BUSCADOR RECOLECTA

© 2020 by the authors., Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussed, This research was funded by the projects PID2019-103914RB-I00 (MICINN, Spain), 19900/GERM/15 (Fundación Séneca de la Región de Murcia, Spain), and 201870E014 and 201770E081 (CSIC, Spain). J.A.G.B. was supported by a Juan de la Cierva contract (IJCI-2016-27633) from the Ministry of Science, Innovation and Universities (Spain) and a Standard European Marie Curie Fellowship from the European Commission. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 838991., Peer reviewed

Caffeic acid is one of the most abundant hydroxycinnamic acids in fruits, vegetables, and beverages. This phenolic compound reaches relevant concentrations in the colon (up to 126 µM) where it could come into contact with the intestinal cells and exert its anti-inflammatory effects. The aim of this investigation was to study the capacity of caffeic acid, at plausible concentrations from an in vivo point of view, to modulate mechanisms related to intestinal inflammation. Consequently, we tested the effects of caffeic acid (50-10 µM) on cyclooxygenase (COX)-2 expression and prostaglandin (PG)E2, cytokines, and chemokines (IL-8, monocyte chemoattractant protein-1 -MCP-1-, and IL-6) biosynthesis in IL-1ß-treated human myofibroblasts of the colon, CCD-18Co. Furthermore, the capacity of caffeic acid to inhibit the angiotensin-converting enzyme (ACE) activity, to hinder advanced glycation end product (AGE) formation, as well as its antioxidant, reducing, and chelating activity were also investigated. Our results showed that (i) caffeic acid targets COX-2 and its product PGE2 as well as the biosynthesis of IL-8 in the IL-1ß-treated cells and (ii) inhibits AGE formation, which could be related to (iii) the high chelating activity exerted. Low anti-ACE, antioxidant, and reducing capacity of caffeic acid was also observed. These effects of caffeic acid expands our knowledge on anti-inflammatory mechanisms against intestinal inflammation., We gratefully acknowledge research grant no. 5056/B/P01/2011/40 from the National Science Center (Poland) and project REFRESH (FP7-REGPOT-2010-1-264103)—Unlocking the potential of the Institute of Animal Reproduction and Food Research for strengthening integration with the European Research Area and region development. Project financed in the area of “Research Potential” of the 7th Framework Program. J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991. J.M.L.-L. is the holder of a “Ramon y Cajal” contract RyC-2015-18083.

Scope: Some polyphenol-derived metabolites reach human breast cancer (BC) tissues at concentrations that induce cell senescence. However, this is unknown for isoflavones, curcuminoids, and lignans. Here, their metabolic profiling in normal (NT) and malignant (MT) mammary tissues of newly-diagnosed BC patients and the tissue-occurring metabolites’ anticancer activity are evaluated. Methods and results: Patients (n = 26) consumed 3 capsules/day (turmeric, red clover, and flaxseed extracts plus resveratrol; 296.4 mg phenolics/capsule) from biopsy-confirmed diagnosis to surgery (5 ± 2 days) or did not consume capsules (n = 13). NT and MT, blood, and urine are analyzed by UPLC-QTOF-MS using targeted metabolomics. Anticancer activity was tested in MCF-7 and MDA-MB-231 BC cells. Mainly phase-II metabolites were detected (108, 84, 49, and 47 in urine, plasma, NT, and MT, respectively). Total metabolite concentrations reached 10.7 ± 11.1 and 2.5 ± 2.4 µmol L in NT and MT, respectively. Free curcumin, but not its glucuronide, was detected in the tissues (1.1 ± 1.8 and 0.2 ± 0.2 µmol L in NT and MT, respectively). Breast tissue-occurring metabolites’ antiproliferation was mainly exerted in p53-wild-type MCF-7 cells by curcuminoids through cell cycle arrest, senescence, and apoptosis induction via p53/p21 induction, while isoflavone-derived metabolites exerted estrogenic-like activity. Conclusion: Curcuminoids could be coadjuvants that might help fight BC upon regular consumption., This research was supported by the Projects 201770E081 from the Spanish National Research Council (CSIC, Spain) and by PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain). J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission. This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991

Angiogenesis is a complex process encompassing endothelial cell proliferation, migration, and tube formation. While numerous studies describe that curcumin exerts antitumor properties (e.g., targeting angiogenesis), information regarding other dietary curcuminoids such as demethoxycurcumin (DMC) and bisdemethoxycurcumin (BisDMC) is scant. In this study, we evaluated the antiangiogenic activities of these three curcuminoids at physiological concentrations (0.1¿5 ¿M) on endothelial cell migration and tubulogenesis and the underlying associated mechanisms on human aortic endothelial cells (HAECs). Results showed that the individual compounds and a representative mixture inhibited the tubulogenic and migration capacity of endothelial cells dose-dependently, while sparing cell viability. Notably, DMC and BisDMC at 0.1 and 1 ¿M showed higher capacity than curcumin inhibiting tubulogenesis. These compounds also reduced phosphorylation of the VEGFR2 and the downstream ERK and Akt pathways in VEGF165-stimulated cells. In silico analysis showed that curcuminoids could bind the VEGFR2 antagonizing the VEGF-mediated angiogenesis. These findings suggest that physiologically concentrations of curcuminoids might counteract pro-angiogenic stimuli relevant to tumorigenic processes., J.A.G.-B. was supported by Standard European Marie Curie Individual Fellowship from the European Commission. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No 838991, and by the project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain)

This article belongs to the Collection Feature Papers in Bioactives and Nutraceuticals., 5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols., This research was supported by the project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain). J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991. CS is supported by NIH awards GM076592 and GM118412., Peer reviewed

Urolithins, metabolites produced by the gut microbiota from the polyphenols ellagitannins and ellagic acid, are discovered by the research group in humans almost 20 years ago. Pioneering research suggests urolithins as pleiotropic bioactive contributors to explain the health benefits after consuming ellagitannin-rich sources (pomegranates, walnuts, strawberries, etc.). Here, this study comprehensively updates the knowledge on urolithins, emphasizing the review of the literature published during the last 5 years. To date, 13 urolithins and their corresponding conjugated metabolites (glucuronides, sulfates, etc.) have been described and, depending on the urolithin, detected in different human fluids and tissues (urine, blood, feces, breastmilk, prostate, colon, and breast tissues). There has been a substantial advance in the research on microorganisms involved in urolithin production, along with the compositional and functional characterization of the gut microbiota associated with urolithins metabolism that gives rise to the so-called urolithin metabotypes (UM-A, UM-B, and UM-0), relevant in human health. The design of in vitro studies using physiologically relevant assay conditions (molecular forms and concentrations) is still a pending subject, making some reported urolithin activities questionable. In contrast, remarkable progress has been made in the research on the safety, bioactivity, and associated mechanisms of urolithin A, including the first human interventions., European Commission:
PolyBiota - Polyphenols and Gut Microbiota interaction in Cardiovascular Health (838991), Peer reviewed

The consumption of pomegranate juices and extracts has long been linked to many health benefits beyond nutrition, described mainly by innumerable preclinical studies. However, the European Food Safety Authority (EFSA) concluded in 2010 that a cause and effect relationship could not be established between the consumption of pomegranate-derived products and all the health claims presented. There are no additional EFSA opinions on health claims specifically addressed to pomegranate in the last decade.

Scope and approach

This review comprehensively compiles all human studies conducted on pomegranate. The aim is to discuss these studies critically to identify possible flaws and propose guidelines that might help establish a cause and effect relationship between pomegranate-derived product consumption and health.

Key findings and conclusions

To date, 86 human studies have evaluated the health benefits of pomegranate juices and extracts. The most promising, albeit scarce, evidence is related to blood pressure improvement. Less evidence deals with inflammation, cancer, cognitive function, physical activity, and gut microbiota modulation (prebiotic effects). After a decade since EFSA's opinion, human evidence remains inconsistent, making it difficult to support most claimed health effects. The lack of effects and(or) data discrepancy might be attributable to design limitations, including insufficient product characterization and interindividual variability that influence pomegranate polyphenols' bioefficacy. New coordinated strategies between policy makers, research/academic institutions, and industry are needed to move forward. Therefore, this review presents a roadmap to conduct well-designed trials and cover existing gaps, which could establish a cause-effect relation between pomegranate consumption and health benefits beyond nutrition., European Commission:
PolyBiota - Polyphenols and Gut Microbiota interaction in Cardiovascular Health (838991), Peer reviewed

Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the individuals' microbial signatures, ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A administration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotection, This work was supported by the Projects PID 2019-103914RB-I00 from the Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033, Spain) and 21647/PDC/21, 20880/PI/18 and 19900/GERM/15 (Fundación Séneca de la Región de Murcia, Spain). C.E.I.-A. holds a predoctoral grant from MICIN (grant number FPU18/03961, Spain). J.A.G.-B. was supported by a Standard European Marie Curie Fellowship from the European Commission (European Union's Horizon, 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 838991)., Peer reviewed

Current knowledge indicates that the consumption of isoflavone-rich foodstuffs can have a beneficial impact on cardiovascular health. To what extent these isoflavones act as the main actors of that benefit is less clear. Genistein (GEN), daidzein (DAZ), and the DAZ-derived microbial metabolite equol (Eq) exhibit antiangiogenic effects in vitro, but their low bloodstream concentrations make it difficult to rationalize the in vivo effects. Their derived phase-II metabolites (glucuronides and sulfates) are major metabolites found in plasma, but their role as antiangiogenic molecules remains unexplored. We aimed here to first assess the anti-angiogenic activities of the main circulating isoflavone metabolites (glucuronides and sulfates) and compare them with their corresponding free forms at physiological concentrations (0.1–10 μM). The effects of the conjugated vs. free forms on tubulogenesis, cell migration, and VEGF-induced signalling were investigated in primary human aortic endothelial cells (HAECs). While (R,S)-equol 7-β-D-glucuronide (Eq 7-glur) exerted dose-dependent inhibition of tubulogenesis and endothelial migration comparable to that exerted by the free forms (GEN, DAZ, and Eq), the rest of the phase-II conjugates exhibited no significant effects. The underlying molecular mechanisms were independent of the bFGF but related to the modulation of the VEGF pathway. Besides, the observed dissimilar cellular metabolism (conjugation/deconjugation) places the phase-II metabolites as precursors of the free forms; however, the question of whether this metabolism impacts their biological activity requires additional studies. These new insights suggest that isoflavones and their circulating metabolites, including Eq 7-glur, may be involved in cardiovascular health (e.g., targeting angiogenesis), J. A. G.-B. was supported by a Standard European Marie Curie Individual Fellowship from the European Commission. D. G.-M. was supported by a Miguel Servet contract (AES 2021; CP21/00028) funded by the Institute Carlos III and by “ERDF a way of making Europe”. This work has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Grant Agreement No. 838991. This work was supported by the Ramón y Cajal grant (RyC2021-032111-I) and by the grants CNS2022-135253 and TED2021-130962B-C22 funded by the MCIN/AEI/10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR” program, grants PID2022-136915NA-I00 and PID2022-136419OB-I00 funded by MCIN/AEI/10.13039/501100011033 and “ERDF A way of making Europe” by the European Union, and the grant 22030/PI/22 funded by the Programa Regional de Fomento de la Investigación Científica y Técnica (Plan de Actuación 2022) de la Fundación Séneca-Agencia de Ciencia y Tecnología de la Región de Murcia, Spain, Peer reviewed