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João Tomé-Carneiro
Laboratory of Functional Foods, Instituto Madrileño de Estudios Avanzados (IMDEA)-Alimentación, CEI UAM+CSIC, 28049 Madrid, Spain

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Journal article
Published: 22 January 2021 in International Journal of Molecular Sciences
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MicroRNAs (miRNAs) are small non-coding RNAs with a known role as mediators of gene expression in crucial biological processes, which converts them into high potential contenders in the ongoing search for effective therapeutic strategies. However, extracellular RNAs are unstable and rapidly degraded, reducing the possibility of successfully exerting a biological function in distant target cells. Strategies aimed at enhancing the therapeutic potential of miRNAs include the development of efficient, tissue-specific and nonimmunogenic delivery methods. Since miRNAs were discovered to be naturally transported within exosomes, a type of extracellular vesicle that confers protection against RNase degradation and increases miRNA stability have been proposed as ideal delivery vehicles for miRNA-based therapy. Although research in this field has grown rapidly in the last few years, a standard, reproducible and cost-effective protocol for exosome isolation and extracellular RNA delivery is lacking. We aimed to evaluate the use of milk-derived extracellular vesicles as vehicles for extracellular RNA drug delivery. With this purpose, exosomes were isolated from raw bovine milk, combining ultracentrifugation and size exclusion chromatography (SEC) methodology. Isolated exosomes were then loaded with exogenous hsa-miR148a-3p, a highly expressed miRNA in milk exosomes. The suitability of exosomes as delivery vehicles for extracellular RNAs was tested by evaluating the absorption of miR-148a-3p in hepatic (HepG2) and intestinal (Caco-2) cell lines. The potential exertion of a biological effect by miR-148a-3p was assessed by gene expression analysis, using microarrays. Results support that bovine milk is a cost-effective source of exosomes which can be used as nanocarriers of functional miRNAs with a potential use in RNA-based therapy. In addition, we show here that a combination of ultracentrifugation and SEC technics improve exosome enrichment, purity, and integrity for subsequent use.

ACS Style

Lorena del Pozo-Acebo; María-Carmen López De Las Hazas; Joao Tomé-Carneiro; Paula Gil-Cabrerizo; Rodrigo San-Cristobal; Rebeca Busto; Almudena García-Ruiz; Alberto Dávalos. Bovine Milk-Derived Exosomes as a Drug Delivery Vehicle for miRNA-Based Therapy. International Journal of Molecular Sciences 2021, 22, 1105 .

AMA Style

Lorena del Pozo-Acebo, María-Carmen López De Las Hazas, Joao Tomé-Carneiro, Paula Gil-Cabrerizo, Rodrigo San-Cristobal, Rebeca Busto, Almudena García-Ruiz, Alberto Dávalos. Bovine Milk-Derived Exosomes as a Drug Delivery Vehicle for miRNA-Based Therapy. International Journal of Molecular Sciences. 2021; 22 (3):1105.

Chicago/Turabian Style

Lorena del Pozo-Acebo; María-Carmen López De Las Hazas; Joao Tomé-Carneiro; Paula Gil-Cabrerizo; Rodrigo San-Cristobal; Rebeca Busto; Almudena García-Ruiz; Alberto Dávalos. 2021. "Bovine Milk-Derived Exosomes as a Drug Delivery Vehicle for miRNA-Based Therapy." International Journal of Molecular Sciences 22, no. 3: 1105.

Review
Published: 08 September 2020 in Molecules
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In support of the J curve that describes the association between wine consumption and all-cause mortality, researchers and the lay press often advocate the health benefits of (poly)phenol consumption via red wine intake and cite the vast amount of in vitro literature that would corroborate the hypothesis. Other researchers dismiss such evidence and call for total abstention. In this review, we take a skeptical, Pythagorean stance and we critically try to move the debate forward by pointing the readers to the many pitfalls of red wine (poly)phenol research, which we arbitrarily treat as if they were pharmacological agents. We conclude that, after 30 years of dedicated research and despite the considerable expenditure, we still lack solid, “pharmacological”, human evidence to confirm wine (poly)phenols’ biological actions. Future research will eventually clarify their activities and will back the current recommendations of responsibly drinking moderate amounts of wine with meals.

ACS Style

Francesco Visioli; Stefan-Alexandru Panaite; Joao Tomé-Carneiro. Wine’s Phenolic Compounds and Health: A Pythagorean View. Molecules 2020, 25, 4105 .

AMA Style

Francesco Visioli, Stefan-Alexandru Panaite, Joao Tomé-Carneiro. Wine’s Phenolic Compounds and Health: A Pythagorean View. Molecules. 2020; 25 (18):4105.

Chicago/Turabian Style

Francesco Visioli; Stefan-Alexandru Panaite; Joao Tomé-Carneiro. 2020. "Wine’s Phenolic Compounds and Health: A Pythagorean View." Molecules 25, no. 18: 4105.

Paper
Published: 15 July 2019 in Food & Function
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Identification of consistently modulated molecular targets of HT reportedin vivowas carried out by means of transcriptomic and proteomic data integration. Validation of selected targets was attempted in liver samples from different HT rodent studies.

ACS Style

María-Carmen López De Las Hazas; J Alfredo Martínez Hernández; María Del Carmen Crespo; Joao Tomé-Carneiro; Lorena Del Pozo-Acebo; María Belén Ruiz-Roso; Joan Carles Escolà-Gil; Jesús Osada; Maria P. Portillo; José Alfredo Martinez; Maria Angeles Navarro; Laura Rubió; María José Motilva; Francesco Visioli; Alberto Davalos. Identification and validation of common molecular targets of hydroxytyrosol. Food & Function 2019, 10, 4897 -4910.

AMA Style

María-Carmen López De Las Hazas, J Alfredo Martínez Hernández, María Del Carmen Crespo, Joao Tomé-Carneiro, Lorena Del Pozo-Acebo, María Belén Ruiz-Roso, Joan Carles Escolà-Gil, Jesús Osada, Maria P. Portillo, José Alfredo Martinez, Maria Angeles Navarro, Laura Rubió, María José Motilva, Francesco Visioli, Alberto Davalos. Identification and validation of common molecular targets of hydroxytyrosol. Food & Function. 2019; 10 (8):4897-4910.

Chicago/Turabian Style

María-Carmen López De Las Hazas; J Alfredo Martínez Hernández; María Del Carmen Crespo; Joao Tomé-Carneiro; Lorena Del Pozo-Acebo; María Belén Ruiz-Roso; Joan Carles Escolà-Gil; Jesús Osada; Maria P. Portillo; José Alfredo Martinez; Maria Angeles Navarro; Laura Rubió; María José Motilva; Francesco Visioli; Alberto Davalos. 2019. "Identification and validation of common molecular targets of hydroxytyrosol." Food & Function 10, no. 8: 4897-4910.

Review article
Published: 03 July 2019 in Journal of Cerebral Blood Flow & Metabolism
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In addition to providing sensory stimuli, usually taste, smell and sight, olive oil contains a range of minor components, mostly phenolic in nature. These components are endowed with pharmacological or pharma‐nutritional properties that are the subject of active research worldwide. Based on our more than 25 years of experience in this field, we critically focus on what we believe are the most pharmacologically prominent actions of the constituents of olive oil. Most of the effects are due to the phenolic compounds in extra virgin olive oil, such as hydroxytyrosol and oleocanthal (which are often mis‐categorized as in vivo antioxidants) and concern the cardiovascular system. Other potentially beneficial activities are still to be investigated in depth. We conclude that—in the context of a proper diet that includes high‐quality products—the use of high‐quality olive oil contributes to achieving and sustaining overall health. Linked Articles This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc

ACS Style

Francesco Visioli; Alberto Davalos; Mª Del Carmen López De Las Hazas; María Del Carmen Crespo; João Tomé-Carneiro. An overview of the pharmacology of olive oil and its active ingredients. Journal of Cerebral Blood Flow & Metabolism 2019, 177, 1316 -1330.

AMA Style

Francesco Visioli, Alberto Davalos, Mª Del Carmen López De Las Hazas, María Del Carmen Crespo, João Tomé-Carneiro. An overview of the pharmacology of olive oil and its active ingredients. Journal of Cerebral Blood Flow & Metabolism. 2019; 177 (6):1316-1330.

Chicago/Turabian Style

Francesco Visioli; Alberto Davalos; Mª Del Carmen López De Las Hazas; María Del Carmen Crespo; João Tomé-Carneiro. 2019. "An overview of the pharmacology of olive oil and its active ingredients." Journal of Cerebral Blood Flow & Metabolism 177, no. 6: 1316-1330.

Journal article
Published: 13 June 2019 in Nutrients
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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.

ACS Style

Diana C. Mantilla-Escalante; María-Carmen López De Las Hazas; Judit Gil-Zamorano; Lorena Del Pozo-Acebo; M. Carmen Crespo; Roberto Martín-Hernández; Andrea Del Saz; Joao Tomé-Carneiro; Fernando Cardona; Isabel Cornejo-Pareja; Almudena García-Ruiz; Olivier Briand; Miguel A. Lasunción; Francesco Visioli; Alberto Dávalos. Postprandial Circulating miRNAs in Response to a Dietary Fat Challenge. Nutrients 2019, 11, 1326 .

AMA Style

Diana C. Mantilla-Escalante, María-Carmen López De Las Hazas, Judit Gil-Zamorano, Lorena Del Pozo-Acebo, M. Carmen Crespo, Roberto Martín-Hernández, Andrea Del Saz, Joao Tomé-Carneiro, Fernando Cardona, Isabel Cornejo-Pareja, Almudena García-Ruiz, Olivier Briand, Miguel A. Lasunción, Francesco Visioli, Alberto Dávalos. Postprandial Circulating miRNAs in Response to a Dietary Fat Challenge. Nutrients. 2019; 11 (6):1326.

Chicago/Turabian Style

Diana C. Mantilla-Escalante; María-Carmen López De Las Hazas; Judit Gil-Zamorano; Lorena Del Pozo-Acebo; M. Carmen Crespo; Roberto Martín-Hernández; Andrea Del Saz; Joao Tomé-Carneiro; Fernando Cardona; Isabel Cornejo-Pareja; Almudena García-Ruiz; Olivier Briand; Miguel A. Lasunción; Francesco Visioli; Alberto Dávalos. 2019. "Postprandial Circulating miRNAs in Response to a Dietary Fat Challenge." Nutrients 11, no. 6: 1326.

Correspondence
Published: 12 November 2018 in Pharmacological Research
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ACS Style

João Tomé-Carneiro; Eduardo Iglesias-Gutierrez; Alberto Dávalos. Response to: Letter to the editor “Some thoughts about the possibility of diet-derived exogenous small RNAs”. Pharmacological Research 2018, 141, 622 .

AMA Style

João Tomé-Carneiro, Eduardo Iglesias-Gutierrez, Alberto Dávalos. Response to: Letter to the editor “Some thoughts about the possibility of diet-derived exogenous small RNAs”. Pharmacological Research. 2018; 141 ():622.

Chicago/Turabian Style

João Tomé-Carneiro; Eduardo Iglesias-Gutierrez; Alberto Dávalos. 2018. "Response to: Letter to the editor “Some thoughts about the possibility of diet-derived exogenous small RNAs”." Pharmacological Research 141, no. : 622.

Review
Published: 11 June 2018 in Foods
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The Mediterranean diet has been long associated with improved cardiovascular prognosis, chemoprevention, and lower incidence of neurodegeneration. Of the multiple components of this diet, olive oil stands out because its use has historically been limited to the Mediterranean basin. The health benefits of olive oil and some of its components are being rapidly decoded. In this paper we review the most recent pharma-nutritional investigations on olive oil biophenols and their health effects, chiefly focusing on recent findings that elucidate their molecular mechanisms of action.

ACS Style

M. Carmen Crespo; Joao Tomé-Carneiro; Alberto Dávalos; Francesco Visioli. Pharma-Nutritional Properties of Olive Oil Phenols. Transfer of New Findings to Human Nutrition. Foods 2018, 7, 90 .

AMA Style

M. Carmen Crespo, Joao Tomé-Carneiro, Alberto Dávalos, Francesco Visioli. Pharma-Nutritional Properties of Olive Oil Phenols. Transfer of New Findings to Human Nutrition. Foods. 2018; 7 (6):90.

Chicago/Turabian Style

M. Carmen Crespo; Joao Tomé-Carneiro; Alberto Dávalos; Francesco Visioli. 2018. "Pharma-Nutritional Properties of Olive Oil Phenols. Transfer of New Findings to Human Nutrition." Foods 7, no. 6: 90.

Review article
Published: 05 April 2018 in Pharmacological Research
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The possibility that diet-derived miRNAs survive the gastrointestinal tract and exert biological effects in target cells is triggering considerable research in the potential abilities of alimentary preventive and therapeutic approaches. Many validation attempts have been carried out and investigators disagree on several issues. The barriers exogenous RNAs must surpass are harsh and adequate copies must reach target cells for biological actions to be carried out. This prospect opened a window for previously unlikely scenarios concerning exogenous non-coding RNAs, such as a potential role for breast milk microRNAs in infants’ development and maturation. This review is focused on the thorny path breast milk miRNAs face towards confirmation as relevant role players in infants’ development and maturation, taking into consideration the research carried out so far on the uptake, gastrointestinal barriers and potential biological effects of diet-derived miRNAs. We also discuss the future pharmacological and pharma-nutritional consequences of appropriate miRNAs research.

ACS Style

João Tomé-Carneiro; Noelia Fernández-Alonso; Cristina Tomás-Zapico; Francesco Visioli; Eduardo Iglesias-Gutierrez; Alberto Dávalos. Breast milk microRNAs harsh journey towards potential effects in infant development and maturation. Lipid encapsulation can help. Pharmacological Research 2018, 132, 21 -32.

AMA Style

João Tomé-Carneiro, Noelia Fernández-Alonso, Cristina Tomás-Zapico, Francesco Visioli, Eduardo Iglesias-Gutierrez, Alberto Dávalos. Breast milk microRNAs harsh journey towards potential effects in infant development and maturation. Lipid encapsulation can help. Pharmacological Research. 2018; 132 ():21-32.

Chicago/Turabian Style

João Tomé-Carneiro; Noelia Fernández-Alonso; Cristina Tomás-Zapico; Francesco Visioli; Eduardo Iglesias-Gutierrez; Alberto Dávalos. 2018. "Breast milk microRNAs harsh journey towards potential effects in infant development and maturation. Lipid encapsulation can help." Pharmacological Research 132, no. : 21-32.

Journal article
Published: 05 March 2018 in Scientific Reports
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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.

ACS Style

María Del Carmen Crespo; João Tomé-Carneiro; Diego Gómez-Coronado; Emma Burgos-Ramos; Alba García-Serrano; Roberto Martin-Hernandez; Shishir Baliyan; Javier Fontecha; César Venero; Alberto Dávalos; Francesco Visioli. Modulation of miRNA expression in aged rat hippocampus by buttermilk and krill oil. Scientific Reports 2018, 8, 1 -12.

AMA Style

María Del Carmen Crespo, João Tomé-Carneiro, Diego Gómez-Coronado, Emma Burgos-Ramos, Alba García-Serrano, Roberto Martin-Hernandez, Shishir Baliyan, Javier Fontecha, César Venero, Alberto Dávalos, Francesco Visioli. Modulation of miRNA expression in aged rat hippocampus by buttermilk and krill oil. Scientific Reports. 2018; 8 (1):1-12.

Chicago/Turabian Style

María Del Carmen Crespo; João Tomé-Carneiro; Diego Gómez-Coronado; Emma Burgos-Ramos; Alba García-Serrano; Roberto Martin-Hernandez; Shishir Baliyan; Javier Fontecha; César Venero; Alberto Dávalos; Francesco Visioli. 2018. "Modulation of miRNA expression in aged rat hippocampus by buttermilk and krill oil." Scientific Reports 8, no. 1: 1-12.

Article
Published: 03 February 2018 in Molecular Neurobiology
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Impaired glucose metabolism and mitochondrial decay greatly increase with age, when cognitive decline becomes rampant. No pharmacological or dietary intervention has proven effective, but proper diet and lifestyle do postpone the onset of neurodegeneration and some nutrients are being investigated. We studied insulin signaling, mitochondrial activity and biogenesis, and synaptic signaling in the hippocampus and cortex following dietary supplementation with bioactive phospholipid concentrates of krill oil (KOC), buttermilk fat globule membranes (BMFC), and a combination of both in aged rats. After 3 months of supplementation, although all groups of animals showed clear signs of peripheral insulin resistance, the combination of KOC and BMFC was able to improve peripheral insulin sensitivity. We also explored brain energy balance. Interestingly, the hippocampus of supplemented rats—mainly when supplemented with BMFC or the combination of KOC and BMFC—showed an increase in intracellular adenosine triphosphate (ATP) levels, whereas no difference was observed in the cerebral cortex. Moreover, we found a significant increase of brain-derived neurotrophic factor (BDNF) in the hippocampus of BMFC+KO animals. In summary, dietary supplementation with KOC and/or BMFC improves peripheral and central insulin resistance, suggesting that their administration could delay the onset of these phenomena. Moreover, n-3 fatty acids (FAs) ingested as phospholipids increase BDNF levels favoring an improvement in energy state within neurons and facilitating both mitochondrial and protein synthesis, which are necessary for synaptic plasticity. Thus, dietary supplementation with n-3 FAs could protect local protein synthesis and energy balance within dendrites, favoring neuronal health and delaying cognitive decline associated to age-related disrepair.

ACS Style

João Tomé-Carneiro; María Del Carmen Crespo; Emma Burgos-Ramos; Cristina Tomas-Zapico; Alba García-Serrano; Pilar Castro-Gómez; César Venero; Inmaculada Pereda-Pérez; Shishir Baliyan; Azucena Valencia; Javier Fontecha; Alberto Dávalos; Francesco Visioli. Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats. Molecular Neurobiology 2018, 55, 7285 -7296.

AMA Style

João Tomé-Carneiro, María Del Carmen Crespo, Emma Burgos-Ramos, Cristina Tomas-Zapico, Alba García-Serrano, Pilar Castro-Gómez, César Venero, Inmaculada Pereda-Pérez, Shishir Baliyan, Azucena Valencia, Javier Fontecha, Alberto Dávalos, Francesco Visioli. Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats. Molecular Neurobiology. 2018; 55 (9):7285-7296.

Chicago/Turabian Style

João Tomé-Carneiro; María Del Carmen Crespo; Emma Burgos-Ramos; Cristina Tomas-Zapico; Alba García-Serrano; Pilar Castro-Gómez; César Venero; Inmaculada Pereda-Pérez; Shishir Baliyan; Azucena Valencia; Javier Fontecha; Alberto Dávalos; Francesco Visioli. 2018. "Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats." Molecular Neurobiology 55, no. 9: 7285-7296.

Journal article
Published: 01 September 2017 in Food and Chemical Toxicology
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Hydroxytyrosol (HT) is the primary phenolic compound of olives, virgin olive oil, and their byproducts. Proteomic analysis of metabolically active tissues helps elucidating novel mechanisms of action and potential targets in cardiometabolic disease. Thus, we aimed at determining the impact of long-term HT supplementation on the proteome of adipose and liver tissue, in mice.C57BL/6J mice received either a control diet or a diet supplemented with nutritionally relevant doses of HT for eight weeks.HT supplementation differentially affects the adipose and liver tissues proteome, as evaluated by super-SILAC. Some oxidative stress-related proteins were modulated in both tissues, such as the multifunctional protein peroxiredoxin 1, which was consistently repressed by HT supplementation. In some cases tissue-dependent modulation was observed, as in the case of FASN.This initial study provided interesting leads regarding the connection between changes seen at tissue proteome level and the metabolic effects of HT, and the use of this pertinent proteomics quantification approach may prove quite useful for the uncovering of novel potential pharmaco-nutritional targets of HT supplementation.

ACS Style

João Tomé-Carneiro; M. Carmen Crespo; Estefanía García-Calvo; José L. Luque-García; Alberto Dávalos; Francesco Visioli. Proteomic evaluation of mouse adipose tissue and liver following hydroxytyrosol supplementation. Food and Chemical Toxicology 2017, 107, 329 -338.

AMA Style

João Tomé-Carneiro, M. Carmen Crespo, Estefanía García-Calvo, José L. Luque-García, Alberto Dávalos, Francesco Visioli. Proteomic evaluation of mouse adipose tissue and liver following hydroxytyrosol supplementation. Food and Chemical Toxicology. 2017; 107 ():329-338.

Chicago/Turabian Style

João Tomé-Carneiro; M. Carmen Crespo; Estefanía García-Calvo; José L. Luque-García; Alberto Dávalos; Francesco Visioli. 2017. "Proteomic evaluation of mouse adipose tissue and liver following hydroxytyrosol supplementation." Food and Chemical Toxicology 107, no. : 329-338.

Article
Published: 20 March 2017 in BioFactors
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Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50–100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD. We hypothesized that hydroxytyrosol (HT, the preeminent polyphenol of olives and olive oil) could exert beneficial effects on IR associated with AD and investigated it mechanisms of action in an astrocytic model of AD. The astrocytic cell line C6 was exposed to Aβ(25-35) and co-incubated with HT for different periods. After treatment with Aβ(25-35), astrocytes' viability was significantly decreased as compared with controls; however, both pre- and post-treatment with HT prevented this effect. Mechanistically, we found that the preventive role of HT on Aβ(25-35)- induced cytotoxicity in astrocytes is moderated by an increased HT-induced activation of Akt, which is mediated by the insulin signaling pathway. In addition, we report that HT prevented the pronounced activation of mTOR, thereby restoring proper insulin signaling. In conclusion, we demonstrate that HT protects Aβ(25-35)-treated astrocytes by improving insulin sensitivity and restoring proper insulin-signaling. These data provide some mechanistic insight on the observed inverse association between olive oil consumption and prevalence of cognitive impairment. © 2017 BioFactors, 2017

ACS Style

María Del Carmen Crespo; João Tomé-Carneiro; Cristina Pintado; Alberto Davalos; Francesco Visioli; Emma Burgos-Ramos. Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease. BioFactors 2017, 43, 540 -548.

AMA Style

María Del Carmen Crespo, João Tomé-Carneiro, Cristina Pintado, Alberto Davalos, Francesco Visioli, Emma Burgos-Ramos. Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease. BioFactors. 2017; 43 (4):540-548.

Chicago/Turabian Style

María Del Carmen Crespo; João Tomé-Carneiro; Cristina Pintado; Alberto Davalos; Francesco Visioli; Emma Burgos-Ramos. 2017. "Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer's disease." BioFactors 43, no. 4: 540-548.

Clinical trial
Published: 31 May 2016 in The Journal of Nutritional Biochemistry
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Dietary microRNAs (miRNAs) modulation could be important for health and wellbeing. Part of the healthful activities of polyphenols might be due to a modulation of miRNAs' expression. Among the most biologically active polyphenols, hydroxytyrosol (HT) has never been studied for its actions on miRNAs. We investigated whether HT could modulate the expression of miRNAs in vivo. We performed an unbiased intestinal miRNA screening in mice supplemented (for 8 weeks) with nutritionally relevant amounts of HT. HT modulated the expression of several miRNAs. Analysis of other tissues revealed consistent HT-induced modulation of only few miRNAs. Also, HT administration increased triglycerides levels. Acute treatment with HT and in vitro experiments provided mechanistic insights. The HT-induced expression of one miRNA was confirmed in healthy volunteers supplemented with HT in a randomized, double-blind and placebo-controlled trial. HT consumption affects specific miRNAs' expression in rodents and humans. Our findings suggest that the modulation of miRNAs' action through HT consumption might partially explain its healthful activities and might be pharmanutritionally exploited in current therapies targeting endogenous miRNAs. However, the effects of HT on triglycerides warrant further investigations

ACS Style

Joao Tomé-Carneiro; María Carmen Crespo; Eduardo Iglesias-Gutierrez; Roberto Martín; Judit Gil-Zamorano; Cristina Tomas-Zapico; Emma Burgos-Ramos; Carlos Correa; Diego Gómez-Coronado; Miguel A. Lasunción; Emilio Herrera; Francesco Visioli; Alberto Dávalos. Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans. The Journal of Nutritional Biochemistry 2016, 34, 146 -155.

AMA Style

Joao Tomé-Carneiro, María Carmen Crespo, Eduardo Iglesias-Gutierrez, Roberto Martín, Judit Gil-Zamorano, Cristina Tomas-Zapico, Emma Burgos-Ramos, Carlos Correa, Diego Gómez-Coronado, Miguel A. Lasunción, Emilio Herrera, Francesco Visioli, Alberto Dávalos. Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans. The Journal of Nutritional Biochemistry. 2016; 34 ():146-155.

Chicago/Turabian Style

Joao Tomé-Carneiro; María Carmen Crespo; Eduardo Iglesias-Gutierrez; Roberto Martín; Judit Gil-Zamorano; Cristina Tomas-Zapico; Emma Burgos-Ramos; Carlos Correa; Diego Gómez-Coronado; Miguel A. Lasunción; Emilio Herrera; Francesco Visioli; Alberto Dávalos. 2016. "Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans." The Journal of Nutritional Biochemistry 34, no. : 146-155.

Article
Published: 29 December 2015 in Molecular Nutrition & Food Research
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Ellagitannins, ellagic acid, and the colonic metabolites urolithins (Uros) exhibit anticancer effects against colon cells, but a comprehensive molecular analysis has not been done. Herein, we used a panel of cell lines to first time evaluate the antiproliferative properties and accompanying molecular responses of two ellagitannin metabolites mixtures mimicking the situation in vivo and of each individual metabolite. We examined cell growth, cell cycle, apoptosis, and the expression of related genes and microRNAs (miRs) in a panel of nonmalignant and malignant colon cell lines. Regardless of the composition, the mixed metabolites similarly inhibited proliferation, induced cycle arrest, and apoptosis. All the metabolites contributed to these effects, but Uro-A, isourolithin A, Uro-C, and Uro-D were more potent than Uro-B and ellagic acid. Despite molecular differences between the cell lines, we discerned relevant changes in key cancer markers and corroborated the induction of CDKN1A (cyclin-dependent kinase inhibitor 1A gene (p21, Cip1); encoding p21) as a common step underlying the anticancer properties of Uros. Interestingly, cell-unique downregulation of miR-224 or upregulation of miR-215 was found associated with CDKN1A induction. Physiologically relevant mixtures of Uros exert anticancer effects against colon cancer cells via a common CDKN1A upregulatory mechanism. Other associated molecular responses are however heterogeneous and mostly cell-specific.

ACS Style

Antonio González-Sarrías; Maria Angeles Nuñez Sanchez; João Tomé-Carneiro; Francisco Tomas-Barberan; Maria Teresa Garcia Conesa; Juan Carlos Espín. Comprehensive characterization of the effects of ellagic acid and urolithins on colorectal cancer and key-associated molecular hallmarks: MicroRNA cell specific induction of CDKN1A (p21) as a common mechanism involved. Molecular Nutrition & Food Research 2015, 60, 701 -716.

AMA Style

Antonio González-Sarrías, Maria Angeles Nuñez Sanchez, João Tomé-Carneiro, Francisco Tomas-Barberan, Maria Teresa Garcia Conesa, Juan Carlos Espín. Comprehensive characterization of the effects of ellagic acid and urolithins on colorectal cancer and key-associated molecular hallmarks: MicroRNA cell specific induction of CDKN1A (p21) as a common mechanism involved. Molecular Nutrition & Food Research. 2015; 60 (4):701-716.

Chicago/Turabian Style

Antonio González-Sarrías; Maria Angeles Nuñez Sanchez; João Tomé-Carneiro; Francisco Tomas-Barberan; Maria Teresa Garcia Conesa; Juan Carlos Espín. 2015. "Comprehensive characterization of the effects of ellagic acid and urolithins on colorectal cancer and key-associated molecular hallmarks: MicroRNA cell specific induction of CDKN1A (p21) as a common mechanism involved." Molecular Nutrition & Food Research 60, no. 4: 701-716.

Review
Published: 12 December 2015 in Phytomedicine
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In addition to prescription drugs, nutraceuticals/functional foods/medical foods are being increasingly added as adjunct treatment of cardiovascular disease (CVD), even though most of them have been exclusively studied in vitro. We review the available evidence (focusing on when the amount of polyphenols’ intake was measured) coming from randomized controlled trials (RCTs) of (poly)phenol-based supplements. We conclude that (poly)phenol-based nutraceuticals and functional foods might be indeed used as adjunct therapy of CVD, but additional long-term RCTs with adequate numerosity and with clinically relevant end points are needed to provide unequivocal evidence of their clinical usefulness.

ACS Style

João Tomé-Carneiro; Francesco Visioli. Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomedicine 2015, 23, 1145 -1174.

AMA Style

João Tomé-Carneiro, Francesco Visioli. Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence. Phytomedicine. 2015; 23 (11):1145-1174.

Chicago/Turabian Style

João Tomé-Carneiro; Francesco Visioli. 2015. "Polyphenol-based nutraceuticals for the prevention and treatment of cardiovascular disease: Review of human evidence." Phytomedicine 23, no. 11: 1145-1174.

Journal article
Published: 29 September 2015 in Journal of Functional Foods
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Ellagic acid (EA) is a polyphenol that must be released from the non-bioavailable ellagitannins in pomegranates, walnuts or strawberries to be absorbed. To estimate whether EA bioavailability could be improved after consumption of a high free EA amount, we conducted a crossover pharmacokinetic study in healthy volunteers that consumed two pomegranate extracts providing either 130 mg punicalagin+524 mg EA (PE-1) or 279 mg punicalagin+25 mg EA (PE-2). Targeted metabolomics (UPLC-ESI-qTOF-MS/MS) identified plasma free EA but not phase-II conjugates. EA pharmacokinetics showed high interindividual variability. Cmax ranged from 12 to 360 nM (PE-1: 74.8 ± 54.4 nM; PE-2: 64.1 ± 76.8 nM). In vitro digestion supported in vivo results. EA bioavailability was limited by the ellagitannin, pH and protein environment. A higher free EA intake does not enhance its bioavailability but promotes urolithin production. Bioavailability of EA, as the unchanged fraction that reaches the systemic circulation, is not as low as previously thought.

ACS Style

Antonio González-Sarrías; Rocio Garcia Villalba; Maria Angeles Nuñez Sanchez; João Tomé-Carneiro; Pilar Zafrilla; Juana Mulero; Francisco Tomas-Barberan; Juan Carlos Espín. Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts. Journal of Functional Foods 2015, 19, 225 -235.

AMA Style

Antonio González-Sarrías, Rocio Garcia Villalba, Maria Angeles Nuñez Sanchez, João Tomé-Carneiro, Pilar Zafrilla, Juana Mulero, Francisco Tomas-Barberan, Juan Carlos Espín. Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts. Journal of Functional Foods. 2015; 19 ():225-235.

Chicago/Turabian Style

Antonio González-Sarrías; Rocio Garcia Villalba; Maria Angeles Nuñez Sanchez; João Tomé-Carneiro; Pilar Zafrilla; Juana Mulero; Francisco Tomas-Barberan; Juan Carlos Espín. 2015. "Identifying the limits for ellagic acid bioavailability: A crossover pharmacokinetic study in healthy volunteers after consumption of pomegranate extracts." Journal of Functional Foods 19, no. : 225-235.

Randomized controlled trial
Published: 01 May 2015 in Pharmacological Research
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The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes' expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the "hormesis hypothesis" that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622).

ACS Style

Maria Carmen Crespo; Joao Tomé-Carneiro; Emma Burgos-Ramos; Viviana Loria Kohen; Maria Isabel Espinosa; Jesus Herranz; Francesco Visioli. One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes. Pharmacological Research 2015, 95-96, 132 -137.

AMA Style

Maria Carmen Crespo, Joao Tomé-Carneiro, Emma Burgos-Ramos, Viviana Loria Kohen, Maria Isabel Espinosa, Jesus Herranz, Francesco Visioli. One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes. Pharmacological Research. 2015; 95-96 ():132-137.

Chicago/Turabian Style

Maria Carmen Crespo; Joao Tomé-Carneiro; Emma Burgos-Ramos; Viviana Loria Kohen; Maria Isabel Espinosa; Jesus Herranz; Francesco Visioli. 2015. "One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes." Pharmacological Research 95-96, no. : 132-137.

Journals
Published: 31 March 2015 in Food & Function
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The ellagic acid-derived gut microbiota metabolite, urolithin A, at concentrations achievable in the human colorectum, enhances the anticancer effects of 5-FU-chemotherapy on three different colon cancer cells.

ACS Style

Antonio González-Sarrías; Joao Tomé-Carneiro; Andrea Bellesia; Francisco Tomas-Barberan; Juan Carlos Espín. The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells. Food & Function 2015, 6, 1460 -1469.

AMA Style

Antonio González-Sarrías, Joao Tomé-Carneiro, Andrea Bellesia, Francisco Tomas-Barberan, Juan Carlos Espín. The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells. Food & Function. 2015; 6 (5):1460-1469.

Chicago/Turabian Style

Antonio González-Sarrías; Joao Tomé-Carneiro; Andrea Bellesia; Francisco Tomas-Barberan; Juan Carlos Espín. 2015. "The ellagic acid-derived gut microbiota metabolite, urolithin A, potentiates the anticancer effects of 5-fluorouracil chemotherapy on human colon cancer cells." Food & Function 6, no. 5: 1460-1469.

Journal article
Published: 30 January 2015 in Molecules
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Soy consumption has been suggested to afford protection from cardiovascular disease (CVD). Indeed, accumulated albeit controversial evidence suggests that daily consumption of ≥25 g of soy protein with its associated phytochemicals intact can improve lipid profiles in hypercholesterolemic humans. However, the belief that soy foods and supplements positively impact human health has become increasingly controversial among the general public because of the reported estrogenic activities of soy isoflavones. In this study, we investigated the nutrigenomic actions of soy isoflavones (in nutritionally-relevant amounts) with a specific focus on the adipose tissue, due to its pivotal role in cardiometabolism. Young C57BL/6 mice were maintained for eight weeks under two different diet regimes: (1) purified control diet; or (2) purified control diet supplemented with 0.45 g% soybean dry purified extract (a genistein/daidzein mix). Soy isoflavones increased plasma total cholesterol concentrations and decreased triglyceride ones. Circulating leptin levels was also increased by soy consumption. Differentially expressed genes in adipose tissue were classified according to their role(s) in cellular or metabolic pathways. Our data show that soy isoflavones, administered in nutritionally-relevant amounts, have diverse nutrigenomic effects on adipose tissue. Taking into account the moderate average exposure to such molecules, their impact on cardiovascular health needs to be further investigated to resolve the issue of whether soy consumption does indeed increase or decrease cardiovascular risk.

ACS Style

Elena Giordano; Alberto Dávalos; Maria Carmen Crespo; Joao Tomé-Carneiro; Diego Gómez-Coronado; Francesco Visioli. Soy Isoflavones in Nutritionally Relevant Amounts Have Varied Nutrigenomic Effects on Adipose Tissue. Molecules 2015, 20, 2310 -2322.

AMA Style

Elena Giordano, Alberto Dávalos, Maria Carmen Crespo, Joao Tomé-Carneiro, Diego Gómez-Coronado, Francesco Visioli. Soy Isoflavones in Nutritionally Relevant Amounts Have Varied Nutrigenomic Effects on Adipose Tissue. Molecules. 2015; 20 (2):2310-2322.

Chicago/Turabian Style

Elena Giordano; Alberto Dávalos; Maria Carmen Crespo; Joao Tomé-Carneiro; Diego Gómez-Coronado; Francesco Visioli. 2015. "Soy Isoflavones in Nutritionally Relevant Amounts Have Varied Nutrigenomic Effects on Adipose Tissue." Molecules 20, no. 2: 2310-2322.

Review
Published: 01 September 2013 in Current Pharmaceutical Design
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Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of foodstuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol- based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.This work has been supported by the Projects CICYT\ud BFU2007-60576 and ALG2011-22447 (Ministry of Economy and\ud Competitiveness, MINECO, Spain), Fundación Séneca (grupo de\ud excelencia GERM 06 04486, Murcia, Spain) and Consolider Ingenio\ud 2010, CSD2007-00063 (Fun-C-Food, Spain). J.T.-C.is holder\ud of a FPI-predoctoral grant (MINECO, Spain).Peer reviewe

ACS Style

João Tomé-Carneiro; Mar Larrosa; Antonio González-Sarrías; Francisco Tomas-Barberan; Maria Teresa Garcia Conesa; Juan Espín. Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence. Current Pharmaceutical Design 2013, 19, 6064 -6093.

AMA Style

João Tomé-Carneiro, Mar Larrosa, Antonio González-Sarrías, Francisco Tomas-Barberan, Maria Teresa Garcia Conesa, Juan Espín. Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence. Current Pharmaceutical Design. 2013; 19 (34):6064-6093.

Chicago/Turabian Style

João Tomé-Carneiro; Mar Larrosa; Antonio González-Sarrías; Francisco Tomas-Barberan; Maria Teresa Garcia Conesa; Juan Espín. 2013. "Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence." Current Pharmaceutical Design 19, no. 34: 6064-6093.