and HP oil to protein localization. Both P and HP oils induced NASH in mice via disturbed hepatocyte transcription. This raises concerns about the content of these oils in several industrialized foods.

Genome-wide expression profiling in muscle and subcutaneous fat of lambs in response to the intake of concentrate supplemented with vitamin E.

BACKGROUND: The objective of this study was to acquire a broader, more comprehensive picture of the transcriptional changes in the L. Thoracis muscle (LT) and subcutaneous fat (SF) of lambs supplemented with vitamin E. Furthermore, we aimed to identify novel genes involved in the metabolism of vitamin E that might also be involved in meat quality. In the first treatment, seven lambs were fed a basal concentrate from weaning to slaughter (CON). In the second treatment, seven lambs received basal concentrate from weaning to 4.71 ± 2.62 days and thereafter concentrate supplemented with 500 mg dl-α-tocopheryl acetate/kg (VE) during the last 33.28 ± 1.07 days before slaughter. RESULTS: The addition of vitamin E to the diet increased the α-tocopherol muscle content and drastically diminished the lipid oxidation of meat. Gene expression profiles for treatments VE and CON were clearly separated from each other in the LT and SF. Vitamin E supplementation had a dramatic effect on subcutaneous fat gene expression, showing general up-regulation of significant genes, compared to CON treatment. In LT, vitamin E supplementation caused down-regulation of genes related to intracellular signaling cascade. Functional analysis of SF showed that vitamin E supplementation caused up-regulation of the lipid biosynthesis process, cholesterol, and sterol and steroid biosynthesis, and it down-regulated genes related to the stress response. CONCLUSIONS: Different gene expression patterns were found between the SF and LT, suggesting tissue specific responses to vitamin E supplementation. Our study enabled us to identify novel genes and metabolic pathways related to vitamin E metabolism that might be implicated in meat quality. Further exploration of these genes and vitamin E could lead to a better understanding of how vitamin E affects the oxidative process that occurs in manufactured meat products.

Modulation of cholesterol-related gene expression by ergosterol and ergosterol-enriched extracts obtained from Agaricus bisporus.

PURPOSE: To investigate the effect of two extracts obtained from Agaricus bisporus on the mRNA expression of cholesterol-related genes. One of the extracts contained ergosterol and other fungal sterols (SFE) and the other contained ß-glucans and fungal sterols (EßG). METHODS: Firstly, the dietary mixed micelles (DMMs) generated after in vitro digestion of standards and SFE were applied to Caco2 cells. Then, the lower compartment after a Caco2-transport experiment was applied to HepG2 cells. The mRNA expression was assessed in both cell lines by low-density arrays (LDA). Mice received the extracts, ergosterol or control drugs after 4 weeks of a high-cholesterol diet. The lipid profile of plasma, liver and feces was determined. LDA assays were performed in liver and intestines. RESULTS: The DMM fraction of SFE up-regulated the LDLR mRNA expression in Caco2 cells. The lower compartment after Caco2-transport experiments up-regulated LDLR and modulated several other lipid-related genes in HepG2 cells. In mice, SFE decreased TC/HDL ratio and reduced hepatic triglycerides paralleled with down-regulation of Dgat1 expression, while EßG did it without transcriptional changes. Addition of SFE or ergosterol induced in jejunum a similar transcriptional response to simvastatin and ezetimibe; they all down-regulated Srebf2 and Nr1h4 (FXR) genes. CONCLUSION: Ergosterol-containing extracts from A. bisporus lowered hepatic triglyceride and modify the mRNA expression of cholesterol-related genes although the transcriptional regulation was unrelated to changes in plasma lipid profile. These extracts may be useful limiting hepatic steatosis and as bioactive ingredients to design novel functional foods preventing lifestyle-related diseases such as non-alcoholic fatty liver disease.

The ellagic acid derivative 4,4'-di-O-methylellagic acid efficiently inhibits colon cancer cell growth through a mechanism involving WNT16.

Ellagic acid (EA) and some derivatives have been reported to inhibit cancer cell proliferation, induce cell cycle arrest, and modulate some important cellular processes related to cancer. This study aimed to identify possible structure-activity relationships of EA and some in vivo derivatives in their antiproliferative effect on both human colon cancer and normal cells, and to compare this activity with that of other polyphenols. Our results showed that 4,4'-di-O-methylellagic acid (4,4'-DiOMEA) was the most effective compound in the inhibition of colon cancer cell proliferation. 4,4'-DiOMEA was 13-fold more effective than other compounds of the same family. In addition, 4,4'-DiOMEA was very active against colon cancer cells resistant to the chemotherapeutic agent 5-fluoracil, whereas no effect was observed in nonmalignant colon cells. Moreover, no correlation between antiproliferative and antioxidant activities was found, further supporting that structure differences might result in dissimilar molecular targets involved in their differential effects. Finally, microarray analysis revealed that 4,4'-DiOMEA modulated Wnt signaling, which might be involved in the potential antitumor action of this compound. Our results suggest that structural-activity differences between EA and 4,4'-DiOMEA might constitute the basis for a new strategy in anticancer drug discovery based on these chemical modifications.

Next-generation sequencing reveals that miR-16-5p, miR-19a-3p, miR-451a, and miR-25-3p cargo in plasma extracellular vesicles differentiates sedentary young males from athletes.

A sedentary lifestyle and Olympic participation are contrary risk factors for global mortality and incidence of cancer and cardiovascular disease. Extracellular vesicle miRNAs have been described to respond to exercise. No molecular characterization of young male sedentary people versus athletes is available; so, our aim was to identify the extracellular vesicle miRNA profile of chronically trained young endurance and resistance male athletes compared to their sedentary counterparts. A descriptive case-control design was used with 16 sedentary young men, 16 Olympic male endurance athletes, and 16 Olympic male resistance athletes. Next-generation sequencing and RT-qPCR and external and internal validation were performed in order to analyze extracellular vesicle miRNA profiles. Endurance and resistance athletes had significant lower levels of miR-16-5p, miR-19a-3p, and miR-451a compared to sedentary people. Taking all together, exercise-trained miRNA profile in extracellular vesicles provides a differential signature of athletes irrespective of the type of exercise compared to sedentary people. Besides, miR-25-3p levels were specifically lower in endurance athletes which defines its role as a specific responder in this type of athletes. In silico analysis of this profile suggests a role in adaptive energy metabolism in this context that needs to be experimentally validated. Therefore, this study provides for the first time basal levels of circulating miRNA in extracellular vesicles emerge as relevant players in intertissue communication in response to chronic exercise exposure in young elite male athletes.

Machine learning combining multi-omics data and network algorithms identifies adrenocortical carcinoma prognostic biomarkers.

Background: Rare endocrine cancers such as Adrenocortical Carcinoma (ACC) present a serious diagnostic and prognostication challenge. The knowledge about ACC pathogenesis is incomplete, and patients have limited therapeutic options. Identification of molecular drivers and effective biomarkers is required for timely diagnosis of the disease and stratify patients to offer the most beneficial treatments. In this study we demonstrate how machine learning methods integrating multi-omics data, in combination with system biology tools, can contribute to the identification of new prognostic biomarkers for ACC. Methods: ACC gene expression and DNA methylation datasets were downloaded from the Xena Browser (GDC TCGA Adrenocortical Carcinoma cohort). A highly correlated multi-omics signature discriminating groups of samples was identified with the data integration analysis for biomarker discovery using latent components (DIABLO) method. Additional regulators of the identified signature were discovered using Clarivate CBDD (Computational Biology for Drug Discovery) network propagation and hidden nodes algorithms on a curated network of molecular interactions (MetaBase™). The discriminative power of the multi-omics signature and their regulators was delineated by training a random forest classifier using 55 samples, by employing a 10-fold cross validation with five iterations. The prognostic value of the identified biomarkers was further assessed on an external ACC dataset obtained from GEO (GSE49280) using the Kaplan-Meier estimator method. An optimal prognostic signature was finally derived using the stepwise Akaike Information Criterion (AIC) that allowed categorization of samples into high and low-risk groups. Results: A multi-omics signature including genes, micro RNA's and methylation sites was generated. Systems biology tools identified additional genes regulating the features included in the multi-omics signature. RNA-seq, miRNA-seq and DNA methylation sets of features revealed a high power to classify patients from stages I-II and stages III-IV, outperforming previously identified prognostic biomarkers. Using an independent dataset, associations of the genes included in the signature with Overall Survival (OS) data demonstrated that patients with differential expression levels of 8 genes and 4 micro RNA's showed a statistically significant decrease in OS. We also found an independent prognostic signature for ACC with potential use in clinical practice, combining 9-gene/micro RNA features, that successfully predicted high-risk ACC cancer patients. Conclusion: Machine learning and integrative analysis of multi-omics data, in combination with Clarivate CBDD systems biology tools, identified a set of biomarkers with high prognostic value for ACC disease. Multi-omics data is a promising resource for the identification of drivers and new prognostic biomarkers in rare diseases that could be used in clinical practice.

Cardiometabolic Health Status, Ethnicity and Health-Related Quality of Life (HRQoL) Disparities in an Adult Population: NutrIMDEA Observational Web-Based Study.

Precision public health supported on online tools is increasingly emerging as a potential strategy to achieve health promotion and disease prevention. Our aim was to assess the relationships of sociodemographic variables, anthropometric data, dietary habits and lifestyle factors with health-related quality of life (HRQoL), cardiometabolic health status and ethnicity in an online recruited adult population (NutrIMDEA Study). NutrIMDEA Study is a web-based cross-sectional survey that included 17,333 adults. Self-reported sociodemographic characteristics, anthropometric data, clinical and family history of cardiometabolic illnesses, dietary habits, lifestyle factors and HRQoL features were collected. Diseased individuals showed significative poorer MedDiet and worse HRQoL than those in the healthy cardiometabolic status group (p < 0.05). In comparison, European/Caucasian individuals reported a significantly better HRQoL, higher MedDiet and HRQoL values compared with those of other ethnicities (p < 0.05). We obtained a total of 16.8% who reported poor/fair, 56.5% good and 26.6% very good/excellent HRQoL. Respondents with very good/excellent HRQoL showed lower BMI, greater adherence to a Mediterranean diet (MedDiet) and higher physical activity. The results suggest the presence of interactions between the mental and physical components of HRQoL with obesity, sedentarism and dietary intake, which were dependent on disease status and ethnicity. Online HRQoL assessment could contribute to wider implementation of precision public health strategies to promote health targeted interventions with policy implications to community health promotion.

Longwise Cluster Analysis for the Prediction of COVID-19 Severity within 72 h of Admission: COVID-DATA-SAVE-LIFES Cohort.

The use of routine laboratory biomarkers plays a key role in decision making in the clinical practice of COVID-19, allowing the development of clinical screening tools for personalized treatments. This study performed a short-term longitudinal cluster from patients with COVID-19 based on biochemical measurements for the first 72 h after hospitalization. Clinical and biochemical variables from 1039 confirmed COVID-19 patients framed on the "COVID Data Save Lives" were grouped in 24-h blocks to perform a longitudinal k-means clustering algorithm to the trajectories. The final solution of the three clusters showed a strong association with different clinical severity outcomes (OR for death: Cluster A reference, Cluster B 12.83 CI: 6.11−30.54, and Cluster C 14.29 CI: 6.66−34.43; OR for ventilation: Cluster-B 2.22 CI: 1.64−3.01, and Cluster-C 1.71 CI: 1.08−2.76), improving the AUC of the models in terms of age, sex, oxygen concentration, and the Charlson Comorbidities Index (0.810 vs. 0.871 with p < 0.001 and 0.749 vs. 0.807 with p < 0.001, respectively). Patient diagnoses and prognoses remarkably diverged between the three clusters obtained, evidencing that data-driven technologies devised for the screening, analysis, prediction, and tracking of patients play a key role in the application of individualized management of the COVID-19 pandemics.

HRQoL and nutritional well-being dissimilarities between two different online collection methods: Value for digital health implementation.

Background: Online health data collection has gained a reputation over the last years to record and process information about health issues for implementing digital health. Objective: The research aim was to appraise two online methods (open and rewarded) to collect information about HRQoL and nutritional well-being and to compare the results between both surveyed populations. Methods: This cross-sectional study is framed on the NUTRiMDEA project. Online data through two different web-based methods (open survey and rewarded survey) were retrieved to assemble data related to sociodemographic, lifestyle (diet, physical activity and sleep patterns) and general health aspects, as well as HRQoL by an evidence-based form such as the SF-12 questionnaire, the IPAQ survey, and MEDAS-14, participants were adults (>18 years old). Results: Overall, 17,332 participants responded to the open survey (OS, n = 11,883) or the rewarded survey (RS, n = 5449). About 65.1% of the participants were female, while the mean age was in the range of 40-70 years. There were significant differences (p < 0.05) between surveyed populations in sociodemographic, lifestyle (diet and physical activity), health and HRQoL data. Conclusions: This investigation implemented an evidence-based online questionnaire that collected demographic, lifestyle factors, phenotypic and health-related aspects as well as compared differential outcomes in HRQoL and nutritional/lifestyle well-being depending on the online mode data collection. Findings demonstrated dissimilarities in most aspects of health, HRQoL, dietary intake and physical activity records between both populations. Overall, OS sample was characterized as a healthier population with superior lifestyle habits than RS participants.

Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity.

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.

Connection between miRNA Mediation and the Bioactive Effects of Broccoli (Brassica oleracea var. italica): Exogenous miRNA Resistance to Food Processing and GI Digestion.

Broccoli (Brassica oleracea var. italica) and its bioactive compounds are associated with beneficial health effects, which might be enabled, at least in part, through miRNA regulation, despite recent controversial studies suggesting that exogenous dietary miRNAs may reach host circulation and target cells to regulate gene expression. Here, a computational analysis was performed to explore the processes and pathways associated with genes targeted either by (1) host-expressed miRNAs (endogenous) modulated by the bioactive compounds in broccoli or (2) miRNAs derived from broccoli (exogenous). In addition, the stability of exogenous miRNAs from broccoli was assessed after broccoli was subjected to the usual processing methods and in vitro digestion-simulating gastrointestinal (GI) conditions. Overall, bioinformatic results show that the anticarcinogenic and cancer-preventive properties attributed to cruciferous vegetables might be mediated, at least in part, through miRNA-related mechanisms. Moreover, results show that broccoli-derived miRNAs can survive common food-processing conditions and GI digestion.

NutriGenomeDB: a nutrigenomics exploratory and analytical platform.

Habitual consumption of certain foods has shown beneficial and protective effects against multiple chronic diseases. However, it is not clear by which molecular mechanisms they may exert their beneficial effects. Multiple -omic experiments available in public databases have generated gene expression data following the treatment of human cells with different food nutrients and bioactive compounds. Exploration of such data in an integrative manner offers excellent possibilities for gaining insights into the molecular effects of food compounds and bioactive molecules at the cellular level. Here we present NutriGenomeDB, a web-based application that hosts manually curated gene sets defined from gene expression signatures, after differential expression analysis of nutrigenomics experiments performed on human cells available in the Gene Expression Omnibus (GEO) repository. Through its web interface, users can explore gene expression data with interactive visualizations. In addition, external gene signatures can be connected with nutrigenomics gene sets using a gene pattern-matching algorithm. We further demonstrate how the application can capture the primary molecular mechanisms of a drug used to treat hypertension and thus connect its mode of action with hosted food compounds.

Identification and validation of common molecular targets of hydroxytyrosol.

Hydroxytyrosol (HT) is involved in healthful activities and is beneficial to lipid metabolism. Many investigations focused on finding tissue-specific targets of HT through the use of different omics approaches such as transcriptomics and proteomics. However, it is not clear which (if any) of the potential molecular targets of HT reported in different studies are concurrently affected in various tissues. Following the bioinformatic analyses of publicly available data from a selection of in vivo studies involving HT-supplementation, we selected differentially expressed lipid metabolism-related genes and proteins common to more than one study, for validation in rodent liver samples from the entire selection. Four miRNAs (miR-802-5p, miR-423-3p, miR-30a-5p, and miR-146b-5p) responded to HT supplementation. Of note, miR-802-5p was commonly regulated in the liver and intestine. Our premise was that, in an organ crucial for lipid metabolism such as the liver, consistent modulation should be found for a specific target of HT even if different doses and duration of HT supplementation were used in vivo. Even though our results show inconsistency regarding differentially expressed lipid metabolism-related genes and proteins across studies, we found Fgf21 and Rora as potential novel targets of HT. Omics approaches should be fine-tuned to better exploit the available databases.

Postprandial Circulating miRNAs in Response to a Dietary Fat Challenge.

Postprandial lipemia has many physiopathological effects, some of which increase the risk of cardiovascular disease. MicroRNAs (miRNAs) can be found in almost all biological fluids, but their postprandial kinetics are poorly described. We aimed to profile circulating miRNAs in response to a fat challenge. In total, 641 circulating miRNAs were assessed by real-time PCR in plasmas from mice two hours after lipid gavage. Mice with intestine-specific loss of Dicer were screened to identify potential miRNAs released by the intestine. A total of 68 miRNAs were selected for further validation. Ten circulating miRNAs were finally validated as responsive to postprandial lipemia, including miR-206-3p, miR-543-3p, miR-466c-5p, miR-27b-5p, miR-409-3p, miR-340-3p, miR-1941-3p, miR-10a-3p, miR-125a-3p, and miR-468-3p. Analysis of their possible tissues of origin/target showed an enrichment of selected miRNAs in liver, intestine, brain, or skeletal muscle. miR-206, miR-27b-5p, and miR-409-3p were validated in healthy humans. Analysis of their predicted target genes revealed their potential involvement in insulin/insulin like growth factor (insulin/IGF), angiogenesis, cholecystokinin B receptor signaling pathway (CCKR), inflammation or Wnt pathways for mice, and in platelet derived growth factor (PDGF) and CCKR signaling pathways for humans. Therefore, the current study shows that certain miRNAs are released in the circulation in response to fatty meals, proposing them as potential novel therapeutic targets of lipid metabolism.

Modulation of miRNA expression in aged rat hippocampus by buttermilk and krill oil.

The increasing incidence of age-induced cognitive decline justifies the search for complementary ways of prevention or delay. We studied the effects of concentrates of phospholipids, sphingolipids, and/or 3-n fatty acids on the expression of genes or miRNAs related to synaptic activity and/or neurodegeneration, in the hippocampus of aged Wistar rats following a 3-month supplementation. The combination of two phospholipidic concentrates of krill oil (KOC) and buttermilk (BMFC) origin modulated the hippocampal expression of 119 miRNAs (11 were common to both BMFC and BMFC + KOC groups). miR-191a-5p and miR-29a-3p changed significantly only in the BMFC group, whereas miR-195-3p and miR-148a-5p did so only in the combined-supplemented group. Thirty-eight, 58, and 72 differentially expressed genes (DEG) were found in the groups supplemented with KOC, BMFC and BMFC + KOC, respectively. Interaction analysis unveiled networks of selected miRNAs with their potential target genes. DEG found in the KOC and BMFC groups were mainly involved in neuroactive processes, whereas they were associated with lysosomes and mRNA surveillance pathways in the BMFC + KOC group. We also report a significant reduction in hippocampal ceramide levels with BMFC + KOC. Our results encourage additional in-depth investigations regarding the potential beneficial effects of these compounds.